Aspartame, a bittersweet pill.

PubMed

Paolini, Moreno; Vivarelli, Fabio; Sapone, Andrea; Canistro, Donatella

2017-12-07

For the first time, the aspartame case shows how a corporation decided to ban an artificial ingredient in the wake of public opinion notwithstanding the regulatory assurance claims that it is safe. PepsiCo Inc. made an unprecedented decision most likely based on life-span carcinogenicity bioassay studies from the Cesare Maltoni Cancer Research Center of the Ramazzini Institute (CMCRC/RI), which provide consistent evidence of aspartame's carcinogenicity in rodents. Although CMCRC/RI experiments have been criticized for not complying with Organisation for Economic Co-operation and Development (OECD) guidelines, the newly launched aspartame-free soft drink may not be an isolated case. In the light of vinyl chloride-, formaldehyde- or benzene-associated carcinogenicity discovered for the first time by CMCRC/RI in the same way, it seems the guidelines need to be re-evaluated to avoid the credibility of international regulatory agencies being compromised by consumer opinion. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Vinyl chloride and 1,2-dichloroethane: classification and assessment of carcinogenicity, guidelines, threshold values, and standards developed by national and international entities, organizations, and agencies].

PubMed

Binetti, R; Costamagna, F M; Marcello, I

2001-01-01

International, national and regulatory classification, evaluation, guidelines and occupational exposure values regarding vinyl chloride and 1,2-dichloroethane, carried out by European Union (EU). Environmental Protection Agency (US EPA), International Agency for Research on Cancer (IARC), Italian National Advisory Toxicological Committee (CCTN), Occupational Safety and Health Administration (OSHA), World Health Organization (WHO), National Institute for Occupational Safety and Health (NIOSH), American Conference of Governmental Industrial Hygienists (ACGIH) and other institutions, have been considered with particular reference to the carcinogenic effects. Moreover information is reported in support of classification and evaluation and a short historical review since early 1970s, when first evidence that occupational exposure to VC could lead to angiosarcoma was published.

Evaluation of the potential carcinogenicity of benzotrichloride (97-07-7). Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1988-06-01

Benzotrichloride is a probable human carcinogen, classified as weight-of-evidence Group B1 under the EPA Guidelines for Carcinogen Risk Assessment. Evidence on potential carcinogenicity from animal studies is Sufficient, and the evidence from human studies is Limited. The potency factor (F) for benzotrichloride is estimated to be 58.0 (mg/kg/day)(-1), placing it in potency group 2 according to the CAG's methodology for evaluating potential carcinogens. Combining the weight-of-evidence group and the potency group, benzotrichloride is assigned a MEDIUM hazard ranking.

Evaluation of the potential carcinogenicity of 4-chloro-o-toluidine hydrochloride (3165-93-3). Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1988-06-01

4-Chloro-o-toluidine hydrochloride is a probable human carcinogen, classified as weight-of-evidence Group B2 under the EPA Guidelines for Carcinogen Risk Assessment. Evidence on potential carcinogenicity from animal studies is Sufficient, and the evidence from human studies is No Data. The potency factor (F) for 4-chloro-o-toluidine hydrochloride is estimated to be 0.40 (mg/kg/day)(-1), placing it in potency group 3 according to the CAG's methodology for evaluating potential carcinogens. Combining the weight-of-evidence group and the potency group, 4-chloro-o-toluidine hydrochloride is assigned a LOW hazard ranking.

WHEN IS THERE ENOUGH EVIDENCE TO PERFORM A NONLINEAR CANCER ASSESSMENT?

EPA Science Inventory

Under U.S. EPA's Proposed Guidelines for Carcinogen Risk Assessment (FR 61:179670-18011, 199996), departure from the default linear cancer assessment may be made for carcinogens for which there is sufficient evidence of a nonlinear mechanism. DCP, and agricultural fumigant that ...

Novel Uses of In Vitro Data to Develop Quantitative Biological Activity Relationship Models for in Vivo Carcinogenicity Prediction.

PubMed

Pradeep, Prachi; Povinelli, Richard J; Merrill, Stephen J; Bozdag, Serdar; Sem, Daniel S

2015-04-01

The availability of large in vitro datasets enables better insight into the mode of action of chemicals and better identification of potential mechanism(s) of toxicity. Several studies have shown that not all in vitro assays can contribute as equal predictors of in vivo carcinogenicity for development of hybrid Quantitative Structure Activity Relationship (QSAR) models. We propose two novel approaches for the use of mechanistically relevant in vitro assay data in the identification of relevant biological descriptors and development of Quantitative Biological Activity Relationship (QBAR) models for carcinogenicity prediction. We demonstrate that in vitro assay data can be used to develop QBAR models for in vivo carcinogenicity prediction via two case studies corroborated with firm scientific rationale. The case studies demonstrate the similarities between QBAR and QSAR modeling in: (i) the selection of relevant descriptors to be used in the machine learning algorithm, and (ii) the development of a computational model that maps chemical or biological descriptors to a toxic endpoint. The results of both the case studies show: (i) improved accuracy and sensitivity which is especially desirable under regulatory requirements, and (ii) overall adherence with the OECD/REACH guidelines. Such mechanism based models can be used along with QSAR models for prediction of mechanistically complex toxic endpoints. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

An integrated approach for prospectively investigating a mode-of-action for rodent liver effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

LeBaron, Matthew J., E-mail: MJLeBaron@dow.com; Geter, David R., E-mail: dave.geter@gmail.com; Rasoulpour, Reza J.

Registration of new plant protection products (e.g., herbicide, insecticide, or fungicide) requires comprehensive mammalian toxicity evaluation including carcinogenicity studies in two species. The outcome of the carcinogenicity testing has a significant bearing on the overall human health risk assessment of the substance and, consequently, approved uses for different crops across geographies. In order to understand the relevance of a specific tumor finding to human health, a systematic, transparent, and hypothesis-driven mode of action (MoA) investigation is, appropriately, an expectation by the regulatory agencies. Here, we describe a novel approach of prospectively generating the MoA data by implementing additional end pointsmore » to the standard guideline toxicity studies with sulfoxaflor, a molecule in development. This proactive MoA approach results in a more robust integration of molecular with apical end points while minimizing animal use. Sulfoxaflor, a molecule targeting sap-feeding insects, induced liver effects (increased liver weight due to hepatocellular hypertrophy) in an initial palatability probe study for selecting doses for subsequent repeat-dose dietary studies. This finding triggered the inclusion of dose-response investigations of the potential key events for rodent liver carcinogenesis, concurrent with the hazard assessment studies. As predicted, sulfoxaflor induced liver tumors in rats and mice in the bioassays. The MoA data available by the time of the carcinogenicity finding supported the conclusion that the carcinogenic potential of sulfoxaflor was due to CAR/PXR nuclear receptor activation with subsequent hepatocellular proliferation. This MoA was not considered to be relevant to humans as sulfoxaflor is unlikely to induce hepatocellular proliferation in humans and therefore would not be a human liver carcinogen. - Highlights: • We prospectively generated MoA data into standard guideline toxicity studies. • A proactive MoA approach integrates all end points while minimizing animal use. • MoA data predicted the rodent carcinogenicity of sulfoxaflor via CAR/PXR. • Liver MoA was considered not relevant to humans and hence not a human carcinogen.« less

The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice.

PubMed

Mogensen, Mette; Jemec, Gregor Be

2010-10-28

In 2009, the WHO listed ultraviolet (UV) radiation as a group 1 carcinogen. In spite of this, each year, millions of people tan indoor in Western countries. The aim of this review is to summarize evidence of tanning bed carcinogenesis and to present guidelines for use of tanning beds and patient safety advice. A narrative review of the literature was conducted based on both PubMed and Medline searches and on literature review of the retrieved papers. Use of indoor tanning beds represents a significant and avoidable risk factor for the development of both melanoma and nonmelanoma skin cancers. Frequent tanners are more often adolescent females. Tanning beds have additional potential adverse effects such as burns, solar skin damage, infection, and possibly also addictive behavior. The effort in preventing UV light-induced carcinogenesis should currently be aimed at developing new strategies for public health information. Tanning beds are one preventable source of UV radiation. In the majority of people solar UV radiation continues to be the major factor and therefore anti-tanning campaigns must always include sunbathers.

The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice

PubMed Central

Mogensen, Mette; Jemec, Gregor BE

2010-01-01

Introduction: In 2009, the WHO listed ultraviolet (UV) radiation as a group 1 carcinogen. In spite of this, each year, millions of people tan indoor in Western countries. The aim of this review is to summarize evidence of tanning bed carcinogenesis and to present guidelines for use of tanning beds and patient safety advice. Methods: A narrative review of the literature was conducted based on both PubMed and Medline searches and on literature review of the retrieved papers. Results: Use of indoor tanning beds represents a significant and avoidable risk factor for the development of both melanoma and nonmelanoma skin cancers. Frequent tanners are more often adolescent females. Tanning beds have additional potential adverse effects such as burns, solar skin damage, infection, and possibly also addictive behavior. Discussion: The effort in preventing UV light-induced carcinogenesis should currently be aimed at developing new strategies for public health information. Tanning beds are one preventable source of UV radiation. In the majority of people solar UV radiation continues to be the major factor and therefore anti-tanning campaigns must always include sunbathers. PMID:21188119

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bogen, K T

2007-01-30

As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate ''linear'' (genotoxic) vs. ''nonlinear'' (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to lowmore » levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach--similar to that used in reference dose procedures for classic toxicity endpoints--can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a ''nonlinear'' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Resulting bounds each provided the basis for a corresponding ''uncertainty'' factor <1 appropriate to apply to estimates of naphthalene risk obtained by linear extrapolation under a default genotoxic MOA assumption. This procedure is proposed as scientifically credible method to address MOA uncertainty for DMOA carcinogens.« less

[Health evaluation of trichloroethylene in indoor air : communication from the German ad-hoc working group on indoor guidelines of the Indoor Air Hygiene Committee and of the states' supreme health authorities].

PubMed

2015-07-01

In the European Hazardous Substances Regulation No 1272/2008 trichloroethylene has been classified as a probable human carcinogen and a suspected mutagen. According to several Committees (German Committee on Hazardous Substances, European Scientific Committee on Occupational Exposure Limits, European Chemicals Agency´s Committee for Risk Assessment (ECHA-RAC)) concentrations of trichloroethylene cytotoxic to renal tubuli may increase the risk to develop renal cancer. At non-cytotoxic concentrations of trichloroethylene a much lower cancer risk may be assumed. Therefore, evaluating the cancer risk to the public following inhalation of trichloroethylene ECHA-RAC has assumed a sublinear exposure-response relationship for carcinogenicity of trichloroethylene. Specifically, ECHA-RAC assessed a cancer risk of 6.4 × 10(- 5) (mg/m(3))(- 1) following life time exposure to trichloroethylene below a NOAEC for renal cytotoxicity of 6 mg trichloroethylene/m(3). Further evaluation yields a life-time risk of 10(- 6) corresponding to 0.02 mg trichloroethylene/m(3). This concentration is well above the reference (e.g. background) concentration of trichloroethylene in indoor air. Consequently the Ad-hoc Working Group on Indoor Guidelines recommends 0.02 mg trichloroethylene/m(3) as a risk-related guideline for indoor air. Measures to reduce exposure are considered inappropriate at concentrations below this guideline.

Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air.

PubMed Central

Boström, Carl-Elis; Gerde, Per; Hanberg, Annika; Jernström, Bengt; Johansson, Christer; Kyrklund, Titus; Rannug, Agneta; Törnqvist, Margareta; Victorin, Katarina; Westerholm, Roger

2002-01-01

Polycyclic aromatic hydrocarbons (PAHs) are formed during incomplete combustion. Domestic wood burning and road traffic are the major sources of PAHs in Sweden. In Stockholm, the sum of 14 different PAHs is 100-200 ng/m(3) at the street-level site, the most abundant being phenanthrene. Benzo[a]pyrene (B[a]P) varies between 1 and 2 ng/m(3). Exposure to PAH-containing substances increases the risk of cancer in humans. The carcinogenicity of PAHs is associated with the complexity of the molecule, i.e., increasing number of benzenoid rings, and with metabolic activation to reactive diol epoxide intermediates and their subsequent covalent binding to critical targets in DNA. B[a]P is the main indicator of carcinogenic PAHs. Fluoranthene is an important volatile PAH because it occurs at high concentrations in ambient air and because it is an experimental carcinogen in certain test systems. Thus, fluoranthene is suggested as a complementary indicator to B[a]P. The most carcinogenic PAH identified, dibenzo[a,l]pyrene, is also suggested as an indicator, although it occurs at very low concentrations. Quantitative cancer risk estimates of PAHs as air pollutants are very uncertain because of the lack of useful, good-quality data. According to the World Health Organization Air Quality Guidelines for Europe, the unit risk is 9 X 10(-5) per ng/m(3) of B[a]P as indicator of the total PAH content, namely, lifetime exposure to 0.1 ng/m(3) would theoretically lead to one extra cancer case in 100,000 exposed individuals. This concentration of 0.1 ng/m(3) of B[a]P is suggested as a health-based guideline. Because the carcinogenic potency of fluoranthene has been estimated to be approximately 20 times less than that of B[a]P, a tentative guideline value of 2 ng/m(3) is suggested for fluoranthene. Other significant PAHs are phenanthrene, methylated phenanthrenes/anthracenes and pyrene (high air concentrations), and large-molecule PAHs such as dibenz[a,h]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, and indeno[1,2,3-cd]pyrene (high carcinogenicity). Additional source-specific indicators are benzo[ghi]perylene for gasoline vehicles, retene for wood combustion, and dibenzothiophene and benzonaphthothiophene for sulfur-containing fuels. PMID:12060843

JaCVAM-organized international validation study of the in vivo rodent alkaline comet assay for detection of genotoxic carcinogens: II. Summary of definitive validation study results.

PubMed

Uno, Yoshifumi; Kojima, Hajime; Omori, Takashi; Corvi, Raffaella; Honma, Masamistu; Schechtman, Leonard M; Tice, Raymond R; Beevers, Carol; De Boeck, Marlies; Burlinson, Brian; Hobbs, Cheryl A; Kitamoto, Sachiko; Kraynak, Andrew R; McNamee, James; Nakagawa, Yuzuki; Pant, Kamala; Plappert-Helbig, Ulla; Priestley, Catherine; Takasawa, Hironao; Wada, Kunio; Wirnitzer, Uta; Asano, Norihide; Escobar, Patricia A; Lovell, David; Morita, Takeshi; Nakajima, Madoka; Ohno, Yasuo; Hayashi, Makoto

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known genotoxic and carcinogenic activity (i.e., genotoxic carcinogens, genotoxic non-carcinogens, non-genotoxic carcinogens, and non-genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity. Copyright © 2015 Elsevier B.V. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bogen, K T

A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained usingmore » separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches to low low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach - similar to that used in reference dose procedures for classic toxicity endpoints - can address MOA uncertainty in a way that avoids explicit modeling of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p pharmacokinetic and 2 harmacokinetic 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat rat-tumor tumor-type specific DMOA DMOA-related uncertainty were obtained using a 2-stage model adapted to reflec reflect the empirical link between genotoxic and cytotoxic effects of t the most potent identified genotoxic naphthalene metabolites, 1,2 1,2- and 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors were then used to reduce naphthalene risk estimated by linear ex extrapolation (under the default genotoxic MOA assumption), to account for the DMOA trapolation exhibited by this compound.« less

INCORPORATION OF MOLECULAR ENDPOINTS INTO QUANTITATIVE RISK ASSESSMENT

EPA Science Inventory

The U.S. Environmental Protection Agency has recently released its Guidelines for Carcinogen Risk Assessment. These new guidelines benefit from the significant progress that has been made in understanding the cancer process and also from the more than 20 years experience that EPA...

A Novel Strategy to Predict Carcinogenicity of Antiparasitics Based on a Combination of DNA Lesions and Bacterial Mutagenicity Tests

PubMed Central

Liu, Qianying; Lei, Zhixin; Zhu, Feng; Ihsan, Awais; Wang, Xu; Yuan, Zonghui

2017-01-01

Genotoxicity and carcinogenicity testing of pharmaceuticals prior to commercialization is requested by regulatory agencies. The bacterial mutagenicity test was considered having the highest accuracy of carcinogenic prediction. However, some evidences suggest that it always results in false-positive responses when the bacterial mutagenicity test is used to predict carcinogenicity. Along with major changes made to the International Committee on Harmonization guidance on genotoxicity testing [S2 (R1)], the old data (especially the cytotgenetic data) may not meet current guidelines. This review provides a compendium of retrievable results of genotoxicity and animal carcinogenicity of 136 antiparasitics. Neither genotoxicity nor carcinogenicity data is available for 84 (61.8%), while 52 (38.2%) have been evaluated in at least one genotoxicity or carcinogenicity study, and only 20 (14.7%) in both genotoxicity and carcinogenicity studies. Among 33 antiparasitics with at least one old result in in vitro genotoxicity, 15 (45.5%) are in agreement with the current ICH S2 (R1) guidance for data acceptance. Compared with other genotoxicity assays, the DNA lesions can significantly increase the accuracy of prediction of carcinogenicity. Together, a combination of DNA lesion and bacterial tests is a more accurate way to predict carcinogenicity. PMID:29170735

AN AIR QUALITY DATA ANALYSIS SYSTEM FOR INTERRELATING EFFECTS, STANDARDS, AND NEEDED SOURCE REDUCTIONS: PART 13. APPLYING THE EPA PROPOSED GUIDELINES FOR CARCINOGEN RISK ASSESSMENT TO A SET OF ASBESTOS LUNG CANCER MORTALITY DATA

EPA Science Inventory

The Clean Air Act Amendments of 1990 (CAAA-90) list 189 hazardous air pollutants (HAPs) for which "safe" ambient concentrations are to be determined. For a carcinogen, such as asbestos, the amendments specify that the safe concentration shall allow one excess cancer case per mi...

Recent Advances in In Vivo Genotoxicity Testing: Prediction of Carcinogenic Potential Using Comet and Micronucleus Assay in Animal Models

PubMed Central

Kang, Seung Hun; Kwon, Jee Young; Lee, Jong Kwon; Seo, Young Rok

2013-01-01

Genotoxic events have been known as crucial step in the initiation of cancer. To assess the risk of cancer, genotoxicity assays, including comet, micronucleus (MN), chromosomal aberration, bacterial reverse, and sister chromatid exchange assay, can be performed. Compared with in vitro genotoxicity assay, in vivo genotoxicity assay has been used to verify in vitro assay result and definitely provide biological significance for certain organs or cell types. The comet assay can detect DNA strand breaks as markers of genotoxicity. Methods of the in vivo comet assay have been established by Japanese Center for the Validation of Alternative Methods (JaCVAM) validation studies depending on tissue and sample types. The MN can be initiated by segregation error and lagging acentric chromosome fragment. Methods of the in vivo MN assay have been established by Organization for Economic Co-operation and Development (OECD) test guidelines and many studies. Combining the in vivo comet and MN assay has been regarded as useful methodology for evaluating genetic damage, and it has been used in the assessment of potential carcinogenicity by complementarily presenting two distinct endpoints of the in vivo genotoxicity individual test. Few studies have investigated the quantitative relation between in vivo genotoxicity results and carcinogenicity. Extensive studies emphasizes that positive correlation is detectable. This review summarizes the results of the in vivo comet and MN assays that have investigated the genotoxicity of carcinogens as classified by the International Agency for Research on Cancer (IARC) carcinogenicity database. As a result, these genotoxicity data may provide meaningful information for the assessment of potential carcinogenicity and for implementation in the prevention of cancer. PMID:25337557

The linearized multistage model and the future of quantitative risk assessment.

PubMed

Crump, K S

1996-10-01

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.

[Exposure to carcinogens in work environment today. State of the art, problems and prospects raised by the Law 626/94].

PubMed

Carnevale, F; Baldasseroni, A

1998-01-01

The implementation in our country of recent legislation on carcinogenic risk assessment and management (VIIth title of Law 626/94) is considered. The authors describe potentialities and limits of the new legislation and of the derived Guidelines issued by the Regions. The health policy in this field and possible evolution in the near future are outlined, bearing in mind the experience of other countries. A short list of questions is suggested as a contribution to the discussion on the future scenario: whether exposure to carcinogens should be lower in the working environment than in the general environment; what is the relative importance of multifactoriality, individual biological variability, individual life-style in the genesis of cancers; whether medical health surveillance is worthwhile in terms of primary prevention; is it always true that there is no threshold limit value for carcinogens; what is the role of individual attitudes to prevention in exposure to carcinogens compared to "objective" protection; which balance between costs and benefits should be aimed at.

Red Meat and Colorectal Cancer

PubMed Central

2015-01-01

Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. More than half of cases occur in more developed countries. The consumption of red meat (beef, pork, lamb, veal, mutton) is high in developed countries and accumulated evidence until today demonstrated a convincing association between the intake of red meat and especially processed meat and CRC risk. In this review, meta-analyses of prospective epidemiological studies addressed to this association, observed link of some subtypes of red meat with CRC risk, potential carcinogenic compounds, their mechanisms and actual recommendations of international guidelines are presented. PMID:26779313

Are mobile phones harmful?

PubMed

Blettner, M; Berg, G

2000-01-01

There is increasing public interest in health risks of mobile phone use. Although there is a vast body of material on the biological effects of radiofrequency fields, current risk assessment is still limited. The article describes several hypotheses and results of biological effects such as thermal effect, genetic and carcinogenic effects and cancer related investigations. Mobile phones transmit and receive waves of frequencies mainly at 800-1800 MHz. Findings on the thermal effect of acute exposure to radiofrequency fields were consistent, resulting in an increase of cellular, tissue or body temperature by 1 degree C or more. Guidelines for risk limits are based on this thermal effect. Experimental investigation suggests that radiofrequency fields are not tumor initiators and that if they are related to carcinogenicity, this would be by tumor promotion or by increasing the uptake of carcinogens in cells. Implications of these experimental results on public health concerns are yet unclear. Few epidemiological studies are available on the use of mobile phones or on the radiofrequency exposure and the development of cancer. Most of these studies have no or little quantitative exposure data and they are limited by the small number of observations. Large epidemiological studies are necessary in order to investigate the use of mobile phones on the development of cancer. It should be emphasized that even a small elevated risk may have a large implication for public health, as the use of mobile phones and the exposure is rapidly increasing.

Pleasure Boatyard Soils are Often Highly Contaminated

NASA Astrophysics Data System (ADS)

Eklund, Britta; Eklund, David

2014-05-01

The contamination in pleasure boatyards has been investigated. Measured concentrations of copper, zinc, lead, mercury, cadmium, tributyltin (TBT), the 16 most common polycyclic aromatic hydrocarbons (∑16 PAHs), and the seven most common polychlorinated biphenyls (∑7 PCBs) from investigations at 34 boatyards along the Swedish coast have been compiled. The maximum concentrations were 7,700 for Cu, 10,200, for Zn, 40,100 for Pb, 188 for Hg, 18 for Cd, 107 for TBT, 630 for carcinogenic PAHs, 1,480 for ∑16 PAHs, and 3.8 mg/kg DW for ∑7 PCB; all 10-2,000 higher than the Swedish environmental qualitative guidelines. In addition, the mean of the median values found at the 34 places shows that the lower guidance value for sensitive use of land was exceeded for the ∑7 PCBs, carcinogenic PAHs, TBT, Pb, Hg, and Cu by a factor of 380, 6.8, 3.6, 2.9, 2.2 and 1.7, respectively. The even higher guideline value for industrial use was exceeded for the ∑7 PCBs and TBT by a factor of 15 and 1.8, respectively. TBT, PAHs, Pb, Cd, and Hg are prioritized substances in the European Water Framework Directive and should be phased out as quickly as possible. Because of the risk of leakage from boatyards, precautions should be taken. The high concentrations measured are considered to be dangerous for the environment and human health and highlight the urgent need for developing and enforcing pleasure boat maintenance guidelines to minimize further soil and nearby water contamination.

Human health risk assessment of polycyclic aromatic hydrocarbons (PAHs) in smoked fish species from markets in Southern Nigeria.

PubMed

Tongo, Isioma; Ogbeide, Ozekeke; Ezemonye, Lawrence

2017-01-01

Polycyclic Aromatic Hydrocarbons (PAHs) levels in four commonly consumed smoked fish species from markets in Southern Nigeria were assessed to evaluate possible human health risks associated with consumption. Varying levels of PAH congeners were observed in the fish tissues with the highest total concentration of PAHs in Scomber scombrus . High concentrations of benzo(a)pyrene was observed in Clarias gariepinus and Ethmalosa fimbriata with values above the guideline value of 0.05 mg/kg. The Dietary Daily Intake (DDI) value for total PAHs (∑PAHs) was highest for S. scombrus while the DDI value for the total carcinogenic PAHs (∑CPAHs) was highest for E. fimbriata . Carcinogenic human health risk assessment using carcinogenic toxic equivalents (TEQ), indicated that consumption of E. fimbriata has a higher potential to cause carcinogenic risks. TEQ values for all the fish species were however, below the estimated screening value (SV) of 3.556 mg/kg, while the estimated cumulative excess cancer risk (ECR) for E. fimbriata and C. gariepinus and PAH4 index for all the assessed fish species exceeded threshold values indicating potential carcinogenic risk from consumption.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pogribny, Igor P., E-mail: igor.pogribny@fda.hhs.g

Human exposure to certain natural and man-made chemical carcinogens is one of the major risk factors for cancer development. The effect of chemical carcinogens on genetic and epigenetic alterations and their significance in the development of cancer has been well-established. In contrast, the role of microRNAs (miRNAs) in the etiology of chemical-associated cancers remains relatively unexplored despite extensive reports on changes in miRNA expression upon carcinogen exposure. This review summarizes the current knowledge for the role of miRNAs as drivers of chemical-induced carcinogenesis by bridging the gap between carcinogen exposure and cancer development through functional studies. It also emphasizes themore » potential for miRNA changes as early indicators of the carcinogenic process, markers for carcinogen exposure, and identification of chemical carcinogenic hazards. - Highlights: • Exposure to chemical carcinogens alters microRNA expression. • MicroRNA alterations may have significance in the development of cancer. • MicroRNAs may be early indicators of the carcinogenic process and carcinogen exposure.« less

Manuscript 116 Mechanisms: DNA Reactive Aagents

EPA Science Inventory

ABSTRACT The U.S. Environmental Protection Agency’s Guidelines for Carcinogen Risk Assessment (2005) uses an analytical framework for conducting a quantitative cancer risk assessment that is based on mode of action/key events and human relevance. The approach stresses the enh...

An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines.

PubMed

Sistare, Frank D; Morton, Daniel; Alden, Carl; Christensen, Joel; Keller, Douglas; Jonghe, Sandra De; Storer, Richard D; Reddy, M Vijayaraj; Kraynak, Andrew; Trela, Bruce; Bienvenu, Jean-Guy; Bjurström, Sivert; Bosmans, Vanessa; Brewster, David; Colman, Karyn; Dominick, Mark; Evans, John; Hailey, James R; Kinter, Lewis; Liu, Matt; Mahrt, Charles; Marien, Dirk; Myer, James; Perry, Richard; Potenta, Daniel; Roth, Arthur; Sherratt, Philip; Singer, Thomas; Slim, Rabih; Soper, Keith; Fransson-Steen, Ronny; Stoltz, James; Turner, Oliver; Turnquist, Susan; van Heerden, Marjolein; Woicke, Jochen; DeGeorge, Joseph J

2011-06-01

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.

MINI REVIEW - EPIGENETIC PROCESSES AND CANCER RISK ASSESSMENT

EPA Science Inventory

Abstract: The U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment encourages the use of mechanistic data in the assessment of human cancer risk at low (environmental) exposure levels. The key events that define a particular mode of action for tumor fo...

Enhanced carcinogenicity by coexposure to arsenic and iron and a novel remediation system for the elements in well drinking water.

PubMed

Kumasaka, Mayuko Y; Yamanoshita, Osamu; Shimizu, Shingo; Ohnuma, Shoko; Furuta, Akio; Yajima, Ichiro; Nizam, Saika; Khalequzzaman, Md; Shekhar, Hossain U; Nakajima, Tamie; Kato, Masashi

2013-03-01

Various carcinomas including skin cancer are explosively increasing in arsenicosis patients who drink arsenic-polluted well water, especially in Bangladesh. Although well drinking water in the cancer-prone areas contains various elements, very little is known about the effects of elements except arsenic on carcinogenicity. In order to clarify the carcinogenic effects of coexposure to arsenic and iron, anchorage-independent growth and invasion in human untransformed HaCaT and transformed A431 keratinocytes were examined. Since the mean ratio of arsenic and iron in well water was 1:10 in cancer-prone areas of Bangladesh, effects of 1 μM arsenic and 10 μM iron were investigated. Iron synergistically promoted arsenic-mediated anchorage-independent growth in untransformed and transformed keratinocytes. Iron additionally increased invasion in both types of keratinocytes. Activities of c-SRC and ERK that regulate anchorage-independent growth and invasion were synergistically enhanced in both types of keratinocytes. Our results suggest that iron promotes arsenic-mediated transformation of untransformed keratinocytes and progression of transformed keratinocytes. We then developed a low-cost and high-performance adsorbent composed of a hydrotalcite-like compound for arsenic and iron. The adsorbent rapidly reduced concentrations of both elements from well drinking water in cancer-prone areas of Bangladesh to levels less than those in WHO health-based guidelines for drinking water. Thus, we not only demonstrated for the first time increased carcinogenicity by coexposure to arsenic and iron but also proposed a novel remediation system for well drinking water.

Pesticides and public health: an analysis of the regulatory approach to assessing the carcinogenicity of glyphosate in the European Union.

PubMed

Clausing, Peter; Robinson, Claire; Burtscher-Schaden, Helmut

2018-03-13

The present paper scrutinises the European authorities' assessment of the carcinogenic hazard posed by glyphosate based on Regulation (EC) 1272/2008. We use the authorities' own criteria as a benchmark to analyse their weight of evidence (WoE) approach. Therefore, our analysis goes beyond the comparison of the assessments made by the European Food Safety Authority and the International Agency for Research on Cancer published by others. We show that not classifying glyphosate as a carcinogen by the European authorities, including the European Chemicals Agency, appears to be not consistent with, and in some instances, a direct violation of the applicable guidance and guideline documents. In particular, we criticise an arbitrary attenuation by the authorities of the power of statistical analyses; their disregard of existing dose-response relationships; their unjustified claim that the doses used in the mouse carcinogenicity studies were too high and their contention that the carcinogenic effects were not reproducible by focusing on quantitative and neglecting qualitative reproducibility. Further aspects incorrectly used were historical control data, multisite responses and progression of lesions to malignancy. Contrary to the authorities' evaluations, proper application of statistical methods and WoE criteria inevitably leads to the conclusion that glyphosate is 'probably carcinogenic' (corresponding to category 1B in the European Union). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

IRIS Toxicological Review of Dichlorobenzenes (2004 External Review Draft)

EPA Science Inventory

The goal of this assessment is to evaluate both carcinogenic and non-cancer toxicity based on the proposed July 1999 Cancer Guidelines and other relevant guidance. This approach will provide a better understanding of the toxicity and will aid in making informed risk-based decisio...

Beryllium Metal II. A Review of the Available Toxicity Data

PubMed Central

Strupp, Christian

2011-01-01

Beryllium metal was classified in Europe collectively with beryllium compounds, e.g. soluble salts. Toxicological equivalence was assumed despite greatly differing physicochemical properties. Following introduction of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation, beryllium metal was classified as individual substance and more investigational efforts to appropriately characterize beryllium metal as a specific substance apart from soluble beryllium compounds was required. A literature search on toxicity of beryllium metal was conducted, and the resulting literature compiled together with the results of a recently performed study package into a comprehensive data set. Testing performed under Organisation for Economic Co-Operation and Development guidelines and Good Laboratory Practice concluded that beryllium metal was neither a skin irritant, an eye irritant, a skin sensitizer nor evoked any clinical signs of acute oral toxicity; discrepancies between the current legal classification of beryllium metal in the European Union (EU) and the experimental results were identified. Furthermore, genotoxicity and carcinogenicity were discussed in the context of the literature data and the new experimental data. It was concluded that beryllium metal is unlikely to be a classical nonthreshold mutagen. Effects on DNA repair and morphological cell transformation were observed but need further investigation to evaluate their relevance in vivo. Animal carcinogenicity studies deliver evidence of carcinogenicity in the rat; however, lung overload may be a species-specific confounding factor in the existing studies, and studies in other species do not give convincing evidence of carcinogenicity. Epidemiology has been intensively discussed over the last years and has the problem that the studies base on the same US beryllium production population and do not distinguish between metal and soluble compounds. It is noted that the correlation between beryllium exposure and carcinogenicity, even including the soluble compounds, remains under discussion in the scientific community and active research is continuing. PMID:21196456

AN EVALUATION OF THE MODE OF ACTION FRAMEWORK FOR MUTAGENIC CARCINOGENSCASE STUDY: CYCLOPHOSPHAMIDE (Journal Article)

EPA Science Inventory

In response to the 2005 revised U.S Envrionmental Protection Agency (EPA) Cancer Guidelines, a Risk Assessment Forum’s Technical Panel is devising a strategy in which genetic toxicology data combined with other information are assessed to determine whether a carcinogen operates t...

Quantitative cancer risk assessment for occupational exposures to asphalt fumes during built-up roofing asphalt (BURA) operations.

PubMed

Rhomberg, Lorenz R; Mayfield, David B; Goodman, Julie E; Butler, Eric L; Nascarella, Marc A; Williams, Daniel R

2015-01-01

The International Agency for Research on Cancer qualitatively characterized occupational exposure to oxidized bitumen emissions during roofing as probably carcinogenic to humans (Group 2A). We examine chemistry, exposure, epidemiology and animal toxicity data to explore quantitative risks for roofing workers applying built-up roofing asphalt (BURA). Epidemiology studies do not consistently report elevated risks, and generally do not have sufficient exposure information or adequately control for confounders, precluding their use for dose-response analysis. Dermal carcinogenicity bioassays using mice report increased tumor incidence with single high doses. In order to quantify potential cancer risks, we develop time-to-tumor model methods [consistent with U.S. Environmental Protection Agency (EPA) dose-response analysis and mixtures guidelines] using the dose-time-response shape of concurrent exposures to benzo[a]pyrene (B[a]P) as concurrent controls (which had several exposure levels) to infer presumed parallel dose-time-response curves for BURA-fume condensate. We compare EPA relative potency factor approaches, based on observed relative potency of BURA to B[a]P in similar experiments, and direct observation of the inferred BURA dose-time-response (scaled to humans) as means for characterizing a dermal unit risk factor. We apply similar approaches to limited data on asphalt-fume inhalation and respiratory cancers in rats. We also develop a method for adjusting potency estimates for asphalts that vary in composition using measured fluorescence. Overall, the various methods indicate that cancer risks to roofers from both dermal and inhalation exposure to BURA are within a range typically deemed acceptable within regulatory frameworks. The approaches developed may be useful in assessing carcinogenic potency of other complex mixtures of polycyclic aromatic compounds.

Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se.

PubMed

Haussmann, Hans-Juergen; Fariss, Marc W

2016-09-01

The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General's 2014 report on the health consequences of nicotine exposure.

Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se

PubMed Central

Haussmann, Hans-Juergen; Fariss, Marc W.

2016-01-01

Abstract The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General’s 2014 report on the health consequences of nicotine exposure. PMID:27278157

[A new update of the SIMLII Guidelines on carcinogens].

PubMed

Pira, Enrico; Giachino, Gian Mario; Discalzi, Gianluigi

2011-01-01

The second update of the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII) guidelines on Cancerogens and Mutagens, first published in 2003 and reviewed in 2007, is presented. The general setting of the guidelines remaines unmodified. In this new release some important developments on regulatory system, risk assessment, and health surveillance are discussed. The relevant evolution of the regulatory rules is illustrated in detail, with particular reference to the recent implementation in European Union and in Italy of the Regulation (EC) 1272/2008 on Classification, Labelling and Packaging of substances and mixtures. The recent tendencies of the European Scientific Committee on Occupational Exposure Limits in risk assessment, are presented. Some remarks on the use of new biomarkers in health surveillance, with reference to lung and bladder cancer, are discussed. The more recent results on the effectiveness of the use of LDTC scan on screening in asymptomatic persons at high risk for lung cancer, are presented. The use of this imaging technique in health surveillance of special group of workers (i.e., subjects with relevant past asbestos exposure and smokers) could be adopted.

New clues on carcinogenicity-related substructures derived from mining two large datasets of chemical compounds.

PubMed

Golbamaki, Azadi; Benfenati, Emilio; Golbamaki, Nazanin; Manganaro, Alberto; Merdivan, Erinc; Roncaglioni, Alessandra; Gini, Giuseppina

2016-04-02

In this study, new molecular fragments associated with genotoxic and nongenotoxic carcinogens are introduced to estimate the carcinogenic potential of compounds. Two rule-based carcinogenesis models were developed with the aid of SARpy: model R (from rodents' experimental data) and model E (from human carcinogenicity data). Structural alert extraction method of SARpy uses a completely automated and unbiased manner with statistical significance. The carcinogenicity models developed in this study are collections of carcinogenic potential fragments that were extracted from two carcinogenicity databases: the ANTARES carcinogenicity dataset with information from bioassay on rats and the combination of ISSCAN and CGX datasets, which take into accounts human-based assessment. The performance of these two models was evaluated in terms of cross-validation and external validation using a 258 compound case study dataset. Combining R and H predictions and scoring a positive or negative result when both models are concordant on a prediction, increased accuracy to 72% and specificity to 79% on the external test set. The carcinogenic fragments present in the two models were compared and analyzed from the point of view of chemical class. The results of this study show that the developed rule sets will be a useful tool to identify some new structural alerts of carcinogenicity and provide effective information on the molecular structures of carcinogenic chemicals.

Polycyclic Aromatic Hydrocarbons in drinking water of Tehran, Iran

PubMed Central

2013-01-01

Distribution and seasonal variation of sixteen priority polycyclic aromatic hydrocarbons (PAHs) were investigated in the drinking water of Tehran, the capital of Iran. Detected single and total PAHs concentrations were in the range of 2.01-38.96 and 32.45-733.10 ng/L, respectively, which were quite high compared to the values recorded in other areas of the world. The average occurrence of PAHs with high molecular weights was 79.55%; for example, chrysene occurred in 60.6% of the samples, with a maximum concentration of 438.96 ng/L. In addition, mean carcinogen to non-carcinogen PAHs ratio was 63.84. Although the concentration of benzo[a]pyrene, as an indicator of water pollution to PAHs, was lower than the guideline value proposed by World Health Organization (WHO) as well as that of Iranian National Drinking Water Standards for all of the samples, the obtained results indicated that carcinogen PAHs present in the drinking water of Tehran can cause threats to human health. PMID:24499505

Role of drosophila in chemical mutagenesis testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nix, C.E.; Brewen, B.

1978-01-01

An important question facing our society is the impact of numerous chemical insults on the health of man and his environment. Faced with a staggering array of chemicals and enormous testing costs, only a few chemicals can be tested for possible carcinogenic effects. Recent results with the Salmonella/mammalian microsome mutagenesis bioassay system demonstrate a striking correlation between carcinogenicity and mutagenicity of many chemical compounds and offer the possibility that mutagenesis assay systems can provide a quick identification of potential carcinogens. Results from microbial assays can serve as a guideline for further mutagenesis testing as well as identify those compounds requiringmore » more extensive analysis in mammalian systems. Reliance on the results from a single mutagenic assay system is rather risky. It would be preferable to use a battery of tests (the tier approach) which would include the rapid microbial assays as well as mammalian systems. Also the use of Drosophila as a bridge between the microbial and mammalian assays has many desirable features which are discussed.« less

Personal exposure and health risk assessment of carbonyls in family cars and public transports-a comparative study in Nanjing, China.

PubMed

Xu, Huaizhou; Zhang, Qin; Song, Ninghui; Guo, Min; Zhang, Shenghu; Ji, Guixiang; Shi, Lili

2017-11-01

To evaluate passenger health risks associated with inhalation exposure to carbonyl compounds mainly emitted from decoration materials of vehicles, we tested the carbonyl concentrations in interior air of 20 family cars, 6 metro lines, and 5 buses in the city of Nanjing. To assess non-carcinogenic health risks, we compared the data to the health guidelines of China, US Environmental Protection Agency (EPA), and Office of Environmental Health Hazard Assessment (OEHHA), respectively. To assess carcinogenic risks, we followed a standard approach proposed by the OEHHA to calculate lifetime cancer risks (LCR) of formaldehyde and acetaldehyde for various age groups. The results showed that there are formaldehyde, acetaldehyde, and acrolein concentrations in 40, 35, and 50% of family car samples exceeded the reference concentrations (RfCs) provided by Chinese guidelines (GB/T 27630-2011 and GB/T 18883-2002). Whereas, in the tested public transports, concentrations of the three carbonyls were all below the Chinese RfCs. Fifty and 90% of family cars had formaldehyde and acrolein concentrations exceeding the guidelines of OEHHA. Only one public transport sample (one bus) possesses formaldehyde and acetaldehyde concentrations above the chronic inhalation reference exposure limits (RELs). Furthermore, the assessments of carcinogenic risk of formaldehyde and acetaldehyde showed that lifetime cancer risks were higher than the limits of EPA for some family cars and public transports. In the study, buses and metros appear to be relatively clean environments, with total carbonyl concentrations that do not exceed 126 μg/m 3 . In family cars, carbonyl levels showed significant variations from 6.1 to 811 μg/m 3 that was greatly influenced by direct emissions from materials inside the vehicles. Public transports seemed to be the first choice for resident trips as compared to family cars. Graphical abstract ᅟ.

Chemical structure determines target organ carcinogenesis in rats

PubMed Central

Carrasquer, C. A.; Malik, N.; States, G.; Qamar, S.; Cunningham, S.L.; Cunningham, A.R.

2012-01-01

SAR models were developed for 12 rat tumour sites using data derived from the Carcinogenic Potency Database. Essentially, the models fall into two categories: Target Site Carcinogen – Non-Carcinogen (TSC-NC) and Target Site Carcinogen – Non-Target Site Carcinogen (TSC-NTSC). The TSC-NC models were composed of active chemicals that were carcinogenic to a specific target site and inactive ones that were whole animal non-carcinogens. On the other hand, the TSC-NTSC models used an inactive category also composed of carcinogens but to any/all other sites but the target site. Leave one out validations produced an overall average concordance value for all 12 models of 0.77 for the TSC-NC models and 0.73 for the TSC-NTSC models. Overall, these findings suggest that while the TSC-NC models are able to distinguish between carcinogens and non-carcinogens, the TSC-NTSC models are identifying structural attributes that associate carcinogens to specific tumour sites. Since the TSC-NTSC models are composed of active and inactive compounds that are genotoxic and non-genotoxic carcinogens, the TSC-NTSC models may be capable of deciphering non-genotoxic mechanisms of carcinogenesis. Together, models of this type may also prove useful in anticancer drug development since they essentially contain chemicals moieties that target specific tumour site. PMID:23066888

Toxico-Cheminformatics and QSPR Modeling of the Carcinogenic Potency Database

EPA Science Inventory

Report on the development of a tiered, confirmatory scheme for prediction of chemical carcinogenicity based on QSAR studies of compounds with available mutagenic and carcinogenic data. For 693 such compounds from the Carcinogenic Potency Database characterized molecular topologic...

Spatial Distribution and Fuzzy Health Risk Assessment of Trace Elements in Surface Water from Honghu Lake.

PubMed

Li, Fei; Qiu, Zhenzhen; Zhang, Jingdong; Liu, Chaoyang; Cai, Ying; Xiao, Minsi

2017-09-04

Previous studies revealed that Honghu Lake was polluted by trace elements due to anthropogenic activities. This study investigated the spatial distribution of trace elements in Honghu Lake, and identified the major pollutants and control areas based on the fuzzy health risk assessment at screening level. The mean total content of trace elements in surface water decreased in the order of Zn (18.04 μg/L) > Pb (3.42 μg/L) > Cu (3.09 μg/L) > Cr (1.63 μg/L) > As (0.99 μg/L) > Cd (0.14 μg/L), within limits of Drinking Water Guidelines. The results of fuzzy health risk assessment indicated that there was no obvious non-carcinogenic risk to human health, while carcinogenic risk was observed in descending order of As > Cr > Cd > Pb. As was regarded to have the highest carcinogenic risk among selected trace elements because it generally accounted for 64% of integrated carcinogenic risk. Potential carcinogenic risk of trace elements in each sampling site was approximately at medium risk level (10 -5 to 10 -4 ). The areas in the south (S4, S13, and S16) and northeast (S8, S18, and S19) of Honghu Lake were regarded as the risk priority control areas. However, the corresponding maximum memberships of integrated carcinogenic risk in S1, S3, S10-S13, S15, and S18 were of relatively low credibility (50-60%), and may mislead the decision-makers in identifying the risk priority areas. Results of fuzzy assessment presented the subordinate grade and corresponding reliability of risk, and provided more full-scale results for decision-makers, which made up for the deficiency of certainty assessment to a certain extent.

Spatial Distribution and Fuzzy Health Risk Assessment of Trace Elements in Surface Water from Honghu Lake

PubMed Central

Qiu, Zhenzhen; Zhang, Jingdong; Liu, Chaoyang; Cai, Ying; Xiao, Minsi

2017-01-01

Previous studies revealed that Honghu Lake was polluted by trace elements due to anthropogenic activities. This study investigated the spatial distribution of trace elements in Honghu Lake, and identified the major pollutants and control areas based on the fuzzy health risk assessment at screening level. The mean total content of trace elements in surface water decreased in the order of Zn (18.04 μg/L) > Pb (3.42 μg/L) > Cu (3.09 μg/L) > Cr (1.63 μg/L) > As (0.99 μg/L) > Cd (0.14 μg/L), within limits of Drinking Water Guidelines. The results of fuzzy health risk assessment indicated that there was no obvious non-carcinogenic risk to human health, while carcinogenic risk was observed in descending order of As > Cr > Cd > Pb. As was regarded to have the highest carcinogenic risk among selected trace elements because it generally accounted for 64% of integrated carcinogenic risk. Potential carcinogenic risk of trace elements in each sampling site was approximately at medium risk level (10−5 to 10−4). The areas in the south (S4, S13, and S16) and northeast (S8, S18, and S19) of Honghu Lake were regarded as the risk priority control areas. However, the corresponding maximum memberships of integrated carcinogenic risk in S1, S3, S10–S13, S15, and S18 were of relatively low credibility (50–60%), and may mislead the decision-makers in identifying the risk priority areas. Results of fuzzy assessment presented the subordinate grade and corresponding reliability of risk, and provided more full-scale results for decision-makers, which made up for the deficiency of certainty assessment to a certain extent. PMID:28869576

Evaluation of the dermal carcinogenicity of lubricant base oils by the mouse skin painting bioassay and other proposed methods.

PubMed

Chasey, K L; McKee, R H

1993-01-01

Lubricant base oils are petroleum products that are predominantly derived from the vacuum distillation of crude oil. Various types of refinement can be employed during the manufacturing process, and evidence suggests that certain of the associated process streams produce skin cancer. Polycyclic aromatic compounds (PACs), some of which are considered as the causative agents, are removed, concentrated or chemically converted during the refinement process. In order to understand the effects of various types of refinement processes on carcinogenic potential, 94 oils were evaluated in the mouse epidermal cancer bioassay. This Exxon database is unique, because of the wide range of crude oils and processing histories represented. Seven processing history classifications are described, and conclusions concerning the impacts of each refinement process on dermal carcinogenicity are discussed. This research also included an evaluation of selected biological and chemical test methods for predicting carcinogenic potential. These included a modified version of the Ames test for mutagenicity, as well as analytical characterizations of the polycyclic aromatic structures in the oils. For classification purposes, a sample was considered to be carcinogenic if it resulted in the production of two or more tumor-bearing animals (in test groups of either 40 or 50 animals). The modified Ames test was considered to be positive if the mutagenicity index was > or = 2.0, and PAC analyses were similarly designated as positive or negative according to proposed guidelines. All of the alternative test methods showed similar agreement with dermal carcinogenicity bioassay data; concordance values were > or = 80%. However, each test was incorrect in ca. 10%-20% of the cases evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)

Global structure–activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors

PubMed Central

Cunningham, Albert R.; Trent, John O.

2012-01-01

Structure–activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby’s structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity. PMID:22678118

Global structure-activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors.

PubMed

Cunningham, Albert R; Carrasquer, C Alex; Qamar, Shahid; Maguire, Jon M; Cunningham, Suzanne L; Trent, John O

2012-10-01

Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby's structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity.

Occupational exposure to carcinogens: Benzene, pesticides and fibers

PubMed Central

Falzone, Luca; Marconi, Andrea; Loreto, Carla; Franco, Sabrina; Spandidos, Demetrios A.; Libra, Massimo

2016-01-01

It is well known that the occupational exposure to contaminants and carcinogens leads to the development of cancer in exposed workers. In the 18th century, Percivall Pott was the first to hypothesize that chronic exposure to dust in the London chimney sweeps was associated with an increased risk of developing cancer. Subsequently a growing body of evidence indicated that other physical factors were also responsible for oncogenic mutations. Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer. Occupational exposure involves several factors and the association between carcinogens, occupational exposure and cancer is still unclear. Only a fraction of factors is recognized as occupational carcinogens and for each factor, there is an increased risk of cancer development associated with a specific work activity. According to the International Agency for Research on Cancer (IARC), the majority of carcinogens are classified as ‘probable’ and ‘possible’ human carcinogens, while, direct evidence of carcinogenicity is provided in epidemiological and experimental studies. In the present review, exposures to benzene, pesticides and mineral fibers are discussed as the most important cancer risk factors during work activities. PMID:27748850

Occupational exposure to carcinogens: Benzene, pesticides and fibers (Review).

PubMed

Falzone, Luca; Marconi, Andrea; Loreto, Carla; Franco, Sabrina; Spandidos, Demetrios A; Libra, Massimo

2016-11-01

It is well known that the occupational exposure to contaminants and carcinogens leads to the development of cancer in exposed workers. In the 18th century, Percivall Pott was the first to hypothesize that chronic exposure to dust in the London chimney sweeps was associated with an increased risk of developing cancer. Subsequently a growing body of evidence indicated that other physical factors were also responsible for oncogenic mutations. Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer. Occupational exposure involves several factors and the association between carcinogens, occupational exposure and cancer is still unclear. Only a fraction of factors is recognized as occupational carcinogens and for each factor, there is an increased risk of cancer development associated with a specific work activity. According to the International Agency for Research on Cancer (IARC), the majority of carcinogens are classified as 'probable' and 'possible' human carcinogens, while, direct evidence of carcinogenicity is provided in epidemiological and experimental studies. In the present review, exposures to benzene, pesticides and mineral fibers are discussed as the most important cancer risk factors during work activities.

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeRosa, C.T.; Choudhury, H.; Schoeny, R.S.

Risk assessment can be thought of as a conceptual approach to bridge the gap between the available data and the ultimate goal of characterizing the risk or hazard associated with a particular environmental problem. To lend consistency to and to promote quality in the process, the US Environmental Protection Agency (EPA) published Guidelines for Risk Assessment of Carcinogenicity, Developmental Toxicity, Germ Cell Mutagenicity and Exposure Assessment, and Risk Assessment of Chemical Mixtures. The guidelines provide a framework for organizing the information, evaluating data, and for carrying out the risk assessment in a scientifically plausible manner. In the absence of sufficientmore » scientific information or when abundant data are available, the guidelines provide alternative methodologies that can be employed in the risk assessment. 4 refs., 3 figs., 2 tabs.« less

76 FR 71037 - Proposed National Toxicology Program (NTP) Review Process for the Report on Carcinogens: Request...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-16

... the list of speakers, will be posted on the NTP Web site ( http://ntp.niehs.nih.gov/go/rocprocess... ( http://ntp.niehs.nih.gov/go/rocprocess ). The guidelines and deadlines published in the Federal... 27560. Registration for the listening session is via the NTP Web site ( http://ntp.niehs.nih.gov/go...

[The Necessity and the Current Status of Safe Handling of Anticancer Drugs].

PubMed

Kanda, Kiyoko

2017-07-01

Number of people who handle anticancer drugs in their profession is increasing. Anticancer drugs, which are hazardous drugs(HD), exert cytocidal effects on cancer cells, but many have also been shown to have mutagenicity, teratogenicity and carcinogenicity; therefore, safe handling of anticancer drugs is necessary. In July 2015, the first Japanese guidelines for exposure control measures, namely, the "Joint Guidelines for Safe Handling of Cancer Chemotherapy Drugs", were published jointly by 3 societies. Our guideline is the creation of the Japanese Society of Cancer Nursing(JSCN), Japanese Society of Medical Oncology(JSMO)and Japanese Society of Pharmaceutical Oncology(JASPO)and has a historical significance. This paper states the necessity of safe handling of anticancer drugs, Japan's recent movement of safe handling, the introduction of joint guidelines of safe handling of anticancer drugs, and new movement of safe handling of USP chapter 800 in the United States.

Recall of indoor tanning salon warnings and safety guidelines among a national sample of tanners.

PubMed

Day, Ashley K; Coups, Elliot J; Manne, Sharon L; Stapleton, Jerod L

2016-12-01

Indoor tanning (IT) is a known carcinogen, and regulation has increased across the USA. However, there is minimal point-of-sale regulation for adult users. The purpose of the present study is to explore whether IT users recall being provided with warnings or safety guidelines at tanning salons. A national sample of 273 young adult, female IT users (mean age = 22.26, SD = 2.38) was surveyed regarding the frequency that they recalled being provided with six different warnings and safety guidelines when at tanning salons. Between 65 and 90.1 % of participants reported recalling the various warnings and guidelines. Having very fair skin was reported by 16.8 % of participants, and these high-risk individuals were less likely to recall having read and signed a consent form than other IT users (p = .002). The current level of regulation is insufficient to provide IT users with consistent warnings and safety guidelines at tanning salons.

How many food additives are rodent carcinogens?

PubMed

Johnson, F M

2002-01-01

One generally assumes that chemical agents added to foods are reasonably free of risks to human health, and practically everyone consumes some additives in his or her food daily throughout life. In the United States, the 1958 Food Additives Amendment to the Federal Food, Drug and Cosmetic Act of 1938 requires food manufacturers to demonstrate the safety of food additives to the Food and Drug Administration (FDA). The Amendment contains a provision that prohibits approval of an additive if it is found to cause cancer in humans or animals. In the present study, data from the National Toxicology Program rodent bioassay (NTPRB) were used to identify a sample of approximately 50 rodent-tested additives and other chemicals added to food that had been evaluated independently of the FDA/food industry. Surprisingly, the sample shows more than 40% of these food chemicals to be carcinogenic in one or more rodent groups. If this percentage is extrapolated to all substances added to food in the United States, it would imply that more than 1000 of such substances are potential rodent carcinogens. The NTP and FDA test guidelines use similar, though not necessarily identical, rodent test procedures, including near lifetime exposures to the maximum tolerated dose. The FDA specifies that test chemicals should be administered by the oral route. However, the oral route includes three methods of delivering chemicals, that is, mixed in the food or water or delivered by stomach tube (gavage). The NTP data show only 1 of 18 food chemicals mixed in the food are rodent carcinogens, but 16 of 23 gavage-administered food chemicals are carcinogenic to rodents. The distribution suggests that among orally delivered chemicals, those administered in the feed will more likely prove to be noncarcinogens than chemicals given by gavage. The rodent data also reveal that effects may vary according to dose and genotype, as well as by route of administration, to further complicate extrapolation to humans. Human experience with known carcinogens such as tobacco, asbestos, and benzidine convinces us that environmental carcinogens constitute a real threat to human health, although predicting human carcinogens from rodent tests involves a number of uncertainties. These uncertainties do not mean that we should simply ignore the presence of carcinogens. Rather, in the interests of public safety, a serious effort should be made to resolve the questions surrounding the presence of chemicals identified as rodent carcinogens in our food. Environ. Mol. Mutagen. 39:69-80, 2002 Published 2002 Wiley-Liss, Inc.

JaCVAM-organized international validation study of the in vivo rodent alkaline comet assay for the detection of genotoxic carcinogens: I. Summary of pre-validation study results.

PubMed

Uno, Yoshifumi; Kojima, Hajime; Omori, Takashi; Corvi, Raffaella; Honma, Masamistu; Schechtman, Leonard M; Tice, Raymond R; Burlinson, Brian; Escobar, Patricia A; Kraynak, Andrew R; Nakagawa, Yuzuki; Nakajima, Madoka; Pant, Kamala; Asano, Norihide; Lovell, David; Morita, Takeshi; Ohno, Yasuo; Hayashi, Makoto

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this validation effort was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The purpose of the pre-validation studies (i.e., Phase 1 through 3), conducted in four or five laboratories with extensive comet assay experience, was to optimize the protocol to be used during the definitive validation study. Copyright © 2015 Elsevier B.V. All rights reserved.

Corporate influence on threshold limit values.

PubMed

Castleman, B I; Ziem, G E

1988-01-01

Investigations into the historical development of specific Threshold Limit Values (TLVs) for many substances have revealed serious shortcomings in the process followed by the American Conference of Governmental Industrial Hygienists. Unpublished corporate communications were important in developing TLVs for 104 substances; for 15 of these, the TLV documentation was based solely on such information. Efforts to obtain written copies of this unpublished material were mostly unsuccessful. Case studies on the TLV Committee's handling of lead and seven carcinogens illustrate various aspects of corporate influence and interaction with the committee. Corporate representatives listed officially as "consultants" since 1970 were given primary responsibility for developing TLVs on proprietary chemicals of the companies that employed them (Dow, DuPont). It is concluded that an ongoing international effort is needed to develop scientifically based guidelines to replace the TLVs in a climate of openness and without manipulation by vested interests.

Predicting carcinogenicity of diverse chemicals using probabilistic neural network modeling approaches

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Kunwar P., E-mail: kpsingh_52@yahoo.com; Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001; Gupta, Shikha

Robust global models capable of discriminating positive and non-positive carcinogens; and predicting carcinogenic potency of chemicals in rodents were developed. The dataset of 834 structurally diverse chemicals extracted from Carcinogenic Potency Database (CPDB) was used which contained 466 positive and 368 non-positive carcinogens. Twelve non-quantum mechanical molecular descriptors were derived. Structural diversity of the chemicals and nonlinearity in the data were evaluated using Tanimoto similarity index and Brock–Dechert–Scheinkman statistics. Probabilistic neural network (PNN) and generalized regression neural network (GRNN) models were constructed for classification and function optimization problems using the carcinogenicity end point in rat. Validation of the models wasmore » performed using the internal and external procedures employing a wide series of statistical checks. PNN constructed using five descriptors rendered classification accuracy of 92.09% in complete rat data. The PNN model rendered classification accuracies of 91.77%, 80.70% and 92.08% in mouse, hamster and pesticide data, respectively. The GRNN constructed with nine descriptors yielded correlation coefficient of 0.896 between the measured and predicted carcinogenic potency with mean squared error (MSE) of 0.44 in complete rat data. The rat carcinogenicity model (GRNN) applied to the mouse and hamster data yielded correlation coefficient and MSE of 0.758, 0.71 and 0.760, 0.46, respectively. The results suggest for wide applicability of the inter-species models in predicting carcinogenic potency of chemicals. Both the PNN and GRNN (inter-species) models constructed here can be useful tools in predicting the carcinogenicity of new chemicals for regulatory purposes. - Graphical abstract: Figure (a) shows classification accuracies (positive and non-positive carcinogens) in rat, mouse, hamster, and pesticide data yielded by optimal PNN model. Figure (b) shows generalization and predictive abilities of the interspecies GRNN model to predict the carcinogenic potency of diverse chemicals. - Highlights: • Global robust models constructed for carcinogenicity prediction of diverse chemicals. • Tanimoto/BDS test revealed structural diversity of chemicals and nonlinearity in data. • PNN/GRNN successfully predicted carcinogenicity/carcinogenic potency of chemicals. • Developed interspecies PNN/GRNN models for carcinogenicity prediction. • Proposed models can be used as tool to predict carcinogenicity of new chemicals.« less

[Principles of establishing occupational exposure limits for carcinogens in Poland and in other EU countries].

PubMed

Skowroń, Jolanta; Czerczak, Slawomir

2013-01-01

The principles of determining exposure limits for carcinogens adopted in Poland, the European Union and in other selected countries of the EC are discussed in this article. Carcinogens and/or mutagens pose a direct health risk to people exposed to them. If carcinogens cannot be eliminated from the work and living environments, their exposure should be kept at the lowest possible level. To assess health risk for carcinogens it is necessary to determine the probability of developing a disease or of death from cancer as a result of occupational exposure to carcinogenic substances.

Health benefits and potential risks related to consumption of fish or fish oil.

PubMed

Sidhu, Kirpal S

2003-12-01

The nutritional benefits of fish consumption relate to the utilization of proteins of high biological value, as well as certain minerals and vitamins that fish provide. Fish or fish oil contains omega-3 polyunsaturated fatty acids (PUFAs) that appear to play several useful roles for human health. Conversely, some carcinogenic contaminants are also stored in the adipose tissue of fish. The objective of this paper is to evaluate the potential health benefits and risks related to the consumption of fish or fish oil. Health benefits related to the consumption of fish or omega-3 PUFAs were obtained by an extensive literature search. Potential health risks related to carcinogenic contaminants (e.g., dioxin, PCB, etc.) in fish were estimated using the U.S. EPA-approved cancer risk assessment guidelines. Potential health risk estimates were evaluated by comparing them with the acceptable excess risk level of 10(-6)-10(-4). Scientific data indicate that the consumption of fish or fish oil containing omega-3 PUFAs reduces the risk of coronary heart disease, decreases mild hypertension, and prevents certain cardiac arrhythmias and sudden death. Risk estimates in humans for carcinogenic environmental contaminants in fish ranged from an excess risk level of 3x10(-6)-9x10(-4). These risk estimates appeared to meet the acceptable excess risk level criteria. Therefore, consumption of fish in accordance with the State of Michigan Fish Advisory Guidelines is safe and should be encouraged. The top 11 fish species [e.g., sardines, mackerel, herring (Atlantic and Pacific), lake trout, salmon (Chinook, Atlantic, and Sockeye), anchovy (European), sablefish, and bluefish] provide an adequate amount of omega-3 PUFAs (2.7-7.5g/meal) and appear to meet the nutritional recommendation of the American Heart Association.

Antagonistic interactions of an arsenic-containing mixture in a multiple organ carcinogenicity bioassay.

PubMed

Pott, W A; Benjamin, S A; Yang, R S

1998-11-27

Inorganic arsenic (As), 1,2-dichloroethane (DCE), vinyl chloride (VC) and trichloroethylene (TCE) are frequently identified as groundwater contaminants near hazardous waste disposal sites. While the carcinogenicity of each of these chemicals has been extensively studied individually, little information exists regarding their carcinogenic potential in combination. Therefore, we investigated the carcinogenic promoting potential of chemical mixtures containing arsenic, DCE, VC and TCE following multiple initiator administration in a multiple organ carcinogenicity bioassay (N. Ito, T. Shirai, S. Fukushima, Medium-term bioassay for carcinogens using multiorgan models, in: N. Ito, H. Sugano (Eds.), Modification of Tumor Development in Rodents, Prog. Exp. Tumor Res., 33, 41-57, Basel, Karger, 1991). Our results reveal a dose-responsive antagonistic effect of this four-chemical mixture on the development of preneoplastic hepatic lesions (altered hepatocellular foci and glutathione S-transferase pi positive foci) as well as bronchioalveolar hyperplasia and adenoma formation.

Fish as a Predictive Model for Epigenetic Carcinogens

DTIC Science & Technology

1993-12-23

increased fatty acyl-CoA oxidase activity. Studies conducted in vitro also showed that the peroxisome proliferating agents displayed relatively low capacity...of Laboratory Resources, National Research Council ( NIH Publication No. 86-23, Revised 1985). For the protection of human subjects, the investigator(s...to the NIH Guidelines for Research Involving Recombinant DNA Molecules. In the conduct of research involving hazardous organisms, the investigator(s

A randomized clinical trial of counseling and nicotine replacement therapy for treatment of African American non-daily smokers: Design, accrual, and baseline characteristics.

PubMed

Nollen, Nicole L; Cox, Lisa Sanderson; Mayo, Matthew S; Ellerbeck, Edward F; Madhusudhana, Sheshadri; Ahluwalia, Jasjit S

2018-05-19

Non-daily smokers (NDS) who smoke on some but not all days are a growing subset of United States (US) tobacco users. Racial/ethnic minorities are more likely to be NDS. African American NDS have strikingly high levels of nicotine and carcinogen exposure, making treatment of this high risk group a priority. The current study is one of three ongoing federally-funded clinical trials of NDS and, to our knowledge the only RCT focused on racial/ethnic minority NDS. The design has been guided by input from Patient and Stakeholder Advisory Panels who helped develop the research questions, design the intervention, and select the outcomes. The objective is to compare the effectiveness of smoking cessation counseling alone (C) or smoking cessation counseling plus participant's choice of nicotine replacement therapy (NRT; C + NRT) for African American NDS. Two-hundred seventy-eight African American NDS will be randomized in a 2:1 fashion to C + NRT or C. All participants receive five sessions of smoking cessation counseling; those randomized to C + NRT receive their choice of nicotine gum, patch, and/or lozenge. Treatment in both groups lasts for 12 weeks. We hypothesize that C + NRT will be more effective than C on the primary outcome of biochemically-confirmed abstinence from smoking at week 12. Secondary aims will compare C + NRT and C on patient- and provider-desired outcomes including abstinence from smoking at week 26, change in biochemically-verified nicotine and carcinogen exposure, days abstinent, and treatment process measures (e.g., NRT use and side effects). Predictors of abstinence will also be explored. Findings will illuminate effective treatment options for African American NDS and contribute to development of evidence-based guidelines for treating the 8.9 million US adult NDS for whom no guidelines currently exist. ClinicalTrials.gov: NCT02244918. Copyright © 2017. Published by Elsevier Inc.

Relevance of Urinary 3-Hydroxybenzo(a)pyrene and 1-Hydroxypyrene to Assess Exposure to Carcinogenic Polycyclic Aromatic Hydrocarbon Mixtures in Metallurgy Workers

PubMed Central

Barbeau, Damien; Persoons, Renaud; Marques, Marie; Hervé, Claire; Laffitte-Rigaud, Gilbert; Maitre, Anne

2014-01-01

Objectives: In metallurgy, workers are exposed to mixtures of polycyclic aromatic hydrocarbons (PAHs) in which some compounds are carcinogenic. Biomonitoring of PAH exposure has been performed by measuring urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene which is not carcinogenic. This study investigated the use of 3-hydroxybenzo(a)pyrene (3-OHBaP), a metabolite of benzo(a)pyrene (BaP) which is the main carcinogenic component in PAHs, to improve carcinogen exposure assessment. Methods: We included 129 metallurgy workers routinely exposed to PAHs during working hours. Urinary samples were collected at three sampling times at the beginning and at the end of the working week for 1-OHP and 3-OHBaP analyses. Results: Workers in anode production showed greater exposure to both biomarkers than those in cathode or silicon production, with respectively, 71, 40, and 30% of 3-OHBaP concentrations exceeding the value of 0.4 nmol mol−1 creatinine. No difference was observed between the 3-OHBaP levels found at the end of the penultimate workday shift and those at the beginning of the last workday shift. Within these plants, the 1-OHP/3-OHBaP ratios varied greatly according to the workers’ activity and emission sources. Using linear regression between these two metabolites, the 1-OHP level corresponding to the guidance value for 3-OHBaP ranged from 0.7 to 2.4 µmol mol−1 creatinine, depending on the industrial sector. Conclusions: This study emphasizes the interest of monitoring urinary 3-OHBaP at the end of the last workday shift when working week exposure is relatively steady, and the irrelevance of a single guideline value for 1-OHP when assessing occupational health risk. PMID:24504174

Recommended health and safety guidelines for coal gasification pilot plants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1978-01-01

The greatest toxic hazards in coal conversion are presented by the known and suspected carcinogens, because they are hazardous at low levels of exposure, have delayed action with no immediate warning, and have grave consequences. As for routes of entry, it is to be noted that various solids and liquids may reach the body by inhalation of particles, deposition of particles, or indirectly by contact with dirty surfaces. Other toxicants are most likely to enter the body by inhalation. The overall carcinogenic hazard cannot be precisely estimated from chemical analysis alone, because the possible interactions are far too complex. Further,more » the hazard cannot at present be quantitatively defined by available biological tests. The same limitations probably apply to toxic effects other than carcinogenesis, with the posible exception of some immediate responses (e.g., chemical asphyxia, primary respiratory irration). It is not practical to recommend comprehensive workplace exposure limits on a basis similar to those for individual toxicants; however, a limit for one important kind of hazard (high-boiling suspected carcinogens) can be recommended. The carcinogenic hazards associated with airborne particles and surface contamination are the most crucial of the whole spectrum and offer a practical target for control, if not for quantitative evaluation. The only direct quantitative evidence now availabl is from epidemiology in analogous circulstances and there are severe limitations on the comprehensiveness and reliability of such evidence. Some specific targets for control through industrial hygiene practices can be identified. The presence of any strong irritant of the respiratory mucosa, other mucous surfaces, and the skin should be regarded as a danger signal because of possible potentiation of carcinogens and other toxicants.« less

Standard setting processes and regulations for environmental contaminants in drinking water: State versus federal needs and viewpoints

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sidhu, K.S.

1991-06-01

The primary objective of a standard setting process is to arrive at a drinking water concentration at which exposure to a contaminant would result in no known or potential adverse health effect on human health. The drinking water standards also serve as guidelines to prevent pollution of water sources and may be applicable in some cases as regulatory remediation levels. The risk assessment methods along with various decision making parameters are used to establish drinking water standards. For carcinogens classified in Groups A and B by the United States Environmental Protection Agency (USEPA) the standards are set by using nonthresholdmore » cancer risk models. The linearized multistage model is commonly used for computation of potency factors for carcinogenic contaminants. The acceptable excess risk level may vary from 10(-6) to 10(-4). For noncarcinogens, a threshold model approach based on application of an uncertainty factor is used to arrive at a reference dose (RfD). The RfD approach may also be used for carcinogens classified in Group C by the USEPA. The RfD approach with an additional uncertainty factory of 10 for carcinogenicity has been applied in the formulation of risk assessment for Group C carcinogens. The assumptions commonly used in arriving at drinking water standards are human life expectancy, 70 years; average human body weight, 70 kg; human daily drinking water consumption, 2 liters; and contribution of exposure to the contaminant from drinking water (expressed as a part of the total environmental exposure), 20%. Currently, there are over 80 USEPA existing or proposed primary standards for organic and inorganic contaminants in drinking water. Some of the state versus federal needs and viewpoints are discussed.« less

Report on carcinogens monograph on 1-bromopropane.

PubMed

2013-09-01

The National Toxicology Program conducted a cancer evaluation on 1 bromopropane for possible listing in the Report on Carcinogens (RoC). The cancer evaluation is captured in the RoC monograph, which was peer reviewed in a public forum. The monograph consists of two components: (Part 1) the cancer evaluation, which reviews the relevant scientific information, assesses its quality, applies the RoC listing criteria to the scientific information, and provides the NTP recommendation for listing status for 1 bromopropane in the RoC, and (Part 2) the substance profile proposed for the RoC, containing the NTP's listing status recommendation, a summary of the scientific evidence considered key to reaching that decision, and data on properties, use, production, exposure, and Federal regulations and guidelines to reduce exposure to 1-bromopropane. This monograph provides an assessment of the available scientific information on 1 bromopropane, including human exposure and properties, disposition and toxicokinetics, cancer studies in experimental animals, and studies of mechanisms and other related effects, including relevant toxicological effects, genetic toxicology, and mechanisms of carcinogenicity. From this assessment, the NTP recommended that 1 bromopropane be listed as reasonably anticipated to be a human carcinogen in the RoC based on sufficient evidence from studies in experimental animals, which found inhalation exposure to 1-bromopropane caused skin tumors in male rats, large intestine tumors in female and male rats, and lung tumors in female mice. Also noted was that 1 bromopropane, either directly or via reactive metabolites, caused molecular alterations that typically are associated with carcinogenesis, including genotoxicity, oxidative stress, and glutathione depletion. These alterations, observed in mainly in vitro and toxicity studies in rodents, are relevant to possible mechanisms of human carcinogenicity and support the relevance of the cancer studies in experimental animals to humans.

Current and emerging challenges in toxicopathology: Carcinogenic threshold of phenobarbital and proof of arsenic carcinogenicity using rat medium-term bioassays for carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukushima, Shoji; Morimura, Keiichirou; Wanibuchi, Hideki

2005-09-01

For the last 25 years, Prof. Nobuyuki Ito and his laboratory have focused on the development of liver medium-term bioassay system for detection of carcinogens in F344 rats utilizing glutathione S-transferase placental form (GST-P)-positive foci as an end point marker. In this presentation, the outline and samples of medium-term bioassay systems were described. Furthermore, our data demonstrated the presence of a threshold for the non-genotoxic carcinogen, phenobarbital (PB), and the lack of linearity in the low-dose area of the dose-response curve, providing evidence for hormesis. In addition, the establishment and applications of multiorgan carcinogenicity bioassay (DMBDD model), used for themore » examination of the carcinogenicity of genotoxic and non-genotoxic chemicals, are discussed. Dimethylarsinic acid, one of organic arsenics, was found to be carcinogenic in rat bladder using DMBDD model and carcinogenicity test.« less

Novel naïve Bayes classification models for predicting the carcinogenicity of chemicals.

PubMed

Zhang, Hui; Cao, Zhi-Xing; Li, Meng; Li, Yu-Zhi; Peng, Cheng

2016-11-01

The carcinogenicity prediction has become a significant issue for the pharmaceutical industry. The purpose of this investigation was to develop a novel prediction model of carcinogenicity of chemicals by using a naïve Bayes classifier. The established model was validated by the internal 5-fold cross validation and external test set. The naïve Bayes classifier gave an average overall prediction accuracy of 90 ± 0.8% for the training set and 68 ± 1.9% for the external test set. Moreover, five simple molecular descriptors (e.g., AlogP, Molecular weight (M W ), No. of H donors, Apol and Wiener) considered as important for the carcinogenicity of chemicals were identified, and some substructures related to the carcinogenicity were achieved. Thus, we hope the established naïve Bayes prediction model could be applied to filter early-stage molecules for this potential carcinogenicity adverse effect; and the identified five simple molecular descriptors and substructures of carcinogens would give a better understanding of the carcinogenicity of chemicals, and further provide guidance for medicinal chemists in the design of new candidate drugs and lead optimization, ultimately reducing the attrition rate in later stages of drug development. Copyright © 2016 Elsevier Ltd. All rights reserved.

In vivo transgenic bioassays and assessment of the carcinogenic potential of pharmaceuticals.

PubMed Central

Contrera, J F; DeGeorge, J J

1998-01-01

There is general agreement in the scientific community on the need to improve carcinogenicity testing and the assessment of human carcinogenic risk and to incorporate more information on mechanisms and modes of action into the risk assessment process. Advances in molecular biology have identified a growing number of genes such as protooncogenes and tumor-suppressor genes that are highly conserved across species and are associated with a wide variety of human and animal cancers. In vivo transgenic rodent models incorporating such mechanisms are used to identify mechanisms involved in tumor formation and as selective tests for carcinogens. Transgenic methods can be considered an extension of genetic manipulation by selective breeding, which long has been employed in science and agriculture. The use of two rodent species in carcinogenicity testing is especially important for identifying transspecies carcinogens. The capacity of a substance to induce neoplasia across species suggests that the mechanism(s) involved in the induction of the neoplasia are conserved and therefore may have significance for humans. Based on available information there is sufficient experience with some in vivo transgenic rodent carcinogenicity models to support their application as complementary second species studies in conjunction with a single 2-year rodent carcinogenicity study. The optional substitution of a second 2-year rodent carcinogenicity study with an alternative study such as an in vivo transgenic carcinogenicity study is part of the International Conference on Harmonization guidance S1B: Testing for Carcinogenicity of Pharmaceuticals. This guidance is intended to be flexible enough to accommodate a wide range of possible carcinogenicity assessment models currently under consideration or models that may be developed in the future. The use of an in vivo transgenic mouse model in place of a second 2-year mouse study will improve the assessment of carcinogenic risk by contributing insights into the mechanisms of tumorigenesis and potential human relevance not available from a standard 2-year bioassay. It is envisioned that this will stimulate the further development of more efficient and relevant methods for identifying and assessing potential human carcinogenic risk, which will benefit public health. PMID:9539006

Exposure to chemicals and radiation during childhood and risk for cancer later in life.

PubMed

Carpenter, David O; Bushkin-Bedient, Sheila

2013-05-01

Many chemical carcinogens are in food, water, air, household products, and personal care products. Although genetic susceptibility is an important factor in how an individual responds to exposure to a carcinogen, heritable genetic factors alone account for only a minor portion of cancer rates. We review the evidence that early life exposure to carcinogenic chemicals and ionizing radiation results in elevations in cancer later in life. Because cells are rapidly dividing and organ systems are developing during childhood and adolescence, exposure to carcinogens during these early life stages is a major risk factor for cancer later in life. Because young people have many expected years of life, the clinical manifestations of cancers caused by carcinogens have more time in which to develop during characteristically long latency periods. Many chemical carcinogens persist in the body for decades and increase risk for all types of cancers. Carcinogens may act via mutagenic, nonmutagenic, or epigenetic mechanisms and may also result from disruption of endocrine systems. The problem is magnified by the fact that many chemical carcinogens have become an integral part of our food and water supply and are in air and the general environment. The early life onset of a lifelong exposure to mixtures of multiple environmental chemical carcinogens and radiation contributes significantly to the etiology of cancer in later life. Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Applicability of a gene expression based prediction method to SD and Wistar rats: an example of CARCINOscreen®.

PubMed

Matsumoto, Hiroshi; Saito, Fumiyo; Takeyoshi, Masahiro

2015-12-01

Recently, the development of several gene expression-based prediction methods has been attempted in the fields of toxicology. CARCINOscreen® is a gene expression-based screening method to predict carcinogenicity of chemicals which target the liver with high accuracy. In this study, we investigated the applicability of the gene expression-based screening method to SD and Wistar rats by using CARCINOscreen®, originally developed with F344 rats, with two carcinogens, 2,4-diaminotoluen and thioacetamide, and two non-carcinogens, 2,6-diaminotoluen and sodium benzoate. After the 28-day repeated dose test was conducted with each chemical in SD and Wistar rats, microarray analysis was performed using total RNA extracted from each liver. Obtained gene expression data were applied to CARCINOscreen®. Predictive scores obtained by the CARCINOscreen® for known carcinogens were > 2 in all strains of rats, while non-carcinogens gave prediction scores below 0.5. These results suggested that the gene expression based screening method, CARCINOscreen®, can be applied to SD and Wistar rats, widely used strains in toxicological studies, by setting of an appropriate boundary line of prediction score to classify the chemicals into carcinogens and non-carcinogens.

Investigating the Mechanisms of Action and the Identification of Breast Carcinogens by Computational Analysis of Female Rodent Carcinogena

DTIC Science & Technology

2004-08-01

of Female Rodent Carcinogens PRINCIPAL INVESTIGATOR: Albert R. Cunningham, Ph.D. CONTRACTING ORGANIZATION : Louisiana State University, Baton Rouge... non -carcinogen) and molecular fragments as SAR descriptors. Therefore, this seemed a reasonable substitute SAR approach for MCASE. However, upon... target site summary (15) we developed a SAR learning set of 100 compounds shown to induce breast cancer in rat. The cat- SAR program develops SAR

76 FR 8674 - Notice of a Public Meeting: Environmental Justice Considerations for Drinking Water Regulatory...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-15

... perchlorate and carcinogenic volatile organic compounds (VOCs). While the Agency is in the very preliminary stages of developing the regulatory efforts for perchlorate and carcinogenic VOCs, EPA plans to discuss..., Regulatory Determinations 3, perchlorate, and carcinogenic VOCs rulemaking efforts. Date and Location: The...

Development of Quantitative Structure-Activity Relationship (QSAR) Models to Predict the Carcinogenic Potency of Chemicals

EPA Science Inventory

Determining the carcinogenicity and carcinogenic potency of new chemicals is both a labor-intensive and time-consuming process. In order to expedite the screening process, there is a need to either: (1) identify alternative toxicity measures (shorter duration) that may be used as...

Combination Effects of Forty Carcinogens Administered at Low Doses to Male Rats

PubMed Central

Takayama, Shozo; Hasegawa, Hirokazu; Ohgaki, Hiroko

1989-01-01

An investigation was conducted to determine whether a mixture of low doses of forty carcinogens that target different organs, including the liver, intestine, thyroid, urinary bladder, and skin, is effective for tumor induction in F344/DuCrj rats. The dose of each carcinogen in the diet was 1/50 of the TD50 value, treatment being continued for 102 weeks. Significant numbers of neoplastic nodules of the liver and follicular cell tumors of the thyroid developed in the animals exposed to the carcinogen mixture, although the question of whether the observed carcinogenic effects were synergistic or additive could not be answered. The results serve to evaluate carcinogenic risk in the search for causes of human cancer. PMID:2511179

Testing strategies in mutagenicity and genetic toxicology: an appraisal of the guidelines of the European Scientific Committee for Cosmetics and Non-Food Products for the evaluation of hair dyes.

PubMed

Kirkland, D J; Henderson, L; Marzin, D; Müller, L; Parry, J M; Speit, G; Tweats, D J; Williams, G M

2005-12-30

The European Scientific Committee on Cosmetics and Non-Food Products (SCCNFP) guideline for testing of hair dyes for genotoxic/mutagenic/carcinogenic potential has been reviewed. The battery of six in vitro tests recommended therein differs substantially from the batteries of two or three in vitro tests recommended in other guidelines. Our evaluation of the chemical types used in hair dyes and comparison with other guidelines for testing a wide range of chemical substances, lead to the conclusion that potential genotoxic activity may effectively be determined by the application of a limited number of well-validated test systems that are capable of detecting induced gene mutations and structural and numerical chromosomal changes. We conclude that highly effective screening for genotoxicity of hair dyes can be achieved by the use of three assays, namely the bacterial gene mutation assay, the mammalian cell gene mutation assay (mouse lymphoma tk assay preferred) and the in vitro micronucleus assay. These need to be combined with metabolic activation systems optimised for the individual chemical types. Recent published evidence [D. Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggests that our recommended three tests will detect all known genotoxic carcinogens, and that increasing the number of in vitro assays further would merely reduce specificity (increase false positives). Of course there may be occasions when standard tests need to be modified to take account of special situations such as a specific pathway of biotransformation, but this should be considered as part of routine testing. It is clear that individual dyes and any other novel ingredients should be tested in this three-test battery. However, new products are formed on the scalp by reaction between the chemicals present in hair-dye formulations. Ideally, these should also be tested for genotoxicity, but at present such experiences are very limited. There is also the possibility that one component could mask the genotoxicity of another (e.g. by being more toxic), and so it is not practical at this time to recommend routine testing of complete hair-dye formulations as well. The most sensible approach would be to establish whether any reaction products within the hair-dye formulation penetrate the skin under normal conditions of use and test only those that penetrate at toxicologically relevant levels in the three-test in vitro battery. Recently published data [D. Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggest the three-test battery will produce a significant number of false as well as real positives. Whilst we are aware of the desire to reduce animal experiments, determining the relevance of positive results in any of the three recommended in vitro assays will most likely have to be determined by use of in vivo assays. The bone marrow micronucleus test using routes of administration such as oral or intraperitoneal may be used where the objective is extended hazard identification. If negative results are obtained in this test, then a second in vivo test should be conducted. This could be an in vivo UDS in rat liver or a Comet assay in a relevant tissue. However, for hazard characterisation, tests using topical application with measurement of genotoxicity in the skin would be more appropriate. Such specific site-of-contact in vivo tests would minimise animal toxicity burden and invasiveness, and, especially for hair dyes, be more relevant to human routes of exposure, but there are not sufficient scientific data available to allow recommendations to be made. The generation of such data is encouraged.

Comparison between carcinogenicity and mutagenicity based on chemicals evaluated in the IARC monographs.

PubMed Central

Bartsch, H; Tomatis, L

1983-01-01

The qualitative relationship between carcinogenicity and mutagenicity (DNA-damaging activity), based on chemicals which are known to be or suspected of being carcinogenic to man and/or to experimental animals, is analyzed using 532 chemicals evaluated in Volumes 1-25 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. About 40 compounds (industrial processes) were found to be either definitely or probably carcinogenic to man, and 130 chemicals have been adequately tested in rodents and most of them also in various short-term assays. For a comparison between the carcinogenicity of a chemical and its behavior in short-term tests, systems were selected that have a value for predicting carcinogenicity. These were divided into mutagenicity in (A) the S. typhimurium/microsome assay, (B) other submammalian systems and (C) cultured mammalian cells; (D) chromosomal abnormalities in mammalian cells; (E) DNA damage and repair; (F) cell transformation (or altered growth properties) in vitro. The following conclusions can be drawn. In the absence of studies in man, long-term animal tests are still today the only ones capable of providing evidence of the carcinogenic effect of a chemical. The development and application of an appropriate combination of short-term tests (despite current limitations) can significantly contribute to the prediction/confirmation of the carcinogenic effects of chemicals in animals/man. Confidence in positive tests results is increased when they are confirmed in multiple short-term tests using nonrepetitive end points and different activation systems. Assays to detect carcinogens which do not act via electrophiles (promoters) need to be developed. The results of a given short-term test should be interpreted in the context of other toxicological data. Increasing demand for quantitative carcinogenicity data requires further examination of whether or not there is a quantitative relationship between the potency of a carcinogen in experimental animals/man, and its genotoxic activity in short-term tests. At present, such a relationship is not sufficiently established for it to be used for the prediction of the carcinogenic potency of new compounds. PMID:6337827

Trace elemental analysis of human breast cancerous blood by advanced PC-WDXRF technique

NASA Astrophysics Data System (ADS)

Singh, Ranjit; Kainth, Harpreet Singh; Prasher, Puneet; Singh, Tejbir

2018-03-01

The objective of this work is to quantify the trace elements of healthy and non-healthy blood samples by using advanced polychromatic source based wavelength dispersive X-ray fluorescence (PC-WDXRF) technique. The imbalances in trace elements present in the human blood directly or indirectly lead to the carcinogenic process. The trace elements 11Na, 12Mg, 15P, 16S, 17Cl, 19K, 20Ca, 26Fe, 29Cu and 30Zn are identified and their concentrations are estimated. The experimental results clearly discuss the variation and role of various trace elements present in the non-healthy blood samples relative to the healthy blood samples. These results establish future guidelines to probe the possible roles of essential trace elements in the breast carcinogenic processes. The instrumental sensitivity and detection limits for measuring the elements in the atomic range 11 ≤ Z ≤ 30 have also been discussed in the present work.

Permitted Daily Exposure for Diisopropyl Ether as a Residual Solvent in Pharmaceuticals

PubMed Central

Evandri, Maria Grazia

2018-01-01

Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the “Guideline Q3C (R6) on impurities: guideline for residual solvents” issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which “no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found”. We performed a risk assessment of DIPE based on available toxicological data, after carefully assessing their reliability using the Klimisch score approach. We found sufficiently reliable studies investigating subchronic, developmental, neurological toxicity and carcinogenicity in rats and genotoxicity in vitro. Recent studies also investigated a wide array of toxic effects of gasoline/DIPE mixtures as compared to gasoline alone, thus allowing identifying the effects of DIPE itself. These data allowed a comprehensive toxicological evaluation of DIPE. The main target organs of DIPE toxicity were liver and kidney. DIPE was not teratogen and had no genotoxic effects, either in vitro or in vivo. However, it appeared to increase the number of malignant tumors in rats. Therefore, DIPE could be considered as a non-genotoxic animal carcinogen and a PDE of 0.98 mg/day was calculated based on the lowest No Observed Effect Level (NOEL) value of 356 mg/m3 (corresponding to 49 mg/kg/day) for maternal toxicity in developmental rat toxicity study. In a worst-case scenario, using an exceedingly high daily dose of 10 g/day, allowed DIPE concentration in pharmaceutical substances would be 98 ppm, which is in the range of concentration limits for ICH Q3C guideline class 2 solvents. This result might be considered for regulatory decisions. PMID:29686773

Communicating confidence in the detection and attribution of trends relevant to climate change

NASA Astrophysics Data System (ADS)

Ebi, K. L.

2015-12-01

Readily understandable and consistent language for describing confidence in detection and attribution statements can be developed based on the approach used by the International Agency for Research on Cancer (IARC). IARC was founded in 1965 to provide government authorities with expert, independent, scientific opinion on the causes of human cancer. IARC developed four standard terms for evaluations of the strength of evidence for carcinogenicity arising from human and experimental animal data, and for the strength of mechanistic evidence. Evidence is categorized as sufficient, limited, inadequate, and lack of carcinogenicity. The IARC process then combines theory, evidence, and degree of agreement into a summary evaluation that includes concise statements of the principal line(s) of argument that emerged, the conclusions of the working group on the strength of the evidence for each group of studies, citations to indicate which studies were pivotal to these conclusions, and the reasons for any differential weighting of data. The summary IARC categories are: Group 1 for agents carcinogenic to humans; Group 2 includes Group 2A (probably carcinogenic to humans) or Group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and mechanistic and other relevant data; Group 3 for agents is not classifiable as to its carcinogenicity to humans; and Group 4 for agents probably not carcinogenic to humans. There are obvious parallels with describing confidence in key findings on detection and attribution of a trend to anthropogenic climate change with the confidence statements used by the IARC. Developing and consistent application of similar categories along with accompanying explanations of the principal lines of evidence, would be a helpful step in clearing communicating the degree and sources of certainty in the findings of detection and attribution.

Consideration of Rat Chronic Progressive Nephropathy in Regulatory Evaluations for Carcinogenicity

PubMed Central

Hard, Gordon C.

2013-01-01

Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical. PMID:23104430

Predictive Models for Carcinogenicity and Mutagenicity ...

EPA Pesticide Factsheets

Mutagenicity and carcinogenicity are endpoints of major environmental and regulatory concern. These endpoints are also important targets for development of alternative methods for screening and prediction due to the large number of chemicals of potential concern and the tremendous cost (in time, money, animals) of rodent carcinogenicity bioassays. Both mutagenicity and carcinogenicity involve complex, cellular processes that are only partially understood. Advances in technologies and generation of new data will permit a much deeper understanding. In silico methods for predicting mutagenicity and rodent carcinogenicity based on chemical structural features, along with current mutagenicity and carcinogenicity data sets, have performed well for local prediction (i.e., within specific chemical classes), but are less successful for global prediction (i.e., for a broad range of chemicals). The predictivity of in silico methods can be improved by improving the quality of the data base and endpoints used for modelling. In particular, in vitro assays for clastogenicity need to be improved to reduce false positives (relative to rodent carcinogenicity) and to detect compounds that do not interact directly with DNA or have epigenetic activities. New assays emerging to complement or replace some of the standard assays include VitotoxTM, GreenScreenGC, and RadarScreen. The needs of industry and regulators to assess thousands of compounds necessitate the development of high-t

Overview of occupational cancer in painters in Korea.

PubMed

Myong, Jun-Pyo; Cho, Younmo; Choi, Min; Kim, Hyoung-Ryoul

2018-01-01

Comprehensive consideration is necessary for setting guidelines to evaluate evidence of occupational cancer in painters due to work-related exposure to carcinogens in paint (a phenomenon termed herein as "work-relatedness"). The aim of the present research is to perform a comprehensive review and to suggest criteria for the provision of compensation for occupational neoplasm among painters in Korea. In order to perform a comprehensive review, this study assessed and evaluated scientific reports of carcinogenicities from the International Agency for Research on Cancer (IARC) and the Industrial Injuries Advisory Council (IIAC), as well as reviewed the existing literature about occupational exposure among painters in Korea and the epidemiologic investigations of claimed cases of cancer among painters in Korea. The IARC declares that occupational exposures in commercial painting are classified as Group 1 carcinogens for lung cancer and bladder cancer among painters. The epidemiologic studies show consistent causal relationships between occupational exposure in painters and cancers such as lung cancer [meta relative risk: 1.34 (95% confidence intervals (CIs): 1.23-1.41)] and bladder cancer [meta relative risk: 1.24 (95% CIs: 1.16-1.33)]. In reviewing occupational cancer risks for commercial painters, the Industrial Injuries Advisory Council (IIAC) confirms occupational cancer risks for lung and bladder cancer among commercial painters. According to the IIAC, however, the elevated cancer risks reported in existing literature are not doubled in either lung or bladder cancer in commercial painters relative to the risks of these cancers in the general population. Based on our review of existing Korean articles on the topic, painters are exposed to potential carcinogens including polycyclic aromatic hydrocarbons (PAHs), benzene, hexavalent chrome, crystalized silica, asbestos, and other agents, and relative levels are estimated within commercial painting processes. However, the cancer risks of occupational exposure to Group 1 carcinogens for lung and bladder cancer in painters per se are not fully assessed in existing Korean articles. Total work duration, potential carcinogens in paint, mixed exposure to paints across various industries such as construction and shipbuilding, exposure periods, latent periods, and other factors should be considered on an individual basis in investigating the work-relatedness of certain types of cancer in commercial painters.

Occurrences and changes of disinfection by-products in small water supply systems.

PubMed

Chowdhury, Shakhawat

2017-12-20

The small water supply systems (WSSs) often report high concentrations of disinfection by-products (DBPs) in drinking water. In this study, occurrences of trihalomethanes (THMs) and haloacetic acids (HAAs) in Newfoundland and Labrador (NL), Canada, were investigated from 441 WSSs for a period of 18 years (1999-2016). The WSSs were divided into groundwater (GWP) and surface water (SWP) systems, which were further classified into eight sub-groups (P1-P8) based on the population served (≤ 100; 101-250; 251-500; 501-1000; 1001-3000; 3001-5000; 5001-10,000; and 10,000+, respectively). The DBPs with probable and possible carcinogenic forms were estimated. Overall, 31.1% of WSSs were GWP, in which averages of THMs and HAAs were 32.2 and 27.7 μg/L, respectively, while the SWP had averages of THMs and HAAs of 97.6 and 129.2 μg/L, respectively. The very small WSSs (P1-P3) of GWP had averages of THMs and HAAs in the ranges of 29.1-43.5 and 15.8-64.3 μg/L, respectively. The P1-P3 of SWP had averages of THMs and HAAs in the ranges of 92.6-112.8 and 108.0-154.0 μg/L, respectively, which often exceeded the Canadian guideline limits. If the samples represented the populations homogenously, the total populations exposed to THMs or HAA 5 above the guideline values would be in the range of 132.08-181.38 in thousands (30.3-41.6% of total populations). The probable and possible carcinogenic forms of THMs in GWP and SWP were in the ranges of 4.8-48.8 and 4.4-7.0% of THMs, respectively. In HAAs, carcinogenic forms were in the ranges of 82.6-98.4 and 97.6-98.7%, respectively. The findings indicated that the SWP might need further attention to better protect human health.

Ingestion Exposure to Nitrosamines in Chlorinated Drinking Water

PubMed Central

Han, Kichan

2011-01-01

Objectives N-Nitrosodimethylamine (NDMA) is classified as a probable human carcinogen by the United States Environmental Protection Agency (US EPA) and is formed during the chlorination of municipal drinking water. In this study, selected nitrosamines were measured in chlorinated drinking water collected from Chuncheon, Kangwon-do, Republic of Korea, and a risk assessment for NDMA was conducted. Methods Twelve water samples were collected from 2 treatment plants and 10 household taps. Samples were analyzed for 6 nitrosamines via solid-phase extraction cleanup followed by conversion to dansyl derivatives and high-performance liquid chromatography-fluorescence detection (HPLC-FLD). Considering the dietary patterns of Korean people and the concentration change of NDMA by boiling, a carcinogenic risk assessment from ingestion exposure was conducted following the US EPA guidelines. Results NDMA concentrations ranged between 26.1 and 112.0 ng/L. NDMA in water was found to be thermally stable, and thus its concentration at the end of boiling was greater than before thermal treatment owing to the decrease in water volume. The estimated excess lifetime carcinogenic risk exceeded the regulatory baseline risk of 10-5. Conclusions This result suggests that more extensive studies need to be conducted on nitrosamine concentration distributions over the country and the source of relatively high nitrosamine concentrations. PMID:22125764

Unconventional oil and gas development and risk of childhood leukemia: Assessing the evidence.

PubMed

Elliott, Elise G; Trinh, Pauline; Ma, Xiaomei; Leaderer, Brian P; Ward, Mary H; Deziel, Nicole C

2017-01-15

The widespread distribution of unconventional oil and gas (UO&G) wells and other facilities in the United States potentially exposes millions of people to air and water pollutants, including known or suspected carcinogens. Childhood leukemia is a particular concern because of the disease severity, vulnerable population, and short disease latency. A comprehensive review of carcinogens and leukemogens associated with UO&G development is not available and could inform future exposure monitoring studies and human health assessments. The objective of this analysis was to assess the evidence of carcinogenicity of water contaminants and air pollutants related to UO&G development. We obtained a list of 1177 chemicals in hydraulic fracturing fluids and wastewater from the U.S. Environmental Protection Agency and constructed a list of 143 UO&G-related air pollutants through a review of scientific papers published through 2015 using PubMed and ProQuest databases. We assessed carcinogenicity and evidence of increased risk for leukemia/lymphoma of these chemicals using International Agency for Research on Cancer (IARC) monographs. The majority of compounds (>80%) were not evaluated by IARC and therefore could not be reviewed. Of the 111 potential water contaminants and 29 potential air pollutants evaluated by IARC (119 unique compounds), 49 water and 20 air pollutants were known, probable, or possible human carcinogens (55 unique compounds). A total of 17 water and 11 air pollutants (20 unique compounds) had evidence of increased risk for leukemia/lymphoma, including benzene, 1,3-butadiene, cadmium, diesel exhaust, and several polycyclic aromatic hydrocarbons. Though information on the carcinogenicity of compounds associated with UO&G development was limited, our assessment identified 20 known or suspected carcinogens that could be measured in future studies to advance exposure and risk assessments of cancer-causing agents. Our findings support the need for investigation into the relationship between UO&G development and risk of cancer in general and childhood leukemia in particular. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Potential ecological and human health risks of heavy metals in surface soils associated with iron ore mining in Pahang, Malaysia.

PubMed

Diami, Siti Merryan; Kusin, Faradiella Mohd; Madzin, Zafira

2016-10-01

The composition of heavy metals (and metalloid) in surface soils of iron ore mine-impacted areas has been evaluated of their potential ecological and human health risks. The mining areas included seven selected locations in the vicinity of active and abandoned iron ore-mining sites in Pahang, Malaysia. Heavy metals such as Fe, Mn, Cu, Zn, Co, Pb, Cr, Ni, and Cd and metalloid As were present in the mining soils of the studied area, while Cu was found exceeding the soil guideline value at all sampling locations. However, the assessment of the potential ecological risk index (RI) indicated low ecological risk (RI between 44 and 128) with respect to Cd, Pb, Cu, As, Zn, Co, and Ni in the surface soils. Contributions of potential ecological risk [Formula: see text]by metal elements to the total potential ecological RI were evident for Cd, As, Pb, and Cu. Contribution of Cu appears to be consistently greater in the abandoned mining area compared to active iron ore-mining site. For non-carcinogenic risk, no significant potential health risk was found to both children and adults as the hazard indices (HIs) were all below than 1. The lifetime cancer risk (LCR) indicated that As has greater potential carcinogenic risk compared to other metals that may induce carcinogenic effects such as Pb, Cr, and Cd, while the LCR of As for children fell within tolerable range for regulatory purposes. Irrespective of carcinogenic or non-carcinogenic risk, greater potential health risk was found among children (by an order of magnitude higher for most metals) compared to adults. The hazard quotient (HQ) and cancer risk indicated that the pathways for the risk to occur were found to be in the order of ingestion > dermal > inhalation. Overall, findings showed that some metals and metalloid were still present at comparable concentrations even long after cessation of the iron ore-mining activities.

Relevance of urinary 3-hydroxybenzo(a)pyrene and 1-hydroxypyrene to assess exposure to carcinogenic polycyclic aromatic hydrocarbon mixtures in metallurgy workers.

PubMed

Barbeau, Damien; Persoons, Renaud; Marques, Marie; Hervé, Claire; Laffitte-Rigaud, Gilbert; Maitre, Anne

2014-06-01

In metallurgy, workers are exposed to mixtures of polycyclic aromatic hydrocarbons (PAHs) in which some compounds are carcinogenic. Biomonitoring of PAH exposure has been performed by measuring urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene which is not carcinogenic. This study investigated the use of 3-hydroxybenzo(a)pyrene (3-OHBaP), a metabolite of benzo(a)pyrene (BaP) which is the main carcinogenic component in PAHs, to improve carcinogen exposure assessment. We included 129 metallurgy workers routinely exposed to PAHs during working hours. Urinary samples were collected at three sampling times at the beginning and at the end of the working week for 1-OHP and 3-OHBaP analyses. Workers in anode production showed greater exposure to both biomarkers than those in cathode or silicon production, with respectively, 71, 40, and 30% of 3-OHBaP concentrations exceeding the value of 0.4 nmol mol(-1) creatinine. No difference was observed between the 3-OHBaP levels found at the end of the penultimate workday shift and those at the beginning of the last workday shift. Within these plants, the 1-OHP/3-OHBaP ratios varied greatly according to the workers' activity and emission sources. Using linear regression between these two metabolites, the 1-OHP level corresponding to the guidance value for 3-OHBaP ranged from 0.7 to 2.4 µmol mol(-1) creatinine, depending on the industrial sector. This study emphasizes the interest of monitoring urinary 3-OHBaP at the end of the last workday shift when working week exposure is relatively steady, and the irrelevance of a single guideline value for 1-OHP when assessing occupational health risk. © The Author 2014. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Health Risk Assessment of Inhalation Exposure to Formaldehyde and Benzene in Newly Remodeled Buildings, Beijing

PubMed Central

Huang, Lihui; Mo, Jinhan; Sundell, Jan; Fan, Zhihua; Zhang, Yinping

2013-01-01

Objective To assess health risks associated with inhalation exposure to formaldehyde and benzene mainly emitted from building and decoration materials in newly remodeled indoor spaces in Beijing. Methods We tested the formaldehyde and benzene concentrations in indoor air of 410 dwellings and 451 offices remodeled within the past year, in which the occupants had health concerns about indoor air quality. To assess non-carcinogenic health risks, we compared the data to the health guidelines in China and USA, respectively. To assess carcinogenic health risks, we first modeled indoor personal exposure to formaldehyde and benzene using the concentration data, and then estimated the associated cancer risks by multiplying the indoor personal exposure by the Inhalation Unit Risk values (IURs) provided by the U.S. EPA Integrated Risk Information System (U.S. EPA IRIS) and the California Office of Environmental Health Hazard Assessment (OEHHA), respectively. Results (1) The indoor formaldehyde concentrations of 85% dwellings and 67% offices were above the acute Reference Exposure Level (REL) recommended by the OEHHA and the concentrations of all tested buildings were above the chronic REL recommended by the OEHHA; (2) The indoor benzene concentrations of 12% dwellings and 32% offices exceeded the reference concentration (RfC) recommended by the U.S. EPA IRIS; (3) The median cancer risks from indoor exposure to formaldehyde and benzene were 1,150 and 106 per million (based on U.S. EPA IRIS IURs), 531 and 394 per million (based on OEHHA IURs). Conclusions In the tested buildings, formaldehyde exposure may pose acute and chronic non-carcinogenic health risks to the occupants, whereas benzene exposure may pose chronic non-carcinogenic risks to the occupants. Exposure to both compounds is associated with significant carcinogenic risks. Improvement in ventilation, establishment of volatile organic compounds (VOCs) emission labeling systems for decorating and refurbishing materials are recommended to reduce indoor VOCs exposure. PMID:24244522

A mechanism-mediated model for carcinogenicity: Model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 organic chemicals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Purdy, R.

A hierarchical model consisting of quantitative structure-activity relationships based mainly on chemical reactivity was developed to predict the carcinogenicity of organic chemicals to rodents. The model is comprised of quantitative structure-activity relationships, QSARs based on hypothesized mechanisms of action, metabolism, and partitioning. Predictors included octanol/water partition coefficient, molecular size, atomic partial charge, bond angle strain, atomic acceptor delocalizibility, atomic radical superdelocalizibility, the lowest unoccupied molecular orbital (LUMO) energy of hypothesized intermediate nitrenium ion of primary aromatic amines, difference in charge of ionized and unionized carbon-chlorine bonds, substituent size and pattern on polynuclear aromatic hydrocarbons, the distance between lone electron pairsmore » over a rigid structure, and the presence of functionalities such as nitroso and hydrazine. The model correctly classified 96% of the carcinogens in the training set of 306 chemicals, and 90% of the carcinogens in the test set of 301 chemicals. The test set by chance contained 84% of the positive thiocontaining chemicals. A QSAR for these chemicals was developed. This posttest set modified model correctly predicted 94% of the carcinogens in the test set. This model was used to predict the carcinogenicity of the 25 organic chemicals the U.S. National Toxicology Program was testing at the writing of this article. 12 refs., 3 tabs.« less

Quantitative Characterization Guidelines of Erionite Series Minerals for Regulatory Agencies

NASA Astrophysics Data System (ADS)

Dogan, A.; Dogan, M.

2013-05-01

Erionite is a major health problem where contaminates an environment, which human population exists. Erionite - mesothelioma relationship was first observed in Turkey in 1980's and now the problem is emerging in other places in the world including Mexico. In the past, there have been in vivo or in vitro biological experiments performed using "not correctly characterized" erionite minerals. In addition, in 1997, the erionite was elevated to series status and new erionite minerals - erionite-Na, -K, -Ca - have been proposed. In 2008, erionite characterization guidelines have been proposed (Dogan and Dogan, 2008) and using these criteria, published data was re-evaluated and re-classified; and new mean chemical formula of erionite-Na, -K, -Ca was proposed. If data do not pass the E% and Mg-tests, then any reference to them in the literature is proposed to be disregarded. In some cases, different results have been reported for erionites from the same location by different authors. In these cases, if data do pass both tests but are characterized as from more than one type of erionite, then the mineral should be classified as "undifferentiated" until further clarification. Therefore, we propose (i) Erionite should be correctly characterized using proposed "positive" identification guidelines. (ii) Erionite species (whether it is -Na or -K or -Ca) should be correctly identified. (iii) There should be a close collaboration between medical community researchers and mineralogists in this field so that animal and cell experiments should be performed only with minerals that have passed "positive" identification tests. (iv) An international data bank should be established at one of the mineralogical societies and new data must be evaluated rigorously before being accepted. (v) Regulatory Agencies should ensure that the proposed guidelines for "positive" identification of erionite series minerals, both for a single fiber and a bulk mineral, are followed closely. (vi) Finally, the erionite series minerals - the most carcinogenic minerals known - require a special attention from the mineralogical community, which is a prerequisite to establish their true carcinogenic properties. References: Dogan, A.U., Baris, Y.I., Dogan, M., Emri, S., Steel, I., Elmishad, A.G., and Carbone, M., 2006. Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey. Cancer Research, v. 66 (10), p. 5063-5068, this research paper is highlighted in Nature Reviews-Cancer, v. 6, p. 489. Dogan, A.U. and Dogan, M., 2008, Re-evaluation and re-classification of erionite series minerals, Environmental Geochemistry and Health, v. 30, p. 355-366. Dogan, A.U., Dogan, M., and Hoskins, J.A. 2008, Erionite series minerals: Mineralogical and carcinogenic properties, Environmental Geochemistry and Health, v. 30, p. 367-381.

Investigating the Mechanisms of Action and the Identification of Breast Carcinogens by Computational Analysis of Female Rodent Carcinogens

DTIC Science & Technology

2005-08-01

QSAR in Environmental Researth was accepted and published in April of 2005. The manuscript described the cat -SAR program in detail. We note the...analysis of this data yielded a very good model. As such, this was a suitable dataset on which to develop and test the cat -SAR program. A copy of the...developed and validated (i.e., a-c) as planned in MCASE and then with the cat -SAR program. We have also updated rodent carcinogenicity models so that

Application of bacterial reverse mutation assay for detection of non-genotoxic carcinogens.

PubMed

Kanode, Rewan; Chandra, Saurabh; Sharma, Sharad

2017-06-01

Non-genotoxic carcinogens may play a significant role in development of cancer. Currently short-term assays for mutagenicity classify genotoxic carcinogens and lack the abilities to detect epigenetic carcinogens. The need to develop an endpoint always remains to recognize potentially carcinogenic agents employing rapid and practical bioassays. For this, the present study utilized TA98 and TA1537 tester strains of Salmonella typhimurium to evaluate four non-genotoxic carcinogenic agents (Coumarin, β-Myrcene, Bis(2-ethylhexyl) phthalate and trans-anethole). These chemicals were tested individually and in combination with promutagens 2-aminoanthracene (2AA) and benzo(a)pyrene (BP) in presence of metabolic activation system (S9) by plate incorporation method. Exposure to all four test chemicals revealed marked increase of revertant colonies in promutagen combined groups as compared to promutagens alone. However significantly greater fold responses were observed with 2AA combination groups (Coumarin +2AA, β-Myrcene +2AA, Bis(2-ethylhexyl) phthalate +2AA and trans-anethole +2AA) with TA98 strain as compared with TA1537, which seems to have enhanced the mutagenic response of 2AA in metabolically activated conditions. It is concluded that out of both tester strains TA98 strain of Salmonella typhimurium has the potential to detect non-genotoxic carcinogens when combined with potent promutgens either by inhibiting or modulating activities of liver microsomal enzymes biochemically which may indirectly contribute to neoplastic alterations. Further this simple, short-term alternative assay may provide rapid information during extrapolative toxicology for differentiating genotoxic and non-genotoxic carcinogens.

Unscheduled DNA synthesis in human bronchial epithelium treated with various chemical carcinogens in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishikawa, T.; Ide, F.; Kodama, K.

1984-07-01

A system was developed in which organ culture of human bronchial epithelium was used in combination with autoradiography for quantitative measurement of unscheduled DNA synthesis (UDS) in bronchial epithelial cells. Human bronchi obtained at surgery were cut into small sections and treated with various carcinogens plus (methyl-/sup 3/H)thymidine in short-term organ culture. Significant numbers of silver grains, indicating UDS, were detected on the nuclei of epithelial cells of human bronchi treated with carcinogens, and the numbers were proportional to the concentrations of carcinogens. In this system seven representative carcinogens induced UDS. Four active metabolites of benzo(a)pyrene, and benz(a)anthracene also weremore » found to induce very active UDS in human bronchial epithelium. These findings suggest that human bronchial epithelial cells can repair different types of DNA modification induced by chemical carcinogens.« less

Micro-total envelope system with silicon nanowire separator for safe carcinogenic chemistry.

PubMed

Singh, Ajay K; Ko, Dong-Hyeon; Vishwakarma, Niraj K; Jang, Seungwook; Min, Kyoung-Ik; Kim, Dong-Pyo

2016-02-26

Exploration and expansion of the chemistries involving toxic or carcinogenic reagents are severely limited by the health hazards their presence poses. Here, we present a micro-total envelope system (μ-TES) and an automated total process for the generation of the carcinogenic reagent, its purification and its utilization for a desired synthesis that is totally enveloped from being exposed to the carcinogen. A unique microseparator is developed on the basis of SiNWs structure to replace the usual exposure-prone distillation in separating the generated reagent. Chloromethyl methyl ether chemistry is explored as a carcinogenic model in demonstrating the efficiency of the μ-TES that is fully automated so that feeding the ingredients for the generation is all it takes to produce the desired product. Syntheses taking days can be accomplished safely in minutes with excellent yields, which bodes well for elevating the carcinogenic chemistry to new unexplored dimensions.

Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs.

PubMed Central

Purchase, I. F.; Kalinowski, A. E.; Ishmael, J.; Wilson, J.; Gore, C. W.; Chart, I. S.

1981-01-01

Groups of male and female beagle dogs were given daily doses of 400 mg of various mixtures of naphthylamines for up to 109 months. Survivors were killed at 128 months. A variety of pathological conditions was diagnosed, but the only effect related to treatment was the induction of bladder neoplasms. All dogs which received pure 2-naphthylamine developed transitional-cell carcinomas of the bladder within 34 months. Two of 8 dogs receiving 6% 2-naphthylamine in 1-naphthylamine developed early carcinoma and 2/8 dogs receiving 0.5% 2-naphthylamine in 1-naphthylamine developed haemangioma of the bladder. Some of the dogs receiving 1-naphthylamine (total dose 950 g) and the controls had focal cystitis or hyperplasia, but no neoplasia of the bladder. These results confirm the carcinogenicity of 2-naphthylamine to dogs. No carcinogenic effect of 1-naphthylamine was observed, indicating that it is at least 200 times less potent as a carcinogen than 2-naphthylamine. The incidence of bladder cancer in dogs fed mixtures of both naphthylamines explains why previous experimental and epidemiological studies of impure 1-naphthylamine have revealed carcinogenicity. Images Fig. 1 Fig. 2 PMID:7326199

The effects of environmental chemical carcinogens on the microRNA machinery.

PubMed

Izzotti, A; Pulliero, A

2014-07-01

The first evidence that microRNA expression is early altered by exposure to environmental chemical carcinogens in still healthy organisms was obtained for cigarette smoke. To date, the cumulative experimental data indicate that similar effects are caused by a variety of environmental carcinogens, including polycyclic aromatic hydrocarbons, nitropyrenes, endocrine disruptors, airborne mixtures, carcinogens in food and water, and carcinogenic drugs. Accordingly, the alteration of miRNA expression is a general mechanism that plays an important pathogenic role in linking exposure to environmental toxic agents with their pathological consequences, mainly including cancer development. This review summarizes the existing experimental evidence concerning the effects of chemical carcinogens on the microRNA machinery. For each carcinogen, the specific microRNA alteration signature, as detected in experimental studies, is reported. These data are useful for applying microRNA alterations as early biomarkers of biological effects in healthy organisms exposed to environmental carcinogens. However, microRNA alteration results in carcinogenesis only if accompanied by other molecular damages. As an example, microRNAs altered by chemical carcinogens often inhibits the expression of mutated oncogenes. The long-term exposure to chemical carcinogens causes irreversible suppression of microRNA expression thus allowing the transduction into proteins of mutated oncogenes. This review also analyzes the existing knowledge regarding the mechanisms by which environmental carcinogens alter microRNA expression. The underlying molecular mechanism involves p53-microRNA interconnection, microRNA adduct formation, and alterations of Dicer function. On the whole, reported findings provide evidence that microRNA analysis is a molecular toxicology tool that can elucidate the pathogenic mechanisms activated by environmental carcinogens. Copyright © 2014 Elsevier GmbH. All rights reserved.

'Carcinogens in a puff': smoking in Hong Kong movies.

PubMed

Ho, Sai-Yin; Wang, Man-Ping; Lai, Hak-Kan; Hedley, Anthony J; Lam, Tai-Hing

2010-12-01

Smoking scenes in movies, exploited by the tobacco industry to circumvent advertisement bans, are linked to adolescent smoking. Recently, a Hong Kong romantic comedy Love in a puff put smoking at centre stage, with numerous smoking scenes and words that glamourise smoking. Although WHO has issued guidelines on reducing the exposure of children to smoking in movies, none is adopted in Hong Kong. Comprehensive tobacco control strategies are urgently needed to protect young people in Hong Kong from cigarette promotion in movies.

The developmental neurotoxicity of arsenic: cognitive and behavioral consequences of early life exposure.

PubMed

Tolins, Molly; Ruchirawat, Mathuros; Landrigan, Philip

2014-01-01

More than 200 million people worldwide are chronically exposed to arsenic. Arsenic is a known human carcinogen, and its carcinogenic and systemic toxicity have been extensively studied. By contrast, the developmental neurotoxicity of arsenic has been less well described. The aim of this review was to provide a comprehensive review of the developmental neurotoxicity of arsenic. We reviewed the published epidemiological and toxicological literature on the developmental neurotoxicity of arsenic. Arsenic is able to gain access to the developing brain and cause neurotoxic effects. Animal models link prenatal and early postnatal exposure to reduction in brain weight, reductions in numbers of glia and neurons, and alterations in neurotransmitter systems. Animal and in vitro studies both suggest that oxidative stress may be a mechanism of arsenic neurotoxicity. Fifteen epidemiological studies indicate that early life exposure is associated with deficits in intelligence and memory. These effects may occur at levels of exposure below current safety guidelines, and some neurocognitive consequences may become manifest only later in life. Sex, concomitant exposures, and timing of exposure appear to modify the developmental neurotoxicity of arsenic. Four epidemiological studies failed to show behavioral outcomes of arsenic exposure. The published literature indicates that arsenic is a human developmental neurotoxicant. Ongoing and future prospective birth cohort studies will allow more precise definition of the developmental consequences of arsenic exposure in early life. Copyright © 2014. Published by Elsevier Inc.

Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma.

PubMed

Kakinuma, Shizuko; Nishimura, Mayumi; Amasaki, Yoshiko; Takada, Mayumi; Yamauchi, Kazumi; Sudo, Satomi; Shang, Yi; Doi, Kazutaka; Yoshinaga, Shinji; Shimada, Yoshiya

2012-09-01

Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-induced point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens. Copyright © 2012 Elsevier B.V. All rights reserved.

Risk of human health by particulate matter as a source of air pollution--comparison with tobacco smoking.

PubMed

Enomoto, Makoto; Tierney, William J; Nozaki, Kohsuke

2008-08-01

Increased air pollution, containing carcinogenic particulate matter smaller than 2.5 microm (PM(2.5)), has gained particular attention in recent years as a causative factor in the increased incidence of respiratory diseases, including lung cancer. Extensive carcinogenicity studies conducted recently under Good Laboratory Practice conditions by National Toxicology Program in the USA, Ramazzini Foundation in Italy or Contract Research Organizations on numerous chemical compounds have demonstrated the importance of considering dose levels, times and duration of exposure in the safety evaluation of carcinogenic as well as classical toxic agents. Data on exposure levels to chemical carcinogens that produce tumor development have contributed to the evaluation of human carcinogens from extrapolation of animal data. A popular held misconception is that the risk from smoking is the result of inhaling assorted particulate matter and by products from burning tobacco rather than the very low ng levels of carcinogens present in smoke. Consider the fact that a piece of toasted bread contains ng levels of the carcinogen urethane (ethyl carbamate). Yet, no one has considered toast to be a human carcinogen. Future human carcinogenic risk assessment should emphasize consideration of inhalation exposure to higher levels of benzo (a) pyrene and other possible carcinogens and particulate matter present in polluted air derived from automobile exhaust, pitch and coal tar on paved roads and asbestos, in addition to other environmental contaminant exposure via the food and drinking water.

Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis.

PubMed

García-Nieto, Pablo E; Schwartz, Erin K; King, Devin A; Paulsen, Jonas; Collas, Philippe; Herrera, Rafael E; Morrison, Ashby J

2017-10-02

The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer. © 2017 The Authors.

A high-throughput next-generation sequencing-based method for detecting the mutational fingerprint of carcinogens

PubMed Central

Besaratinia, Ahmad; Li, Haiqing; Yoon, Jae-In; Zheng, Albert; Gao, Hanlin; Tommasi, Stella

2012-01-01

Many carcinogens leave a unique mutational fingerprint in the human genome. These mutational fingerprints manifest as specific types of mutations often clustering at certain genomic loci in tumor genomes from carcinogen-exposed individuals. To develop a high-throughput method for detecting the mutational fingerprint of carcinogens, we have devised a cost-, time- and labor-effective strategy, in which the widely used transgenic Big Blue® mouse mutation detection assay is made compatible with the Roche/454 Genome Sequencer FLX Titanium next-generation sequencing technology. As proof of principle, we have used this novel method to establish the mutational fingerprints of three prominent carcinogens with varying mutagenic potencies, including sunlight ultraviolet radiation, 4-aminobiphenyl and secondhand smoke that are known to be strong, moderate and weak mutagens, respectively. For verification purposes, we have compared the mutational fingerprints of these carcinogens obtained by our newly developed method with those obtained by parallel analyses using the conventional low-throughput approach, that is, standard mutation detection assay followed by direct DNA sequencing using a capillary DNA sequencer. We demonstrate that this high-throughput next-generation sequencing-based method is highly specific and sensitive to detect the mutational fingerprints of the tested carcinogens. The method is reproducible, and its accuracy is comparable with that of the currently available low-throughput method. In conclusion, this novel method has the potential to move the field of carcinogenesis forward by allowing high-throughput analysis of mutations induced by endogenous and/or exogenous genotoxic agents. PMID:22735701

A high-throughput next-generation sequencing-based method for detecting the mutational fingerprint of carcinogens.

PubMed

Besaratinia, Ahmad; Li, Haiqing; Yoon, Jae-In; Zheng, Albert; Gao, Hanlin; Tommasi, Stella

2012-08-01

Many carcinogens leave a unique mutational fingerprint in the human genome. These mutational fingerprints manifest as specific types of mutations often clustering at certain genomic loci in tumor genomes from carcinogen-exposed individuals. To develop a high-throughput method for detecting the mutational fingerprint of carcinogens, we have devised a cost-, time- and labor-effective strategy, in which the widely used transgenic Big Blue mouse mutation detection assay is made compatible with the Roche/454 Genome Sequencer FLX Titanium next-generation sequencing technology. As proof of principle, we have used this novel method to establish the mutational fingerprints of three prominent carcinogens with varying mutagenic potencies, including sunlight ultraviolet radiation, 4-aminobiphenyl and secondhand smoke that are known to be strong, moderate and weak mutagens, respectively. For verification purposes, we have compared the mutational fingerprints of these carcinogens obtained by our newly developed method with those obtained by parallel analyses using the conventional low-throughput approach, that is, standard mutation detection assay followed by direct DNA sequencing using a capillary DNA sequencer. We demonstrate that this high-throughput next-generation sequencing-based method is highly specific and sensitive to detect the mutational fingerprints of the tested carcinogens. The method is reproducible, and its accuracy is comparable with that of the currently available low-throughput method. In conclusion, this novel method has the potential to move the field of carcinogenesis forward by allowing high-throughput analysis of mutations induced by endogenous and/or exogenous genotoxic agents.

The limits of two-year bioassay exposure regimens for identifying chemical carcinogens.

PubMed

Huff, James; Jacobson, Michael F; Davis, Devra Lee

2008-11-01

Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans. Most rodent bioassays begin several weeks after birth and expose animals to chemicals or other substances, including workplace and environmental pollutants, for 2 years. New findings indicate the need to extend the timing and duration of exposures used in the rodent bioassay. In this Commentary, we propose that the sensitivity of chemical carcinogenesis bio-assays would be enhanced by exposing rodents beginning in utero and continuing for 30 months (130 weeks) or until their natural deaths at up to about 3 years. Studies of three chemicals of different structures and uses-aspartame, cadmium, and toluene-suggest that exposing experimental animals in utero and continuing exposure for 30 months or until their natural deaths increase the sensitivity of bioassays, avoid false-negative results, and strengthen the value and validity of results for regulatory agencies. Government agencies, drug companies, and the chemical industry should conduct and compare the results of 2-year bioassays of known carcinogens or chemicals for which there is equivocal evidence of carcinogenicity with longer-term studies, with and without in utero exposure. If studies longer than 2 years and/or with in utero exposure are found to better identify potential human carcinogens, then regulatory agencies should promptly revise their testing guidelines, which were established in the 1960s and early 1970s. Changing the timing and dosing of the animal bioassay would enhance protection of workers and consumers who are exposed to potentially dangerous workplace or home contaminants, pollutants, drugs, food additives, and other chemicals throughout their lives.

The Limits of Two-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens

PubMed Central

Huff, James; Jacobson, Michael F.; Davis, Devra Lee

2008-01-01

Background Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans. Most rodent bioassays begin several weeks after birth and expose animals to chemicals or other substances, including workplace and environmental pollutants, for 2 years. New findings indicate the need to extend the timing and duration of exposures used in the rodent bioassay. Objectives In this Commentary, we propose that the sensitivity of chemical carcinogenesis bio-assays would be enhanced by exposing rodents beginning in utero and continuing for 30 months (130 weeks) or until their natural deaths at up to about 3 years. Discussion Studies of three chemicals of different structures and uses—aspartame, cadmium, and toluene—suggest that exposing experimental animals in utero and continuing exposure for 30 months or until their natural deaths increase the sensitivity of bioassays, avoid false-negative results, and strengthen the value and validity of results for regulatory agencies. Conclusions Government agencies, drug companies, and the chemical industry should conduct and compare the results of 2-year bioassays of known carcinogens or chemicals for which there is equivocal evidence of carcinogenicity with longer-term studies, with and without in utero exposure. If studies longer than 2 years and/or with in utero exposure are found to better identify potential human carcinogens, then regulatory agencies should promptly revise their testing guidelines, which were established in the 1960s and early 1970s. Changing the timing and dosing of the animal bioassay would enhance protection of workers and consumers who are exposed to potentially dangerous workplace or home contaminants, pollutants, drugs, food additives, and other chemicals throughout their lives. PMID:19057693

Characterization of PAHs and metals in indoor/outdoor PM10/PM2.5/PM1 in a retirement home and a school dormitory.

PubMed

Hassanvand, Mohammad Sadegh; Naddafi, Kazem; Faridi, Sasan; Nabizadeh, Ramin; Sowlat, Mohammad Hossein; Momeniha, Fatemeh; Gholampour, Akbar; Arhami, Mohammad; Kashani, Homa; Zare, Ahad; Niazi, Sadegh; Rastkari, Noushin; Nazmara, Shahrokh; Ghani, Maryam; Yunesian, Masud

2015-09-15

In the present work, we investigated the characteristics of polycyclic aromatic hydrocarbons (PAHs) and metal(loid)s in indoor/outdoor PM10, PM2.5, and PM1 in a retirement home and a school dormitory in Tehran from May 2012 to May 2013. The results indicated that the annual levels of indoor and outdoor PM10 and PM2.5 were much higher than the guidelines issued by the World Health Organization (WHO). The most abundant detected metal(loid)s in PM were Si, Fe, Zn, Al, and Pb. We found higher percentages of metal(loid)s in smaller size fractions of PM. Additionally, the results showed that the total PAHs (ƩPAHs) bound to PM were predominantly (83-88%) found in PM2.5, which can penetrate deep into the alveolar regions of the lungs. In general, carcinogenic PAHs accounted for 40-47% of the total PAHs concentrations; furthermore, the smaller the particle size, the higher the percentage of carcinogenic PAHs. The percentages of trace metal(loid)s and carcinogenic PAHs in PM2.5 mass were almost twice as high as those in PM10. This can most likely be responsible for the fact that PM2.5 can cause more adverse health effects than PM10 can. The average BaP-equivalent carcinogenic (BaP-TEQ) levels both indoors and outdoors considerably exceeded the maximum permissible risk level of 1 ng/m(3) of BaP. The enrichment factors and diagnostic ratios indicated that combustion-related anthropogenic sources, such as gasoline- and diesel-fueled vehicles as well as natural gas combustion, were the major sources of PAHs and trace metal(loid)s bound to PM. Copyright © 2015 Elsevier B.V. All rights reserved.

The International Agency for Research on Cancer (IARC) evaluation of the carcinogenicity of outdoor air pollution: focus on China.

PubMed

Loomis, Dana; Huang, Wei; Chen, Guosheng

2014-04-01

The International Agency for Research on Cancer (IARC) has classified outdoor air pollution and the particulate matter (PM) in outdoor air pollution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are discussed. The air pollution levels in Chinese cities are among the highest observed in the world today and frequently exceed health-based national and international guidelines. Data from high-quality epidemiologic studies in Asia, Europe, and North America consistently show positive associations between lung cancer and PM exposure and other indicators of air pollution, which persist after adjustment for important lung cancer risk factors, such as tobacco smoking. Epidemiologic data from China are limited but nevertheless indicate an increased risk of lung cancer associated with several air pollutants. Excess cancer risk is also observed in experimental animals exposed to polluted outdoor air or extracted PM. The exposure of several species to outdoor air pollution is associated with markers of genetic damage that have been linked to increased cancer risk in humans. Numerous studies from China, especially genetic biomarker studies in exposed populations, support that the polluted air in China is genotoxic and carcinogenic to humans. The evaluation by IARC indicates both the need for further research into the cancer risks associated with exposure to air pollution in China and the urgent need to act to reduce exposure to the population.

The International Agency for Research on Cancer (IARC) evaluation of the carcinogenicity of outdoor air pollution: focus on China

PubMed Central

Loomis, Dana; Huang, Wei; Chen, Guosheng

2014-01-01

The International Agency for Research on Cancer (IARC) has classified outdoor air pollution and the particulate matter (PM) in outdoor air pollution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are discussed. The air pollution levels in Chinese cities are among the highest observed in the world today and frequently exceed health-based national and international guidelines. Data from high-quality epidemiologic studies in Asia, Europe, and North America consistently show positive associations between lung cancer and PM exposure and other indicators of air pollution, which persist after adjustment for important lung cancer risk factors, such as tobacco smoking. Epidemiologic data from China are limited but nevertheless indicate an increased risk of lung cancer associated with several air pollutants. Excess cancer risk is also observed in experimental animals exposed to polluted outdoor air or extracted PM. The exposure of several species to outdoor air pollution is associated with markers of genetic damage that have been linked to increased cancer risk in humans. Numerous studies from China, especially genetic biomarker studies in exposed populations, support that the polluted air in China is genotoxic and carcinogenic to humans. The evaluation by IARC indicates both the need for further research into the cancer risks associated with exposure to air pollution in China and the urgent need to act to reduce exposure to the population. PMID:24694836

Report on carcinogens monograph on cumene.

PubMed

2013-09-01

The National Toxicology Program conducted a cancer evaluation on cumene for possible listing in the Report on Carcinogens (RoC). The cancer evaluation is captured in the RoC monograph, which was peer reviewed in a public forum. The monograph consists of two components: (Part 1) the cancer evaluation, which reviews the relevant scientific information, assesses its quality, applies the RoC listing criteria to the scientific information, and provides the NTP recommendation for listing status for cumene in the RoC, and (Part 2) the substance profile proposed for the RoC, containing the NTP's listing status recommendation, a summary of the scientific evidence considered key to reaching that decision, and data on properties, use, production, exposure, and Federal regulations and guidelines to reduce exposure to cumene. This monograph provides an assessment of the available scientific information on cumene, including human exposure and properties, disposition and toxicokinetics, cancer studies in experimental animals, and studies of mechanisms and other related effects, including relevant toxicological effects, genetic toxicology, and mechanisms of carcinogenicity. From this assessment, the NTP recommended that cumene be listed as reasonably anticipated to be a human carcinogen in the RoC based on sufficient evidence from studies in experimental animals, which found that cumene exposure caused lung tumors in male and female mice and liver tumors in female mice. Several proposed mechanisms of carcinogenesis support the relevance to humans of the lung and liver tumors observed in experimental animals. Specifically, there is evidence that humans and experimental animals metabolize cumene through similar metabolic pathways. In addition, mutations of the K-ras oncogene and p53 tumor-suppressor gene observed in cumene-induced lung tumors in mice, along with altered expression of many other genes, resemble molecular alterations found in human lung and other cancers.

[COMPARATIVE ASSESSMENT OF THE MULTIMEDIA CANCER HEALTH RISKS CAUSED BY CONTAMINATION OF THE KRASNOIARSK KRAĬ REGIONS' ENVIRONMENT].

PubMed

Novikov, S M; Shashina, T A; Dodina, N S; Kislitsin, V A; Vorobieva, L M; Goriaev, D V; Tikhonova, I V; Kurkatov, S V

2015-01-01

Krasnoyarsk Krai is a region with developed mining and processing industries, notoriously known industries, as sources of carcinogenic emission. For 55 administrative units of the Krai 303 large enterprises' industrial emissions were preliminary prioritized and their location was designated. Only 52% out of the carcinogens emitted into the ambient air by industries were controlled, in other environments the figures ranged from 20% (soil, food) to 48% (drinking water), 10 carcinogens were not controlled in the environment at all. Based on the results of ranking carcinogenic emission and analysis of the carcinogens monitoring in the environment in 2007-2011 31 substances were selected. A comparative analysis of multiple environmental carcinogenic risks showed that 78% of the areas, based on the receipt ofcarcinogensfrom two media, and 80% ofthe areas taking into account the receipt ofcarcinogens from three media attributed to the alarming level of risk for population, that requires continuous monitoring and routine health interventions for its mitigation. The maximal multiple environmental risk values that took into account inputs from all sources were close to the upper boundary alarming level of risk, in Divnogorsk (7,80E-04), Norilsk (7,97 E-04), Krasnoyarsk (8,84E-04) and Achinsk (9,4 E-04). The greatest inputs to total individual cancer risk from polluted ambient air were made by benzene, chromium VI, formaldehyde and nickel, from drinking water--by arsenic, aldrin and heptachlor from soil--by arsenic and lead. The ambient air input into total multiple environmental carcinogenic risk ranged from 31.5 to 99.5%, drinking water input--from 0.5 to 68.5%, soil--up to 0.1%. Areas with maximum levels of total carcinogenic risk are characterized by the highest levels of average long-term indices of cancer development. The study discussed in this article has screening nature. Further in-depth researches for carcinogenic and toxic multimedia risks are required.

NON-NEOPLASTIC LESIONS: USE OF DATA FROM PRE- OR NON-NEOPLASTIC LESIONS THAT MAY INDICATE POTENTIAL FOR CARCINOGENESIS

EPA Science Inventory

The Toxicology and Microbiology Division of the US EPA, Health Effects Research Laboratory has initiated a research program to develop a matrix of short-term tests to distinguish carcinogens from non-carcinogens among genotoxic substances and to develop methods for predicting rel...

Structure-Activity Relationship Models for Rat Carcinogenesis and Assessing the Role Mutagens Play in Model Predictivity

PubMed Central

Carrasquer, C. Alex; Batey, Kaylind; Qamar, Shahid; Cunningham, Albert R.; Cunningham, Suzanne L.

2016-01-01

We previously demonstrated that fragment based cat-SAR carcinogenesis models consisting solely of mutagenic or non-mutagenic carcinogens varied greatly in terms of their predictive accuracy. This led us to investigate how well the rat cancer cat-SAR model predicted mutagens and non-mutagens in their learning set. Four rat cancer cat-SAR models were developed: Complete Rat, Transgender Rat, Male Rat, and Female Rat, with leave-one-out (LOO) validation concordance values of 69%, 74%, 67%, and 73%, respectively. The mutagenic carcinogens produced concordance values in the range of 69–76% as compared to only 47–53% for non-mutagenic carcinogens. As a surrogate for mutagenicity comparisons between single site and multiple site carcinogen SAR models was analyzed. The LOO concordance values for models consisting of 1-site, 2-site, and 4+-site carcinogens were 66%, 71%, and 79%, respectively. As expected, the proportion of mutagens to non-mutagens also increased, rising from 54% for 1-site to 80% for 4+-site carcinogens. This study demonstrates that mutagenic chemicals, in both SAR learning sets and test sets, are influential in assessing model accuracy. This suggests that SAR models for carcinogens may require a two-step process in which mutagenicity is first determined before carcinogenicity can be accurately predicted. PMID:24697549

Comparison of acrylamide intake from Western and guideline based diets using probabilistic techniques and linear programming.

PubMed

Katz, Josh M; Winter, Carl K; Buttrey, Samuel E; Fadel, James G

2012-03-01

Western and guideline based diets were compared to determine if dietary improvements resulting from following dietary guidelines reduce acrylamide intake. Acrylamide forms in heat treated foods and is a human neurotoxin and animal carcinogen. Acrylamide intake from the Western diet was estimated with probabilistic techniques using teenage (13-19 years) National Health and Nutrition Examination Survey (NHANES) food consumption estimates combined with FDA data on the levels of acrylamide in a large number of foods. Guideline based diets were derived from NHANES data using linear programming techniques to comport to recommendations from the Dietary Guidelines for Americans, 2005. Whereas the guideline based diets were more properly balanced and rich in consumption of fruits, vegetables, and other dietary components than the Western diets, acrylamide intake (mean±SE) was significantly greater (P<0.001) from consumption of the guideline based diets (0.508±0.003 μg/kg/day) than from consumption of the Western diets (0.441±0.003 μg/kg/day). Guideline based diets contained less acrylamide contributed by French fries and potato chips than Western diets. Overall acrylamide intake, however, was higher in guideline based diets as a result of more frequent breakfast cereal intake. This is believed to be the first example of a risk assessment that combines probabilistic techniques with linear programming and results demonstrate that linear programming techniques can be used to model specific diets for the assessment of toxicological and nutritional dietary components. Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical speciation of trace metals emitted from Indonesian peat fires for health risk assessment

NASA Astrophysics Data System (ADS)

Betha, Raghu; Pradani, Maharani; Lestari, Puji; Joshi, Umid Man; Reid, Jeffrey S.; Balasubramanian, Rajasekhar

2013-03-01

Regional smoke-induced haze in Southeast Asia, caused by uncontrolled forest and peat fires in Indonesia, is of major environmental and health concern. In this study, we estimated carcinogenic and non-carcinogenic health risk due to exposure to fine particles (PM2.5) as emitted from peat fires at Kalimantan, Indonesia. For the health risk analysis, chemical speciation (exchangeable, reducible, oxidizable, and residual fractions) of 12 trace metals (Al, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Ti, V and Zn) in PM2.5 was studied. Results indicate that Al, Fe and Ti together accounted for a major fraction of total metal concentrations (~ 83%) in PM2.5 emissions in the immediate vicinity of peat fires. Chemical speciation reveals that a major proportion of most of the metals, with the exception of Cr, Mn, Fe, Ni and Cd, was present in the residual fraction. The exchangeable fraction of metals, which represents their bioavailability, could play a major role in inducing human health effects of PM2.5. This fraction contained carcinogenic metals such as Cd (39.2 ng m- 3) and Ni (249.3 ng m- 3) that exceeded their WHO guideline values by several factors. Health risk estimates suggest that exposure to PM2.5 emissions in the vicinity of peat fires poses serious health threats.

Development of a screening tool to prioritize testing for the carcinogenic hazard of residual aromatic extracts and related petroleum streams.

PubMed

Goyak, Katy O; Kung, Ming H; Chen, Min; Aldous, Keith K; Freeman, James J

2016-12-15

Residual aromatic extracts (RAE) are petroleum substances with variable composition predominantly containing aromatic hydrocarbons with carbon numbers greater than C25. Because of the high boiling nature of RAEs, the aromatics present are high molecular weight, with most above the range of carcinogenic polycyclic aromatic hydrocarbons (PAHs). However, refinery distillations are imperfect; some PAHs and their heteroatom-containing analogs (collectively referred to as polycyclic aromatic content or PAC) may remain in the parent stream and be extracted into the RAE, and overall PAC content is related to the carcinogenic potential of an RAE. We describe here a real-time analytical chemistry-based tool to assess the carcinogenic hazard of RAE via the development of a functional relationship between carcinogenicity and boiling point. Samples representative of steps along the RAE manufacturing process were obtained from five refineries to evaluate relationships between mutagenicity index (MI), PAC ring content and gas chromatographic distillation (GCD) curves. As expected, a positive linear relationship between MI and PAC ring content occurred, most specifically for 3-6 ring PAC (R 2 =0.68). A negative correlation was found between MI and temperature at 5% vaporization by GCD (R 2 =0.72), indicating that samples with greater amounts of lower boiling constituents were more likely to be carcinogenic. The inverse relationship between boiling range and carcinogenicity was further demonstrated by fractionation of select RAE samples (MI=0.50+0.07; PAC=1.70+0.51wt%; n=5) into low and high boiling fractions, where lower boiling fractions were both more carcinogenic than the higher boiling fractions (MI=2.36±0.55 and 0.17±0.11, respectively) and enriched in 3-6 ring PACs (5.20+0.70wt% and 0.97+0.35wt%, respectively). The criteria defining carcinogenicity was established as 479°C for the 5% vaporization points by GCD, with an approximate 95% probability of a future sample having an MI below the recommended limit of 0.4 for RAEs. Overall, these results provide a cost-efficient and real-time tool by which the carcinogenic potential of RAEs can be assessed at the refinery level, ultimately providing a means to readily monitor and minimize the carcinogenic potential of RAEs. Copyright © 2016. Published by Elsevier Ireland Ltd.

Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valerio, Luis G.; Arvidson, Kirk B.; Chanderbhan, Ronald F.

2007-07-01

Consistent with the U.S. Food and Drug Administration (FDA) Critical Path Initiative, predictive toxicology software programs employing quantitative structure-activity relationship (QSAR) models are currently under evaluation for regulatory risk assessment and scientific decision support for highly sensitive endpoints such as carcinogenicity, mutagenicity and reproductive toxicity. At the FDA's Center for Food Safety and Applied Nutrition's Office of Food Additive Safety and the Center for Drug Evaluation and Research's Informatics and Computational Safety Analysis Staff (ICSAS), the use of computational SAR tools for both qualitative and quantitative risk assessment applications are being developed and evaluated. One tool of current interest ismore » MDL-QSAR predictive discriminant analysis modeling of rodent carcinogenicity, which has been previously evaluated for pharmaceutical applications by the FDA ICSAS. The study described in this paper aims to evaluate the utility of this software to estimate the carcinogenic potential of small, organic, naturally occurring chemicals found in the human diet. In addition, a group of 19 known synthetic dietary constituents that were positive in rodent carcinogenicity studies served as a control group. In the test group of naturally occurring chemicals, 101 were found to be suitable for predictive modeling using this software's discriminant analysis modeling approach. Predictions performed on these compounds were compared to published experimental evidence of each compound's carcinogenic potential. Experimental evidence included relevant toxicological studies such as rodent cancer bioassays, rodent anti-carcinogenicity studies, genotoxic studies, and the presence of chemical structural alerts. Statistical indices of predictive performance were calculated to assess the utility of the predictive modeling method. Results revealed good predictive performance using this software's rodent carcinogenicity module of over 1200 chemicals, comprised primarily of pharmaceutical, industrial and some natural products developed under an FDA-MDL cooperative research and development agreement (CRADA). The predictive performance for this group of dietary natural products and the control group was 97% sensitivity and 80% concordance. Specificity was marginal at 53%. This study finds that the in silico QSAR analysis employing this software's rodent carcinogenicity database is capable of identifying the rodent carcinogenic potential of naturally occurring organic molecules found in the human diet with a high degree of sensitivity. It is the first study to demonstrate successful QSAR predictive modeling of naturally occurring carcinogens found in the human diet using an external validation test. Further test validation of this software and expansion of the training data set for dietary chemicals will help to support the future use of such QSAR methods for screening and prioritizing the risk of dietary chemicals when actual animal data are inadequate, equivocal, or absent.« less

Risk assessment of carcinogens in food.

PubMed

Barlow, Susan; Schlatter, Josef

2010-03-01

Approaches for the risk assessment of carcinogens in food have evolved as scientific knowledge has advanced. Early methods allowed little more than hazard identification and an indication of carcinogenic potency. Evaluation of the modes of action of carcinogens and their broad division into genotoxic and epigenetic (non-genotoxic, non-DNA reactive) carcinogens have played an increasing role in determining the approach followed and provide possibilities for more detailed risk characterisation, including provision of quantitative estimates of risk. Reliance on experimental animal data for the majority of risk assessments and the fact that human exposures to dietary carcinogens are often orders of magnitude below doses used in experimental studies has provided a fertile ground for discussion and diverging views on the most appropriate way to offer risk assessment advice. Approaches used by national and international bodies differ, with some offering numerical estimates of potential risks to human health, while others express considerable reservations about the validity of quantitative approaches requiring extrapolation of dose-response data below the observed range and instead offer qualitative advice. Recognising that qualitative advice alone does not provide risk managers with information on which to prioritise the need for risk management actions, a "margin of exposure" approach for substances that are both genotoxic and carcinogenic has been developed, which is now being used by the World Health Organization and the European Food Safety Authority. This review describes the evolution of risk assessment advice on carcinogens and discusses examples of ways in which carcinogens in food have been assessed in Europe.

Interrelationships among carcinogenicity, mutagenicity, acute toxicity, and chemical structure in a genotoxicity data base

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benigni, R.; Andreoli, C.; Giuliani, A.

1989-01-01

The interrelationships among carcinogenicity, mutagenicity, acute toxicity (LD50), and a number of molecular descriptors were studied by computerized data analysis methods on the data base generated by the International Program for the Evaluation of Short-Term Test for Carcinogens (IPESTTC). With the use of statistical regression methods, three main associations were evidenced: (1) the well-known correlation between carcinogenicity and mutagenicity; (2) a correlation between mutagenicity and toxicity (LD50 ip in mice); and (3) a correlation between toxicity and a recently introduced estimator of the free energy of binding of the molecules to biological receptors. As expected on the basis of themore » large variety of chemical classes represented in the IPESTTC data base, no simple relationship between mutagenicity or carcinogenicity and chemical descriptors was found. To overcome this problem, a new pattern recognition method (REPAD), developed by us for structure-activity studies of noncongeneric chemicals, has been used. This allowed us to highlight a significant difference between the whole patterns of relationships among chemicophysical variables in the two groups to active (mutagenicity and/or carcinogenic) and inactive chemicals. This approach generated a classification rule able to correctly assign about 80% of carcinogens or mutagens.« less

78 FR 44117 - Notice of a Public Comment Period on the Draft IRIS Carcinogenicity Assessment for Ethylene Oxide

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-23

... Assessment (NCEA) within the EPA Office of Research and Development (ORD). The 45-day public comment period... anticipates will be undertaken by the Science Advisory Board. EPA is releasing this draft carcinogenicity... Research and Development (ORD). The public has been provided an opportunity to comment on a previous...

The silence: the asbestos industry and early occupational cancer research--a case study.

PubMed Central

Lilienfeld, D E

1991-01-01

To gain insight into corporate activities regarding the identification of occupational carcinogens earlier in this century, the actions of one industry, the asbestos industry, were reviewed. This industry, in concert with many of its insurers, systematically developed and then suppressed information on the carcinogenicity of asbestos. The development of warnings for those exposed to the asbestos was delayed. As a result, millions of workers were exposed to the carcinogen and hundreds of thousands died. These events are placed into the context of similar activities in other industries during this time. Images p792-a p793-a p796-a PMID:2029056

Comparison of Reversibility of Rat Forestomach Lesions Induced by Genotoxic and Non‐genotoxic Carcinogens

PubMed Central

Kagawa, Masataka; Hakoi, Kazuo; Yamamoto, Atsushi; Futakuchi, Mitsuru

1993-01-01

Reversibility of forestomach lesions induced by genotoxic and non‐genotoxic carcinogens was compared histopathologically. Groups of 30 to 33 male F344 rats were given dietary 0.1% 8‐nitroquinoline, dietary 0.4–0.2% 2‐(2‐furyl)‐3‐(5‐nitro‐2‐furyl)acrylamide, an intragastric dose of 20 mg/kg body weight N‐methyl‐N′‐nitro‐N‐nitrosoguanidine once a week, or 20 ppm N‐methylnitrosourethane in the drinking water as a genotoxic carcinogen, or 2% butylated hydroxyanisole, 2% caffeic acid, 2% sesamol or 2% 4‐methoxyphenol in the diet as a non‐genotoxic carcinogen for 24 weeks. Ten or 11 rats in each group were killed at week 24. Half of the remainder were maintained on basal diet alone for an additional 24 weeks and the other half were given the same chemical for 48 weeks, and then killed. Forestomach lesions induced by genotoxic carcinogens did not regress after removal of carcinogens. In contrast, simple or papillary hyperplasia (SPH), but not basal cell hyperplasia (BCH), induced by non‐genotoxic carcinogens clearly regressed after cessation of insult. SFH labeling indices in the non‐genotoxic carcinogen‐treated cases decreased after removal of the carcinogenic stimulus whereas BCH values were low irrespective of treatment. Atypical hyperplasia (AH), observed at high incidences in rats treated with genotoxic carcinogens, was also evident in animals receiving non‐genotoxic agents, even after their withdrawal, albeit at low incidences. AH labeling indices remained high even without continued insult. These results indicate that even with non‐genotoxic carcinogens, heritable alterations at the DNA level could occur during strong cell proliferation and result in AH development. This putative preneoplastic lesion might then progress to produce carcinomas. PMID:8276717

Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation

PubMed Central

Herceg, Zdenko

2013-01-01

Remarkable progress in the field of epigenetics has turned academic, medical and public attention to the potential applications of these new advances in medicine and various fields of biomedical research. The result is a broader appreciation of epigenetic phenomena in the a etiology of common human diseases, most notably cancer. These advances also represent an exciting opportunity to incorporate epigenetics and epigenomics into carcinogen identification and safety assessment. Current epigenetic studies, including major international sequencing projects, are expected to generate information for establishing the ‘normal’ epigenome of tissues and cell types as well as the physiological variability of the epigenome against which carcinogen exposure can be assessed. Recently, epigenetic events have emerged as key mechanisms in cancer development, and while our search of the Monograph Volume 100 revealed that epigenetics have played a modest role in evaluating human carcinogens by the International Agency for Research on Cancer (IARC) Monographs so far, epigenetic data might play a pivotal role in the future. Here, we review (i) the current status of incorporation of epigenetics in carcinogen evaluation in the IARC Monographs Programme, (ii) potential modes of action for epigenetic carcinogens, (iii) current in vivo and in vitro technologies to detect epigenetic carcinogens, (iv) genomic regions and epigenetic modifications and their biological consequences and (v) critical technological and biological issues in assessment of epigenetic carcinogens. We also discuss the issues related to opportunities and challenges in the application of epigenetic testing in carcinogen identification and evaluation. Although the application of epigenetic assays in carcinogen evaluation is still in its infancy, important data are being generated and valuable scientific resources are being established that should catalyse future applications of epigenetic testing. PMID:23749751

Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays.

PubMed

Paini, Alicia; Scholz, Gabriele; Marin-Kuan, Maricel; Schilter, Benoît; O'Brien, John; van Bladeren, Peter J; Rietjens, Ivonne M C M

2011-09-01

This study aimed at quantitatively comparing the occurrence/formation of DNA adducts with the carcinogenicity induced by a selection of DNA-reactive genotoxic carcinogens. Contrary to previous efforts, we used a very uniform set of data, limited to in vivo rat liver studies in order to investigate whether a correlation can be obtained, using a benchmark dose (BMD) approach. Dose-response data on both carcinogenicity and in vivo DNA adduct formation were available for six compounds, i.e. 2-acetylaminofluorene, aflatoxin B1, methyleugenol, safrole, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and tamoxifen. BMD(10) values for liver carcinogenicity were calculated using the US Environmental Protection Agency BMD software. DNA adduct levels at this dose were extrapolated assuming linearity of the DNA adduct dose response. In addition, the levels of DNA adducts at the BMD(10) were compared to available data on endogenous background DNA damage in the target organ. Although for an individual carcinogen the tumour response increases when adduct levels increase, our results demonstrate that when comparing different carcinogens, no quantitative correlation exists between the level of DNA adduct formation and carcinogenicity. These data confirm that the quantity of DNA adducts formed by a DNA-reactive compound is not a carcinogenicity predictor but that other factors such as type of adduct and mutagenic potential may be equally relevant. Moreover, comparison to background DNA damage supports the notion that the mere occurrence of DNA adducts above or below the level of endogenous DNA damage is neither correlated to development of cancer. These data strongly emphasise the need to apply the mode of action framework to understand the contribution of other biological effect markers playing a role in carcinogenicity.

Too many rodent carcinogens: Mitogenesis increases mutagenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ames, B.N.; Gold, L.S.

1990-08-31

A clarification of the mechanism of carcinogenesis is developing at a rapid rate. This new understanding undermines many assumptions of current regulatory policy toward rodent carcinogens and necessitates rethinking the utility and meaning of routine animal cancer tests. At a recent watershed meeting on carcinogenesis, much evidence was presented suggesting that mitogenesis plays a dominant role in carcinogenesis. Our own rethinking of mechanism was prompted by our findings that: spontaneous DNA damage caused by endogenous oxidants is remarkably frequent and in chronic testing at the maximum tolerated dose (MTD), more than half of all chemicals tested (both natural and synthetic)more » are carcinogens in rodents, and a high percentage of these carcinogens are not mutagens.« less

Different carcinogenic process in cholangiocarcinoma cases epidemically developing among workers of a printing company in Japan.

PubMed

Sato, Yasunori; Kubo, Shoji; Takemura, Shigekazu; Sugawara, Yasuhiko; Tanaka, Shogo; Fujikawa, Masahiro; Arimoto, Akira; Harada, Kenichi; Sasaki, Motoko; Nakanuma, Yasuni

2014-01-01

Recently, cholangiocarcinoma has epidemically developed among young adult workers of a printing company in Japan. Exposure to organic solvents including 1,2-dichloropropane and/or dichloromethane is supposed to be associated with the carcinoma development. The metabolism of dichloromethane proceeds through a Theta-class glutathione S-transferase (GST) T1-1-catalyzed pathway, where its reactive intermediates have been implicated in genotoxicity and carcinogenicity. This study examined features of the carcinogenic process of the cholangiocarcinoma developed in the printing company. Surgically resected specimens of the cholangiocarcinoma cases were analyzed, where all cases were associated with precursor lesions such as biliary intraepithelial neoplasia (BilIN) and/or intraductal papillary neoplasm of the bile duct (IPNB). Immunohistochemical analysis confirmed constitutional expression of GST T1-1 in normal hepatobiliary tract. Immunostaining of γ-H2AX, a marker of DNA double strand break, showed that its expression was significantly increased in foci of BilIN, IPNB and invasive carcinoma as well as in non-neoplastic biliary epithelial cells of the printing company cases when compared to that of control groups. In the printing company cases, immunohistochemical expression of p53 was observed in non-neoplastic biliary epithelial cells and BilIN-1. Mutations of KRAS and GNAS were detected in foci of BilIN in one out of 3 cases of the printing company. These results revealed different carcinogenic process of the printing company cases, suggesting that the exposed organic solvents might act as a carcinogen for biliary epithelial cells by causing DNA damage, thereby contributing to the carcinoma development.

Smokeless tobacco: challenges, products and, cessation.

PubMed

Rankin, K Vendrell; Jones, Daniel L; Benton, Elain

2010-06-01

Tobacco companies continue to develop and aggressively market new products for oral use. Most new products are intended to dissolve in the mouth and swallow rather than spit out the juices. These products effectively circumvent smoke-free policies, decrease tobacco cessation efforts, and create individuals who use both smokeless tobacco (ST) and cigarettes. All ST products contain nicotine, carcinogens, and pose multiple health risks. The cancer and health risks associated with ST use extend well beyond the changes in the oral cavity and the risk of oral cancer. Unlike cigarettes, the contents of ST vary widely by brand and product posing difficulty in the use of the available pharmacotherapy for cessation. Although no uniform guidelines exist for the use of pharmacotherapy for smokeless tobacco cessation, research suggests that use of these drugs is effective. The most important motivator for quitting ST cessation remains in the hands of the dentist.

Risk assessment of carcinogens in food

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barlow, Susan, E-mail: suebarlow@mistral.co.u; Schlatter, Josef; Federal Office of Public Health, Consumer Protection Directorate, Stauffacherstrasse 101, CH-8004 Zuerich

2010-03-01

Approaches for the risk assessment of carcinogens in food have evolved as scientific knowledge has advanced. Early methods allowed little more than hazard identification and an indication of carcinogenic potency. Evaluation of the modes of action of carcinogens and their broad division into genotoxic and epigenetic (non-genotoxic, non-DNA reactive) carcinogens have played an increasing role in determining the approach followed and provide possibilities for more detailed risk characterisation, including provision of quantitative estimates of risk. Reliance on experimental animal data for the majority of risk assessments and the fact that human exposures to dietary carcinogens are often orders of magnitudemore » below doses used in experimental studies has provided a fertile ground for discussion and diverging views on the most appropriate way to offer risk assessment advice. Approaches used by national and international bodies differ, with some offering numerical estimates of potential risks to human health, while others express considerable reservations about the validity of quantitative approaches requiring extrapolation of dose-response data below the observed range and instead offer qualitative advice. Recognising that qualitative advice alone does not provide risk managers with information on which to prioritise the need for risk management actions, a 'margin of exposure' approach for substances that are both genotoxic and carcinogenic has been developed, which is now being used by the World Health Organization and the European Food Safety Authority. This review describes the evolution of risk assessment advice on carcinogens and discusses examples of ways in which carcinogens in food have been assessed in Europe.« less

NANOSTRUCTURED POROUS SILICON AND LUMINESCENT POLYSILOLES AS CHEMICAL SENSORS FOR CARCINOGENIC CHROMIUM(VI) AND ARSENIC(V)

EPA Science Inventory

The chief goal is to develop new selective solid state sensors for carcinogenic and toxic chromium(VI) and arsenic(V) in water based on redox quenching of the luminescence from nanostructured porous silicon and polysiloles.

Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations.

PubMed

Vahle, John L; Finch, Gregory L; Heidel, Shawn M; Hovland, David N; Ivens, Inge; Parker, Suezanne; Ponce, Rafael A; Sachs, Clifford; Steigerwalt, Ronald; Short, Brian; Todd, Marque D

2010-06-01

An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling.

CarcinoPred-EL: Novel models for predicting the carcinogenicity of chemicals using molecular fingerprints and ensemble learning methods.

PubMed

Zhang, Li; Ai, Haixin; Chen, Wen; Yin, Zimo; Hu, Huan; Zhu, Junfeng; Zhao, Jian; Zhao, Qi; Liu, Hongsheng

2017-05-18

Carcinogenicity refers to a highly toxic end point of certain chemicals, and has become an important issue in the drug development process. In this study, three novel ensemble classification models, namely Ensemble SVM, Ensemble RF, and Ensemble XGBoost, were developed to predict carcinogenicity of chemicals using seven types of molecular fingerprints and three machine learning methods based on a dataset containing 1003 diverse compounds with rat carcinogenicity. Among these three models, Ensemble XGBoost is found to be the best, giving an average accuracy of 70.1 ± 2.9%, sensitivity of 67.0 ± 5.0%, and specificity of 73.1 ± 4.4% in five-fold cross-validation and an accuracy of 70.0%, sensitivity of 65.2%, and specificity of 76.5% in external validation. In comparison with some recent methods, the ensemble models outperform some machine learning-based approaches and yield equal accuracy and higher specificity but lower sensitivity than rule-based expert systems. It is also found that the ensemble models could be further improved if more data were available. As an application, the ensemble models are employed to discover potential carcinogens in the DrugBank database. The results indicate that the proposed models are helpful in predicting the carcinogenicity of chemicals. A web server called CarcinoPred-EL has been built for these models ( http://ccsipb.lnu.edu.cn/toxicity/CarcinoPred-EL/ ).

Predictive Models for Carcinogenicity and Mutagenicity: Frameworks, State-of-the-Art, and Perspectives

EPA Science Inventory

Mutagenicity and carcinogenicity are endpoints of major environmental and regulatory concern. These endpoints are also important targets for development of alternative methods for screening and prediction due to the large number of chemicals of potential concern and the tremendou...

Predictive Models for Carcinogenicity and Mutagenicity: Frameworks,State-of-the-Art, and Perspectives

EPA Science Inventory

Mutagenicity and carcinogenicity are endpoints of major environmental and regulatory concern. These endpoints are also important targets for development of alternative methods for screening and prediction due to the large number of chemicals of potential concern and the tremendou...

Cancer in Experimental Animals Exposed to Arsenic and Arsenic Compounds

PubMed Central

Tokar, Erik J.; Benbrahim-Tallaa, Lamia; Ward, Jerold M.; Lunn, Ruth; Sams, Reeder L.; Waalkes, Michael P.

2011-01-01

Inorganic arsenic is a ubiquitous environmental contaminant that has long been considered a human carcinogen. Recent studies raise further concern about the metalloid as a major, naturally occurring carcinogen in the environment. However, during this same period it has proven difficult to provide experimental evidence of the carcinogenicity of inorganic arsenic in laboratory animals and, until recently, there was considered to be a lack of clear evidence for carcinogenicity of any arsenical in animals. More recent work with arsenical methylation metabolites and early life exposures to inorganic arsenic has now provided evidence of carcinogenicity in rodents. Given that tens of millions of people worldwide are exposed to potentially unhealthy levels of environmental arsenic, in vivo rodent models of arsenic carcinogenesis are a clear necessity for resolving critical issues, like mechanisms of action, target tissue specificity, and sensitive subpopulations, and in developing strategies to reduce cancers in exposed human populations. This work reviews the available rodent studies considered relevant to carcinogenic assessment of arsenicals, taking advantage of the most recent review by the International Agency for Research on Cancer (IARC) that has not yet appeared as a full monograph but has been summarized (IARC 2009). Many valid studies show that arsenic can interact with other carcinogens/agents to enhance oncogenesis, and help elucidate mechanisms, and these too are summarized in this review. Finally, this body of rodent work is discussed in light of its impact on mechanisms and in the context of the persistent argument that arsenic is not carcinogenic in animals. PMID:20812815

Differences in the Rate of In Situ Mammary Gland Development and Other Developmental Endpoints in Three Strains of Female Rat Commonly Used in Mammary Carcinogenesis Studies: Implications for Timing of Carcinogen Exposure

PubMed Central

Stanko, Jason P.; Kissling, Grace E.; Chappell, Vesna A.; Fenton, Suzanne E.

2016-01-01

The potential of chemicals to alter susceptibility to mammary tumor formation is often assessed using a carcinogen-induced study design in various rat strains. The rate of mammary gland development must be considered so that the timing of carcinogen administration is impactful. In this study, in situ mammary gland (MG) development was assessed in females of the Harlan Sprague Dawley (Hsd:SD), Charles River Sprague Dawley (Crl:SD), and Charles River Long Evans (Crl:LE) rat strains at postnatal day (PND) 25, 33, and 45. Development was evaluated by physical assessment of growth parameters, developmental scoring, and quantitative morphometric analysis. Though body weight was consistently lower and day of vaginal opening (VO) occurred latest in female Hsd:SD rats, they exhibited accelerated pre-and peripubertal MG development compared to other strains. Glands of Crl:SD and Crl:LE rats exhibited significantly more terminal end buds (TEBs) and TEB/mm than Hsd:SD rats around the time of VO. These data suggest a considerable difference in rate of MG development across commonly used strains, which is independent of body weight and timing of VO. In mammary tumor induction studies employing these strains, administration of the carcinogen should be timed appropriately, based on strain, to specifically target the peak of TEB occurrence. PMID:27613105

Mutagenicity testing with transgenic mice. Part II: Comparison with the mouse spot test

PubMed Central

Wahnschaffe, Ulrich; Bitsch, Annette; Kielhorn, Janet; Mangelsdorf, Inge

2005-01-01

The mouse spot test, an in vivo mutation assay, has been used to assess a number of chemicals. It is at present the only in vivo mammalian test system capable of detecting somatic gene mutations according to OECD guidelines (OECD guideline 484). It is however rather insensitive, animal consuming and expensive type of test. More recently several assays using transgenic animals have been developed. From data in the literature, the present study compares the results of in vivo testing of over twenty chemicals using the mouse spot test and compares them with results from the two transgenic mouse models with the best data base available, the lacI model (commercially available as the Big Blue® mouse), and the lacZ model (commercially available as the Muta™ Mouse). There was agreement in the results from the majority of substances. No differences were found in the predictability of the transgenic animal assays and the mouse spot test for carcinogenicity. However, from the limited data available, it seems that the transgenic mouse assay has several advantages over the mouse spot test and may be a suitable test system replacing the mouse spot test for detection of gene but not chromosome mutations in vivo. PMID:15676065

Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action

PubMed Central

Gusenleitner, Daniel; Auerbach, Scott S.; Melia, Tisha; Gómez, Harold F.; Sherr, David H.; Monti, Stefano

2014-01-01

Background Despite an overall decrease in incidence of and mortality from cancer, about 40% of Americans will be diagnosed with the disease in their lifetime, and around 20% will die of it. Current approaches to test carcinogenic chemicals adopt the 2-year rodent bioassay, which is costly and time-consuming. As a result, fewer than 2% of the chemicals on the market have actually been tested. However, evidence accumulated to date suggests that gene expression profiles from model organisms exposed to chemical compounds reflect underlying mechanisms of action, and that these toxicogenomic models could be used in the prediction of chemical carcinogenicity. Results In this study, we used a rat-based microarray dataset from the NTP DrugMatrix Database to test the ability of toxicogenomics to model carcinogenicity. We analyzed 1,221 gene-expression profiles obtained from rats treated with 127 well-characterized compounds, including genotoxic and non-genotoxic carcinogens. We built a classifier that predicts a chemical's carcinogenic potential with an AUC of 0.78, and validated it on an independent dataset from the Japanese Toxicogenomics Project consisting of 2,065 profiles from 72 compounds. Finally, we identified differentially expressed genes associated with chemical carcinogenesis, and developed novel data-driven approaches for the molecular characterization of the response to chemical stressors. Conclusion Here, we validate a toxicogenomic approach to predict carcinogenicity and provide strong evidence that, with a larger set of compounds, we should be able to improve the sensitivity and specificity of the predictions. We found that the prediction of carcinogenicity is tissue-dependent and that the results also confirm and expand upon previous studies implicating DNA damage, the peroxisome proliferator-activated receptor, the aryl hydrocarbon receptor, and regenerative pathology in the response to carcinogen exposure. PMID:25058030

Fluorescence-based recombination assay for sensitive and specific detection of genotoxic carcinogens in human cells.

PubMed

Ireno, Ivanildce C; Baumann, Cindy; Stöber, Regina; Hengstler, Jan G; Wiesmüller, Lisa

2014-05-01

In vitro genotoxicity tests are known to suffer from several shortcomings, mammalian cell-based assays, in particular, from low specificities. Following a novel concept of genotoxicity detection, we developed a fluorescence-based method in living human cells. The assay quantifies DNA recombination events triggered by DNA double-strand breaks and damage-induced replication fork stalling predicted to detect a broad spectrum of genotoxic modes of action. To maximize sensitivities, we engineered a DNA substrate encompassing a chemoresponsive element from the human genome. Using this substrate, we screened various human tumor and non-transformed cell types differing in the DNA damage response, which revealed that detection of genotoxic carcinogens was independent of the p53 status but abrogated by apoptosis. Cell types enabling robust and sensitive genotoxicity detection were selected for the generation of reporter clones with chromosomally integrated DNA recombination substrate. Reporter cell lines were scrutinized with 21 compounds, stratified into five sets according to the established categories for identification of carcinogenic compounds: genotoxic carcinogens ("true positives"), non-genotoxic carcinogens, compounds without genotoxic or carcinogenic effect ("true negatives") and non-carcinogenic compounds, which have been reported to induce chromosomal aberrations or mutations in mammalian cell-based assays ("false positives"). Our results document detection of genotoxic carcinogens in independent cell clones and at levels of cellular toxicities <60 % with a sensitivity of >85 %, specificity of ≥90 % and detection of false-positive compounds <17 %. Importantly, through testing cyclophosphamide in combination with primary hepatocyte cultures, we additionally provide proof-of-concept for the identification of carcinogens requiring metabolic activation using this novel assay system.

MUTAGENICITY AND CARCINOGENICITY ASSESSMENT OF 1,3-BUTADIENE. REVIEW DRAFT

EPA Science Inventory

The Mutagenicity and Carcinogenicity Assessment of 1,3-Butadiene was prepared to serve as a source document for Agency-wide use. In the development of this assessment document, the scientific literature has been inventoried, key studies have been evaluated, and the summary and co...

ARSENIC: CARCINOGENIC MECHANISMS, RISK ASSESSMENT AND THE MAXIMUM CONTAMINANT LEVEL (MCL)

EPA Science Inventory

This workshop will provide an up-to-date overview on key issues related to cancer risk assessment of arsenic: carcinogenic mechanisms; application of mechanistic information to risk assessment models; and the development of the MCL for arsenic in drinking water. The two prese...

New public QSAR model for carcinogenicity

PubMed Central

2010-01-01

Background One of the main goals of the new chemical regulation REACH (Registration, Evaluation and Authorization of Chemicals) is to fulfill the gaps in data concerned with properties of chemicals affecting the human health. (Q)SAR models are accepted as a suitable source of information. The EU funded CAESAR project aimed to develop models for prediction of 5 endpoints for regulatory purposes. Carcinogenicity is one of the endpoints under consideration. Results Models for prediction of carcinogenic potency according to specific requirements of Chemical regulation were developed. The dataset of 805 non-congeneric chemicals extracted from Carcinogenic Potency Database (CPDBAS) was used. Counter Propagation Artificial Neural Network (CP ANN) algorithm was implemented. In the article two alternative models for prediction carcinogenicity are described. The first model employed eight MDL descriptors (model A) and the second one twelve Dragon descriptors (model B). CAESAR's models have been assessed according to the OECD principles for the validation of QSAR. For the model validity we used a wide series of statistical checks. Models A and B yielded accuracy of training set (644 compounds) equal to 91% and 89% correspondingly; the accuracy of the test set (161 compounds) was 73% and 69%, while the specificity was 69% and 61%, respectively. Sensitivity in both cases was equal to 75%. The accuracy of the leave 20% out cross validation for the training set of models A and B was equal to 66% and 62% respectively. To verify if the models perform correctly on new compounds the external validation was carried out. The external test set was composed of 738 compounds. We obtained accuracy of external validation equal to 61.4% and 60.0%, sensitivity 64.0% and 61.8% and specificity equal to 58.9% and 58.4% respectively for models A and B. Conclusion Carcinogenicity is a particularly important endpoint and it is expected that QSAR models will not replace the human experts opinions and conventional methods. However, we believe that combination of several methods will provide useful support to the overall evaluation of carcinogenicity. In present paper models for classification of carcinogenic compounds using MDL and Dragon descriptors were developed. Models could be used to set priorities among chemicals for further testing. The models at the CAESAR site were implemented in java and are publicly accessible. PMID:20678182

Parasite Infection, Carcinogenesis and Human Malignancy.

PubMed

van Tong, Hoang; Brindley, Paul J; Meyer, Christian G; Velavan, Thirumalaisamy P

2017-02-01

Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Cytogenetic insights into DNA damage and repair of lesions induced by a monomethylated trivalent arsenical

EPA Science Inventory

Arsenic is a human carcinogen, and only recently have animal models been developed that are useful in investigating its carcinogenic mode ofaction (MOA). However, how arsenic induces cancer is still an open question. In a previous paper, we proposed a model detailing how arsenic ...

GENE EXPRESSION PROFILING OF RESPONSES TO DIMETHYLARSINIC ACID IN FEMALE F344 RAT UROTHELIUM

EPA Science Inventory

Arsenic is a human carcinogen and epidemiologic evidence implicates it in the development of urinary bladder cancer. Even though several mechanisms have been proposed for arsenic carcinogenicity, the mode of action of inorganic arsenic (iAs) is confounded by the limited availabil...

[Hygienic assessment of carcinogenic and noncarcinogenic risks of oral intake of drinking water chemical agents].

PubMed

Ignat'eva, L P; Pogorelova, I G; Potapova, M O

2006-01-01

Based on the quantitative and qualitative determination of drinking water pollution by a large number of substances of varying toxicity and hazard, the authors calculated a possible risks of their adverse impact on the body by the development of carcinogenic and noncarcinogenic effects.

Application of Toxicogenomics to Develop a Mode of Action for a Carcinogenic Conazole Fungicide

EPA Science Inventory

Conazoles are a common class of fungicides used to control fungal growth in the environment and in humans. Some of these agents have adverse toxicological outcomes in mammals as carcinogens, reproductive toxins, and hepatotoxins. We coupled the results from genomic analyses with ...

Final Report from the External Peer Review of the IRIS Reassessment of the Inhalation Carcinogenicity of Naphthalene

EPA Science Inventory

This document is the final report for the 2004 external peer review for the EPA IRIS Reassessment of the Inhalation Carcinogenicity of Naphthalene, prepared by the Office of Research and Development's National Center for Environmental Assessment (NCEA), for the Integrated ...

An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether (Egbe)

EPA Science Inventory

This position paper, An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether, was developed in support of the EPA's evaluation of a petition from the American Chemistry Council requesting to delist EGBE per the Clean Air Act Amendments (CAAA), Titl...

Greek employee awareness of carcinogenic exposure.

PubMed

Chatzis, Christos; Karvounis, Kiki; Hatziara, Panayiota; Riza, Elena; Nikolaou, Vasilis; Linos, Athena

2004-10-01

Occupational risk factors contribute significantly to the development of lung cancer; however, little is known about the extent to which employees are informed of occupational exposure to carcinogenic substances. Through a case-control study, we estimated the level of awareness among Greek employees potentially exposed to known carcinogenic substances within various occupational settings. Only 6.6% of men (n = 482) employed in occupations with potential exposure to carcinogenic substances were aware of such occupational exposures. Age, education, and residence were significantly associated with awareness. Employees having at least a secondary level of education were 3.5 times more aware than those having at most 6 years of educational training. Assessing awareness among workers potentially exposed to occupational risk factors and promoting occupational health education are important steps for increasing health and safety at the workplace.

Emissions and efficiency performance of industrial-coal-stoker fired boilers: inorganic trace elements and polynuclear aromatic hydrocarbon emissions. Volume 2. [74 inorganic trace elements and 21 polycyclic aromatic hydrocarbons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1981-08-01

This report presents the results of tests for polynuclear aromatic hydrocarbons (PAH) and inorganic trace elements in the effluent of eleven coal stoker fired boilers. These data are part of a larger stoker test program whose main objective was to produce information which will increase the ability of the boiler manufacturers to design and fabricate stoker boilers that are an economical and environmentally satisfactory alternative to oil and gas-fired units. The objectives of the SASS testing portion of this program are to determine the organic and inorganic makeup of boiler emissions which cannot be detected by using the standard EPAmore » Method 5 train. SASS tests were conducted in accordance with EPA Level 1 guidelines. Twenty-three SASS tests were run on 11 different coal stoker fired boilers to determine emissions data for 74 inorganic trace elements and 21 PAHs. The emissions of most concern are the suspected carcinogens or the emissions with high probability of being carcinogens. The inorganic trace elements that were investigated and are listed as carcinogens and high probability carcinogens by the Office of Air Quality Planning and Standards are: arsenic, beryllium, cadmium, and nickel. The SASS emissions data are presented in three different sets of units: nonograms per joule of energy input, micrograms per dry standard cubic meter of flue gas sampled, and grams per kilograms of fuel input. To protect the interests of the host boiler facilities, each site has been given a letter designation. A complete description of each unit and all tests run at each site can be found in the corresponding site reports referenced at the end of this report. This report contains a description of the test equipment and procedures, analytical procedures, data reduction techniques, the test data, and a brief description of each facility tested and the coals fired. 4 figures, 16 tables.« less

Occurrence, sources, and potential human health risks of polycyclic aromatic hydrocarbons in agricultural soils of the coal production area surrounding Xinzhou, China.

PubMed

Zhao, Long; Hou, Hong; Shangguan, Yuxian; Cheng, Bin; Xu, Yafei; Zhao, Ruifen; Zhang, Yigong; Hua, Xiaozan; Huo, Xiaolan; Zhao, Xiufeng

2014-10-01

A comprehensive investigation of the levels, distribution patterns, and sources of polycyclic aromatic hydrocarbons (PAHs) in agricultural soils of the coal production area surrounding Xinzhou, China, was conducted, and the potential human health risks associated with the levels observed were addressed. A total of 247 samples collected from agricultural soils from the area were analyzed for sixteen PAHs, including highly carcinogenic isomers. The PAH concentrations had a range of n.d. to 782ngg(-1), with a mean value of 202ngg(-1). The two-three ring PAHs were the dominant species, making up 60 percent of total PAHs. Compared with the pollution levels and carcinogenic potential risks reported in other studies, the soil PAH concentrations in the study area were in the low to intermediate range. A positive matrix factorization model indicates that coal/biomass combustion, coal and oil combustion, and coke ovens are the primary PAH sources, accounting for 33 percent, 26 percent, and 24 percent of total PAHs, respectively. The benzo[a]pyrene equivalent (BaPeq) concentrations had a range of n.d. to 476ngg(-1) for PAH7c, with a mean value of 34ngg(-1). The BaPeq concentrations of PAH7c accounted for more than 99 percent of the ∑PAH16, which suggests that seven PAHs were major carcinogenic contributors of ∑PAH16. According to the Canadian Soil Quality Guidelines, only six of the soil samples had concentrations above the safe BaPeq value of 600ngg(-1); the elevated concentrations observed at these sites can be attributed to coal combustion and industrial activities. Exposure to these soils through direct contact probably poses a significant risk to human health as a result of the carcinogenic effects of PAHs. Copyright © 2014 Elsevier Inc. All rights reserved.

Transgenic and gene knockout mice in gastric cancer research

PubMed Central

Jiang, Yannan; Yu, Yingyan

2017-01-01

Mouse models are useful tool for carcinogenic study. They will greatly enrich the understanding of pathogenesis and molecular mechanisms for gastric cancer. However, only few of mice could develop gastric cancer spontaneously. With the development and improvement of gene transfer technology, investigators created a variety of transgenic and knockout/knockin mouse models of gastric cancer, such as INS-GAS mice and gastrin knockout mice. Combined with helicobacter infection and carcinogens treatment, these transgenic/knockout/knockin mice developed precancerous or cancerous lesions, which are proper for gene function study or experimental therapy. Here we review the progression of genetically engineered mouse models on gastric cancer research, and emphasize the effects of chemical carcinogens or infectious factors on carcinogenesis of genetically modified mouse. We also emphasize the histological examination on mouse stomach. We expect to provide researchers with some inspirations on this field. PMID:27713138

RENAL CARCINOGENICITY OF INDIVIDUAL AND A MIXTURE OF DRINKING WATER DISINFECTION BY-PRODUCTS (DBP) IN EKER RATS

EPA Science Inventory

RENAL CARCINOGENICITY OF INDIVIDUAL AND A MIXTURE OF DRINKING / WATER DISINFECTION BY -PRODUCTS (DBP) IN EKER RATS.

Eker rats develop hereditary renal cell carcinoma secondary to a germline mutation in the tuberous sclerosis 2 tumor suppressor gene, and are highly suscepti...

An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether (An Interim Position Paper)

EPA Science Inventory

To determine the merit of a petition to remove ethylene glycol ether (EGBE) from the Agency's Hazardous Air Pollutant (HAP) list, EPA has developed an interim final position paper, called An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether, tha...

AGE-RELATED DIFFERENCES IN SUSCEPTIBILITY TO CARCINOGENESIS II, APPROACHES FOR APPLICATION AND UNCERTAINTY ANALYSES FOR INDIVIDUAL GENETICALLY ACTING CARCINOGENS

EPA Science Inventory

An earlier paper (Hattis et al., 2003) developed a quantitative likelihood-based statistical analysis of the differences in apparent sensitivity of rodents to mutagenic carcinogens across three life stages (fetal, birth-weaning, and weaning-60 days) relative to exposures in adult...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yusuf, Nabiha; Skin Diseases Research Center, University of Alabama at Birmingham, 1530 Third Avenue South, Birmingham, AL 35294-0009; Timares, Laura

Polyaromatic hydrocarbons are ubiquitous environmental pollutants that are potent mutagens and carcinogens. Researchers have taken advantage of these properties to investigate the mechanisms by which chemicals cause cancer of the skin and other organs. When applied to the skin of mice, several carcinogenic polyaromatic hydrocarbons have also been shown to interact with the immune system, stimulating immune responses and resulting in the development of antigen-specific T-cell-mediated immunity. Development of cell-mediated immunity is strain-specific and is governed by Ah receptor genes and by genes located within the major histocompatibility complex. CD8{sup +} T cells are effector cells in the response, whereasmore » CD4{sup +} T cells down-regulate immunity. Development of an immune response appears to have a protective effect since strains of mice that develop a cell-mediated immune response to carcinogenic polyaromatic hydrocarbons are less likely to develop tumors when subjected to a polyaromatic hydrocarbon skin carcinogenesis protocol than mice that fail to develop an immune response. With respect to innate immunity, TLR4-deficient C3H/HeJ mice are more susceptible to polyaromatic hydrogen skin tumorigenesis than C3H/HeN mice in which TLR4 is normal. These findings support the hypothesis that immune responses, through their interactions with chemical carcinogens, play an active role in the prevention of chemical skin carcinogenesis during the earliest stages. Efforts to augment immune responses to the chemicals that cause tumors may be a productive approach to the prevention of tumors caused by these agents.« less

A current global view of environmental and occupational cancers.

PubMed

Yang, Mihi

2011-07-01

This review is focused on current information of avoidable environmental pollution and occupational exposure as causes of cancer. Approximately 2% to 8% of all cancers are thought to be due to occupation. In addition, occupational and environmental cancers have their own characteristics, e.g., specific chemicals and cancers, multiple factors, multiple causation and interaction, or latency period. Concerning carcinogens, asbestos/silica/wood dust, soot/polycyclic aromatic hydrocarbons [benzo(a) pyrene], heavy metals (arsenic, chromium, nickel), aromatic amines (4-aminobiphenyl, benzidine), organic solvents (benzene or vinyl chloride), radiation/radon, or indoor pollutants (formaldehyde, tobacco smoking) are mentioned with their specific cancers, e.g., lung, skin, and bladder cancers, mesothelioma or leukemia, and exposure routes, rubber or pigment manufacturing, textile, painting, insulation, mining, and so on. In addition, nanoparticles, electromagnetic waves, and climate changes are suspected as future carcinogenic sources. Moreover, the aspects of environmental and occupational cancers are quite different between developing and developed countries. The recent follow-up of occupational cancers in Nordic countries shows a good example for developed countries. On the other hand, newly industrializing countries face an increased burden of occupational and environmental cancers. Developing countries are particularly suffering from preventable cancers in mining, agriculture, or industries without proper implication of safety regulations. Therefore, industrialized countries are expected to educate and provide support for developing countries. In addition, citizens can encounter new environmental and occupational carcinogen nominators such as nanomaterials, electromagnetic wave, and climate exchanges. As their carcinogenicity or involvement in carcinogenesis is not clearly unknown, proper consideration for them should be taken into account. For these purposes, new technologies with a balance of environment and gene are required. Currently, various approaches with advanced technologies--genomics, exposomics, etc.--have accelerated development of new biomarkers for biological monitoring of occupational and environmental carcinogens. These advanced approaches are promising to improve quality of life and to prevent occupational and environmental cancers.

Mammalian models of chemically induced primary malignancies exploitable for imaging-based preclinical theragnostic research

PubMed Central

Liu, Yewei; Yin, Ting; Feng, Yuanbo; Cona, Marlein Miranda; Huang, Gang; Liu, Jianjun; Song, Shaoli; Jiang, Yansheng; Xia, Qian; Swinnen, Johannes V.; Bormans, Guy; Himmelreich, Uwe; Oyen, Raymond

2015-01-01

Compared with transplanted tumor models or genetically engineered cancer models, chemically induced primary malignancies in experimental animals can mimic the clinical cancer progress from the early stage on. Cancer caused by chemical carcinogens generally develops through three phases namely initiation, promotion and progression. Based on different mechanisms, chemical carcinogens can be divided into genotoxic and non-genotoxic ones, or complete and incomplete ones, usually with an organ-specific property. Chemical carcinogens can be classified upon their origins such as environmental pollutants, cooked meat derived carcinogens, N-nitroso compounds, food additives, antineoplastic agents, naturally occurring substances and synthetic carcinogens, etc. Carcinogen-induced models of primary cancers can be used to evaluate the diagnostic/therapeutic effects of candidate drugs, investigate the biological influential factors, explore preventive measures for carcinogenicity, and better understand molecular mechanisms involved in tumor initiation, promotion and progression. Among commonly adopted cancer models, chemically induced primary malignancies in mammals have several advantages including the easy procedures, fruitful tumor generation and high analogy to clinical human primary cancers. However, in addition to the time-consuming process, the major drawback of chemical carcinogenesis for translational research is the difficulty in noninvasive tumor burden assessment in small animals. Like human cancers, tumors occur unpredictably also among animals in terms of timing, location and the number of lesions. Thanks to the availability of magnetic resonance imaging (MRI) with various advantages such as ionizing-free scanning, superb soft tissue contrast, multi-parametric information, and utility of diverse contrast agents, now a workable solution to this bottleneck problem is to apply MRI for noninvasive detection, diagnosis and therapeutic monitoring on those otherwise uncontrollable animal models with primary cancers. Moreover, it is foreseeable that the combined use of chemically induced primary cancer models and molecular imaging techniques may help to develop new anticancer diagnostics and therapeutics. PMID:26682141

Contributions of Human Enzymes in Carcinogen Metabolism

PubMed Central

Rendic, Slobodan; Guengerich, F. Peter

2012-01-01

Considerable support exists for roles of metabolism in modulating the carcinogenic properties of chemicals. In particular, many of these compounds are procarcinogens that require activation to electrophilic forms to exert genotoxic effects. We systematically analyzed the existing literature on metabolism of carcinogens by human enzymes, which has been developed largely in the past 25 years. The metabolism and especially bioactivation of carcinogens are dominated by cytochrome P450 enzymes (66% of bioactivations). Within this group, six P450s—1A1, 1A2, 1B1, 2A6, 2E1, and 3A4—accounted for 77% of the P450 activation reactions. The roles of these P450s can be compared with those estimated for drug metabolism and should be considered in issues involving enzyme induction, chemoprevention, molecular epidemiology, inter-individual variations, and risk assessment. PMID:22531028

Synergism of herpes simplex virus and tobacco-specific N'-nitrosamines in cell transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, N.H.; Dokko, H.; Li, S.L.

1991-03-01

Previous studies indicate that herpes simplex virus (HSV) enhances the carcinogenic activity of smokeless tobacco and tobacco-related chemical carcinogens in animals. Since tobacco-specific N'-nitrosamines (TSNAs) such as N'-nitrosonornicotine (NNN) and 4-(N-methyl-N'-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are major chemical carcinogens of smokeless tobacco and are known to be responsible for the development of oral cancers in smokeless tobacco users, the combined effects of TSNAs and HSV in cell transformation were investigated. Exposure of cells to NNN or NNK followed by virus infection resulted in a significant enhancement of transformation frequency when compared with that observed with chemical carcinogens or virus alone. This study suggestsmore » that TSNAs and HSV can interact together and show synergism in cell transformation.« less

Modulation of carcinogen bioavailability by immunisation with benzo[a]pyrene-conjugate vaccines.

PubMed

Grova, Nathalie; Prodhomme, Emmanuel J F; Schellenberger, Mario T; Farinelle, Sophie; Muller, Claude P

2009-06-24

Benzo[a]pyrene (B[a]P) conjugate vaccines based on ovalbumin, tetanus toxoid and diphtheria toxoid (DT) as carrier proteins were developed to investigate the effect of specific antibodies on the bioavailability of this ubiquitous carcinogen and its metabolites. After metabolic activation of this prototype carcinogen, B[a]P forms DNA adducts which initiate chemical carcinogenesis. B[a]P-DT conjugate induced the most robust immune response. The antibodies reacted not only with B[a]P but also with the proximate carcinogen 7,8-diol-B[a]P. Antibodies modulated the bioavailability of B[a]P and its metabolic activation in a dose-dependent manner by sequestration in the blood. Our results showed that this immune prophylactic strategy influences the pharmacokinetic of B[a]P and further studies to investigate their effects on chemical carcinogenesis are warranted.

An Evaluation of the Human Carcinogenic Potential of ...

EPA Pesticide Factsheets

This position paper, An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether, was developed in support of the EPA's evaluation of a petition from the American Chemistry Council requesting to delist EGBE per the Clean Air Act Amendments (CAAA), Title III, section 112(b)(1). The position paper was a key component of the Agency's recent determination to grant this petition. It will also be used in the Agency's IRIS assessment of ethylene glycol butyl ether (EGBE). An NTP (1998; 2000) study has reported some evidence of carcinogenic activity in male B6C3F1 mice based on increased incidence of hemangiosarcomas of the liver, and some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidence of forestomach squamous cell papillomas or carcinomas.

A computational method for the identification of new candidate carcinogenic and non-carcinogenic chemicals.

PubMed

Chen, Lei; Chu, Chen; Lu, Jing; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong

2015-09-01

Cancer is one of the leading causes of human death. Based on current knowledge, one of the causes of cancer is exposure to toxic chemical compounds, including radioactive compounds, dioxin, and arsenic. The identification of new carcinogenic chemicals may warn us of potential danger and help to identify new ways to prevent cancer. In this study, a computational method was proposed to identify potential carcinogenic chemicals, as well as non-carcinogenic chemicals. According to the current validated carcinogenic and non-carcinogenic chemicals from the CPDB (Carcinogenic Potency Database), the candidate chemicals were searched in a weighted chemical network constructed according to chemical-chemical interactions. Then, the obtained candidate chemicals were further selected by a randomization test and information on chemical interactions and structures. The analyses identified several candidate carcinogenic chemicals, while those candidates identified as non-carcinogenic were supported by a literature search. In addition, several candidate carcinogenic/non-carcinogenic chemicals exhibit structural dissimilarity with validated carcinogenic/non-carcinogenic chemicals.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laulicht, Freda; Brocato, Jason; Cartularo, Laura

Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten (W), remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. Here, for the first time, we demonstrate tungsten's ability to induce carcinogenic related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer-related pathways in transformed clones as determined by RNA sequencing. Human bronchial epithelial cell line (Beas-2B) exposed to tungsten developed carcinogenic properties. Inmore » a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA-sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. Taken together, our data show the carcinogenic potential of tungsten. Further tests are needed, including in vivo and human studies, in order to validate tungsten as a carcinogen to humans. - Highlights: • Tungsten (W) induces cell transformation and increases migration in vitro. • W increases xenograft growth in nude mice. • W altered the expression of cancer-related genes such as those involved in leukemia. • Some of the dysregulated leukemia genes include, CD74, CTGF, MST4, and HOXB5. • For the first time, data is presented that demonstrates tungsten's carcinogenic potential.« less

Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard.

PubMed

Rusyn, Ivan; Chiu, Weihsueh A; Lash, Lawrence H; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z

2014-01-01

The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. © 2013.

Trichloroethylene: Mechanistic, Epidemiologic and Other Supporting Evidence of Carcinogenic Hazard

PubMed Central

Rusyn, Ivan; Chiu, Weihsueh A.; Lash, Lawrence H.; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z.

2013-01-01

The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including from hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. Strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin's lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. PMID:23973663

CAREX Canada: an enhanced model for assessing occupational carcinogen exposure

PubMed Central

Peters, Cheryl E; Ge, Calvin B; Hall, Amy L; Davies, Hugh W; Demers, Paul A

2015-01-01

Objectives To estimate the numbers of workers exposed to known and suspected occupational carcinogens in Canada, building on the methods of CARcinogen EXposure (CAREX) projects in the European Union (EU). Methods CAREX Canada consists of estimates of the prevalence and level of exposure to occupational carcinogens. CAREX Canada includes occupational agents evaluated by the International Agency for Research on Cancer as known, probable or possible human carcinogens that were present and feasible to assess in Canadian workplaces. A Canadian Workplace Exposure Database was established to identify the potential for exposure in particular industries and occupations, and to create exposure level estimates among priority agents, where possible. CAREX EU data were reviewed for relevance to the Canadian context and the proportion of workers likely to be exposed by industry and occupation in Canada was assigned using expert assessment and agreement by a minimum of two occupational hygienists. These proportions were used to generate prevalence estimates by linkage with the Census of Population for 2006, and these estimates are available by industry, occupation, sex and province. Results CAREX Canada estimated the number of workers exposed to 44 known, probable and suspected carcinogens. Estimates of levels of exposure were further developed for 18 priority agents. Common exposures included night shift work (1.9 million exposed), solar ultraviolet radiation exposure (1.5 million exposed) and diesel engine exhaust (781 000 exposed). Conclusions A substantial proportion of Canadian workers are exposed to known and suspected carcinogens at work. PMID:24969047

Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium

PubMed Central

Thompson, Chad M.; Haws, Laurie C.; Harris, Mark A.; Gatto, Nicole M.; Proctor, Deborah M.

2011-01-01

Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment. Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models. An MOA analysis, consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment, was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium (Cr(VI)) in drinking water. Based on review of the literature, key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, direct and/or indirect DNA modification, and mutagenesis. Although available data generally support the plausibility of these key events, several unresolved questions and data gaps were identified, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range. Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species. This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment. PMID:20947717

Beryllium Laboratory Analysis--The Regulations May Drive the Science

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taruru, Seuri K

Beryllium has many industry-specific applications, such as medical X-ray windows for diagnostic equipment, nuclear reactors, aerospace applications, precision instrumentation, and other consumer products for which lightness and rigidity is essential. According to the National Toxicology Program, beryllium oxide (BeO) is one of the most significant beryllium compounds in production. Although beryllium and its compounds have a wide array of beneficial uses, due to its unique properties it is not an ideal metal to be used in all situations. Exposure to beryllium is linked to beryllium sensitization and Chronic Beryllium Disease (CBD), which is incurable, debilitating, and potentially fatal. The Internationalmore » Agency for Research on Cancer classifies beryllium and beryllium compounds as “carcinogenic to humans” (Group I), and EPA classifies beryllium as a likely human carcinogen, the lung being the primary target organ. Laboratory analysis for beryllium samples has always presented a challenge to the analytical community. While most metals of interest to industrial hygienists have occupational exposure limits (OELs) in milligrams per cubic meter (mg/m 3), the beryllium OELs are in micrograms per cubic meter (μg/m3). Some regulatory agencies have recently published beryllium OELs so low that in some cases a laboratory limit of detection (LOD) in nanograms (ng) is required. For most substances, science drives the regulations, but for beryllium, regulations appear to be driving science to develop laboratory analytical methods that can adequately support the proposed OELs. (EPA has issued guidelines regarding ambient and community airborne beryllium exposure, but this article focuses on beryllium from an occupational exposure perspective.)« less

Beryllium Laboratory Analysis--The Regulations May Drive the Science

DOE PAGES

Taruru, Seuri K

2017-08-01

Beryllium has many industry-specific applications, such as medical X-ray windows for diagnostic equipment, nuclear reactors, aerospace applications, precision instrumentation, and other consumer products for which lightness and rigidity is essential. According to the National Toxicology Program, beryllium oxide (BeO) is one of the most significant beryllium compounds in production. Although beryllium and its compounds have a wide array of beneficial uses, due to its unique properties it is not an ideal metal to be used in all situations. Exposure to beryllium is linked to beryllium sensitization and Chronic Beryllium Disease (CBD), which is incurable, debilitating, and potentially fatal. The Internationalmore » Agency for Research on Cancer classifies beryllium and beryllium compounds as “carcinogenic to humans” (Group I), and EPA classifies beryllium as a likely human carcinogen, the lung being the primary target organ. Laboratory analysis for beryllium samples has always presented a challenge to the analytical community. While most metals of interest to industrial hygienists have occupational exposure limits (OELs) in milligrams per cubic meter (mg/m 3), the beryllium OELs are in micrograms per cubic meter (μg/m3). Some regulatory agencies have recently published beryllium OELs so low that in some cases a laboratory limit of detection (LOD) in nanograms (ng) is required. For most substances, science drives the regulations, but for beryllium, regulations appear to be driving science to develop laboratory analytical methods that can adequately support the proposed OELs. (EPA has issued guidelines regarding ambient and community airborne beryllium exposure, but this article focuses on beryllium from an occupational exposure perspective.)« less

Ozonation of mutagenic and carcinogenic polyaromatic amines and polyaromatic hydrocarbons in water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burleson, G.R.; Caulfield, M.J.; Pollard, M.

1979-06-01

The Salmonella-microsome assay for mutagenesis was used to determine the effect of ozone on the mutagenesis of selected carcinogens and mutagens in water. Short periods of ozonation were shown to completely inactivate the mutagenicity of several polyaromatic amine mutagens including acriflavine, proflavine, and beta-naphthylamine. Selected polyaromatic hydrocarbons were also sensitive to ozonation. Kinetic studies revealed that the mutagenicity of benzo(a)pyrene, 3-methylcholanthrene, and 7,12-dimethylbenz(a)anthracene was destroyed after short periods of ozonation. To correlate loss of mutagenicity with loss of carcinogenicity, two polyaromatic hydrocarbons were treated with ozone, extracted from water with hexane, and tested for carcinogenicity in mice. When 7,12-dimethyl-benz(a)anthracene andmore » 3-methyl-cholanthrene were treated with ozone, there was a substantial reduction in carcinogenicity compared to control groups treated with oxygen alone. However, a small number of tumors developed in the group of animals receiving a hexane extract of ozonated 7,12-dimethylbenz(a)anthracene. This activity may be due to breakdown products of 7,12-dimethylbenz(a)anthracene that are not mutagenic.« less

Estimation of environment-related properties of chemicals for design of sustainable processes: development of group-contribution+ (GC+) property models and uncertainty analysis.

PubMed

Hukkerikar, Amol Shivajirao; Kalakul, Sawitree; Sarup, Bent; Young, Douglas M; Sin, Gürkan; Gani, Rafiqul

2012-11-26

The aim of this work is to develop group-contribution(+) (GC(+)) method (combined group-contribution (GC) method and atom connectivity index (CI) method) based property models to provide reliable estimations of environment-related properties of organic chemicals together with uncertainties of estimated property values. For this purpose, a systematic methodology for property modeling and uncertainty analysis is used. The methodology includes a parameter estimation step to determine parameters of property models and an uncertainty analysis step to establish statistical information about the quality of parameter estimation, such as the parameter covariance, the standard errors in predicted properties, and the confidence intervals. For parameter estimation, large data sets of experimentally measured property values of a wide range of chemicals (hydrocarbons, oxygenated chemicals, nitrogenated chemicals, poly functional chemicals, etc.) taken from the database of the US Environmental Protection Agency (EPA) and from the database of USEtox is used. For property modeling and uncertainty analysis, the Marrero and Gani GC method and atom connectivity index method have been considered. In total, 22 environment-related properties, which include the fathead minnow 96-h LC(50), Daphnia magna 48-h LC(50), oral rat LD(50), aqueous solubility, bioconcentration factor, permissible exposure limit (OSHA-TWA), photochemical oxidation potential, global warming potential, ozone depletion potential, acidification potential, emission to urban air (carcinogenic and noncarcinogenic), emission to continental rural air (carcinogenic and noncarcinogenic), emission to continental fresh water (carcinogenic and noncarcinogenic), emission to continental seawater (carcinogenic and noncarcinogenic), emission to continental natural soil (carcinogenic and noncarcinogenic), and emission to continental agricultural soil (carcinogenic and noncarcinogenic) have been modeled and analyzed. The application of the developed property models for the estimation of environment-related properties and uncertainties of the estimated property values is highlighted through an illustrative example. The developed property models provide reliable estimates of environment-related properties needed to perform process synthesis, design, and analysis of sustainable chemical processes and allow one to evaluate the effect of uncertainties of estimated property values on the calculated performance of processes giving useful insights into quality and reliability of the design of sustainable processes.

Development of human cell models for assessing the carcinogenic potential of chemicals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pang Yaqin; Li Wenxue; Ma Rulin

2008-11-01

To develop human cell models for assessing the carcinogenic potential of chemicals, we established transgenic human cell lines and tested the sensitivity of known carcinogens using a cell transformation assay. A retroviral vector encoding an oncogenic allele of H-Ras (HBER) or c-Myc (HBEM) was introduced into human bronchial epithelial cells (HBE) immortalized by SV40 large T (LT) antigen, leading to increased cell proliferation but failing to confer a transformed phenotype characterized by anchorage-independent cell growth and tumor formation of immunodeficient mice. When these pre-transformed cells were treated with nickel sulfate (NiSO{sub 4}), we found that it shortened the latency ofmore » malignant transformation at least by 19 wk in HBER cells or 16 wk in HBEM cells compared to vector control cells. Similarly, the latency of cell transformation was shorter by 15 wk in HBER cells or 9 wk in HBEM cells when cells were treated with benzo(a)pyrenediol epoxide (BPDE). HBER cells appeared to be more sensitive to TPA, NiSO{sub 4} or BPDE-induced cell transformation compared to human embryonic kidney cells expressing H-Ras (HEKR), implying that cell-type specificity is one of important factors determining the effectiveness of the assay. Using AFB{sub 1} and BaP as the representative pro-carcinogens, we also compared the efficiency of three different metabolic conditions in mediating cell transformation. Low dose chemical induction seems to be a prospective system used for metabolic activation of pro-carcinogens. Our findings provided direct evidence that a genetically modified human cell transformation model can be applied to the assessment of potent carcinogens.« less

A study of tobacco carcinogenesis XLVIII. Carcinogenicity of N'-nitrosonornicotine in mink (Mustela vison).

PubMed

Koppang, N; Rivenson, A; Reith, A; Dahle, H K; Evensen, O; Hoffmann, D

1992-11-01

During tobacco processing and smoking, nicotine and nornicotine give rise to N'-nitrosonornicotine (NNN), a highly abundant, strong carcinogen. NNN is known to exert carcinogenic activity in mice, rats and hamsters. Major target organs for NNN carcinogenicity in the rat are the esophagus and the nasal mucosa, and in the Syrian golden hamster trachea and nasal mucosa. In comparison with the rat, the mink (Mustela vison) has a markedly expanded nasal mucosa. Therefore, we explored in this study whether the mink could serve as a non-rodent model for nasal carcinogenesis using NNN as the carcinogen. Twenty random-bred mink, beginning at the age of 3 weeks, received twice weekly s.c. injections of NNN, a total dose of 11.9 mM per animal over a 38 week period. All of the 19 mink at risk developed malignant tumors of both the respiratory and the olfactory region of the nose within 3.5 years. In most animals the malignant tumors, primarily esthesioneuroepithelioma, invaded the brain. Remarkably, NNN induced no other tumors in the mink. None of the control animals developed nasal tumors nor tumors at other sites during the 3.5 years of the assay. The historical data from the farm did not reveal any spontaneous occurrence of nasal tumors in mink at any age. This study supports the concept that NNN is a proven carcinogen for multiple species of mammals and that the mink can serve as a non-rodent, non-inbred animal model for nasal carcinogenesis, especially since NNN induces only tumors in the nasal cavity in this species and not at other sites, as it does in mice, rats and hamsters.

Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brink, Willem van den; Emerenciana, Annette

Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinearmore » mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2 years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. - Highlights: • An integrative PKPD model is applied to study GLP-1r agonist carcinogenicity. • C-cell carcinogenicity is impacted by both pharmacokinetics and pharmacodynamics. • The relation of GLP-1r stimulation and C-cell hyperplasia appears drug-independent. • Understanding carcinogenic risk needs a pharmacological basis.« less

CARCINOGENICITY OF INDIVIDUAL AND A MIXTURE OF DRINKING WATER DISINFECTION BY-PRODUCTS IN A RAT MODEL OF HEREDITARY RENAL CELL CARCINOMA

EPA Science Inventory

Carcinogenicity of Individual and a Mixture of Drinking Water Disinfection By-Products in a Rat Model of Hereditary Renal Cell Carcinoma

Eker rats develop hereditary renal cell carcinoma secondary to a germline mutation in the tuberous sclerosis 2 (Tsc2) gene and are ligh...

Risk assessment of low-level chemical exposures from consumer products under the U.S. Consumer Product Safety Commission chronic hazard guidelines.

PubMed Central

Babich, M A

1998-01-01

The U.S. Consumer Product Safety Commission (CPSC) is an independent regulatory agency that was created in 1973. The CPSC has jurisdiction over more the 15,000 types of consumer products used in and around the home or by children, except items such as food, drugs, cosmetics, medical devices, pesticides, certain radioactive materials, products that emit radiation (e.g., microwave ovens), and automobiles. The CPSC has investigated many low-level exposures from consumer products, including formaldehyde emissions from urea-formaldehyde foam insulation and pressed wood products, CO and NO2 emmissions from combustion appliances, and dioxin in paper products. Many chemical hazards are addressed under the Federal Hazardous Substances Act (FHSA), which applies to acute and chronic health effects resulting from high- or low-level exposures. In 1992 the Commission issued guidelines for assessing chronic hazards under the FHSA, including carcinogenicity, neurotoxicity, reproductive/developmental toxicity, exposure, bioavailability, risk assessment, and acceptable risk. The chronic hazard guidelines describe a series of default assumptions, which are used in the absence of evidence to the contrary. However, the guidelines are intended to be sufficiently flexible to incorporate the latest scientific information. The use of alternative procedures is permissible, on a case-by-case basis, provided that the procedures used are scientifically defensible and supported by appropriate data. The application of the chronic hazard guidelines in assessing the risks from low-level exposures is discussed. PMID:9539035

Epidemiologic characteristics of compensated occupational lung cancers among Korean workers.

PubMed

Ahn, Yeon-Soon; Jeong, Kyoung Sook

2014-11-01

An understanding of the characteristics of occupational lung cancer is important to establish policies that prevent carcinogen exposure and to compensate workers exposed to lung carcinogens. This study analyzed the characteristics of occupational lung cancers in workers who were compensated under the Industrial Accident Compensation Insurance Law between 1994 and 2011. A total of 179 occupational lung cancers were compensated. The main carcinogenic exposure was asbestos, followed by crystalline silica and hexavalent chromium. The mean exposure duration and latency were 19.8 and 23.2 yr. The most common industry was manufacturing, followed by construction and transportation. The most common occupation was maintenance and repair, followed by foundry work, welding, painting, and spinning or weaving. Although asbestos was predominant carcinogen, the proportion of these cases was relatively low compared to other developed countries. Proper surveillance system is needed to monitor occupational lung cancer and improve prevention measures.

Indoor air - assessment: Methods of analysis for environmental carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peterson, M.R.; Naugle, D.F.; Berry, M.A.

1990-06-01

The monograph describes, in a general way, published sampling procedures and analytical approaches for known and suspected carcinogens. The primary focus is upon carcinogens found in indoor air, although the methods described are applicable to other media or environments. In cases where there are no published methods for a particular pollutant in indoor air, methods developed for the workplace and for ambient air are included since they should be adaptable to indoor air. Known and suspected carcinogens have been grouped into six categories for the purposes of this and related work. The categories are radon, asbestos, organic compounds, inorganic species,more » particles, and non-ionizing radiation. Some methods of assessing exposure that are not specific to any particular pollutant category are covered in a separate section. The report is the fifth in a series of EPA/Environmental Criteria and Assessment Office Monographs.« less

The carcinogenicity of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU).

PubMed

Warzok, R; Martin, J; Mendel, J; Thust, R; Schwarz, H

1983-01-01

In long-term experiments with Hooded rats the carcinogenic potential of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU) could be demonstrated for the first time. Br-MPNU is formed also endogenously after combined administration of 1-methyl-3(p-bromophenyl)-urea (Br-MPU) and sodium nitrite. After repeated intragastric administration of 0.33 mmol Br-MPU and 0.73 mmol NaNO2 per kg b.w. papillomas and carcinomas of the forestomach developed in 83%. After repeated administration of 0.28 mmol Br-MPNU per kg b.w. these neoplasms were observed in 88%. The comparison of results obtained in similar experiments with 1-methyl-3-phenyl-1-nitrosourea shows that bromine substitution led to a reduction of the carcinogenic activity. The present paper is part of a complex program studying the interrelationships between structure, physico-chemical properties, mutagenicity and carcinogenicity of nitrosoureas.

Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide ...

EPA Pesticide Factsheets

EPA has finalized its Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide. This assessment addresses the potential carcinogenicity from long-term inhalation exposure to ethylene oxide. Now final, this assessment updates the carcinogenicity information in EPA’s 1985 Health Assessment Document. EPA’s program and regional offices may use this assessment to inform decisions to protect human health. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science consultation materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Ammonia and the charge to external peer reviewers, are posted on this site.

Arsenic in private drinking water wells: an assessment of jurisdictional regulations and guidelines for risk remediation in North America.

PubMed

Chappells, Heather; Parker, Louise; Fernandez, Conrad V; Conrad, Cathy; Drage, John; O'Toole, Gary; Campbell, Norma; Dummer, Trevor J B

2014-09-01

Arsenic is a known carcinogen found globally in groundwater supplies due to natural geological occurrence. Levels exceeding the internationally recognized safe drinking water standard of 10 μg/L have been found in private drinking water supplies in many parts of Canada and the United States. Emerging epidemiological evidence confirms groundwater arsenic to be a significant health concern, even at the low to moderate levels typically found in this region. These findings, coupled with survey data reporting limited public adherence to testing and treatment guidelines, have prompted calls for improved protective measures for private well users. The purpose of this review is to assess current jurisdictional provisions for private well water protection in areas where arsenic is known to naturally occur in groundwater at elevated levels. Significant limitations in risk management approaches are identified, including inconsistent and uncoordinated risk communication approaches, lack of support mechanisms for routine water testing and limited government resources to check that testing and treatment guidelines are followed. Key action areas are discussed that can help to build regulatory, community and individual capacity for improved protection of private well water supplies and enhancement of public health.

Health effects of coal mining and combustion: carcinogens and cofactors.

PubMed Central

Falk, H L; Jurgelski, W

1979-01-01

Some polynuclear aromatics (PNA) have been found to be potent carcinogens for all tissues and organs of experimental animals that have been exposed to them, but different dose levels are needed for these effects. They have been known for decades to cause cancer at the site of application but also at certain sites distant from the area of contact. Although some hydrocarbons are potent and complete carcinogens, the majority of related hydrocarbons was originally found to be inactive. Since they generally appear together, it was important to know more about their interaction, particularly whether they would synergize, or antagonize. The polycyclic hydrocarbons have been studied by subcutaneous injection, where they prove very potent carcinogens. They are also very active on the skin of mice where they produce cancer on prolonged application. Inhalation studies, require larger doses yielded negative results until particulate matter was introduced which facilitated the development of lung tumors. Although iron oxide dust was used initially, other dusts were also capable of enhancing the response of the tissue to benzo(a)pyrene carcinogenesis. This point is of importance, particularly since the inhalation of PNA in situations of air pollution or coal mining involves particulates, although of a different type. Soot is not a homogenous substance and several factors determine its properties. Soots will lose some of the absorbed chemicals during their residence in air, but they retain their PNAs for long periods of time when they reach the soil. The carcinogenicity of PNAs in the adsorbed state may be completely absent, depending on particle size of the soot and availability of eluting capability of the tissues or cells in contact with the soot. Whenever the carcinogenic polynuclear aromatics can be eluted they will be active in producing cancer if their residence is adequate. There seems to be no reason to assume that a large increase in coal combustion in the future will by necessity lead to greater risks of cancer to the coal miners or the general urban dweller, because activities to be started now can take into consideration the requirements necessary for control of air pollution in mines as well as in cities. If new uses of coal will be developed, it will be a completely different situation, and statements about the carcinogenic risk from coal utilization do not apply there. Although some of the same carcinogenic PNAs are involved in the health hazards from those processes, other carcinogens and also cocarcinogens will be present, and the exposed workers will not have the apparent benefits of adsorption of PNAs on soot. PMID:540618

[New perspectives in monitoring of exposures to carcinogens].

PubMed

Pavanello, Sofia; Lotti, Marcello

2011-01-01

Biomonitoring occupational and environmental exposures to carcinogens is a common practice and several biomarkers have been developed for risk assessment. However, in particular, because of the lack of prospective studies, the place of these biomarkers within the complex scenario of the gene-environment interactions leading to cancer cannot be defined. New opportunities and suggestions for biomonitoring exposures to carcinogens could derive from exploring the exposome, from the results of genomewide association and omic studies. Based on these premises it is possible to envisage personalized biomonitoring procedures, as those already actuated in nutrition and clinical oncology, allowing a better predictivity of biomarkers in the preventive settings.

Animal studies on growth and development.

PubMed

Lerchl, Alexander

2011-12-01

Despite the fact that no plausible biological mechanism has yet been identified how electromagnetic fields below recommended exposure limits could negatively affect health of animals or humans, many experiments have been performed in various animal species, mainly mice and rats, to investigate the possible effects on growth and development. While older studies often suffered from sub-optimal exposure conditions, recent investigations, using sophisticated exposure devices and thus preventing thermal effects, have been performed without these limitations. In principle, two types of studies can be addressed: those which have investigated the carcinogenic or co-carcinogenic effects of exposure in developing animals, and those which have been done in developing animals without the focus on carcinogenic or co-carcinogenic effects. In both areas, the vast majority of publications did not show adverse effects. The largest study so far has been done in normal mice which have been chronically exposed to UMTS signals up to 1.3 W/kg SAR, thus 16 times higher than the whole-body exposure limit for humans. Even after four generations, no systematic or dose-dependent alterations in development or fertility could be found, supporting the view that negative effects on humans are very unlikely. Ongoing experiments in our laboratory investigate the effects of head-only exposure in rats (up to 10 W/kg local SAR) which are exposed from 14 days of age daily for 2 h. A battery of behavioral tests is performed in young, adult, and pre-senile animals. The results will help to clarify possible effects of exposure on brain development. Copyright © 2011 Elsevier Ltd. All rights reserved.

Recommendations for the Diagnosis and Management of Asbestos-Related Pleural and Pulmonary Disease.

PubMed

Diego Roza, Carmen; Cruz Carmona, M Jesús; Fernández Álvarez, Ramón; Ferrer Sancho, Jaume; Marín Martínez, Belén; Martínez González, Cristina; Rodríguez Portal, José Antonio; Romero Valero, Fernando; Villena Garrido, Victoria

2017-08-01

Asbestos is the term used for a set of mineral silicates that tend to break up into fibers. Its use has been associated with numerous diseases affecting the lung and pleura in particular, all of which are characterized by their long period of latency. Asbestos, moreover, has been recognized by the WHO as a Group IA carcinogen since 1987 and its use was banned in Spain in 2002. The publication in 2013 of the 3rd edition of the specific asbestos health monitoring protocol, together with the development of new diagnostic techniques, prompted the SEPAR EROM group to sponsor publication of guidelines, which review the clinical, radiological and functional aspects of the different asbestos-related diseases. Recommendations have also been made for the diagnosis and follow-up of exposed patients. These recommendations were drawn up in accordance with the GRADE classification system. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

Application of the key characteristics of carcinogens in cancer hazard identification

PubMed Central

Guyton, Kathryn Z; Rusyn, Ivan; Chiu, Weihsueh A; Corpet, Denis E; van den Berg, Martin; Ross, Matthew K; Christiani, David C; Beland, Frederick A; Smith, Martyn T

2018-01-01

Abstract Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics (KCs), one or more of which are commonly exhibited by established human carcinogens. The KCs reflect the properties of a cancer-causing agent, such as ‘is genotoxic,’ ‘is immunosuppressive’ or ‘modulates receptor-mediated effects,’ and are distinct from the hallmarks of cancer, which are the properties of tumors. To assess feasibility and limitations of applying the KCs to diverse agents, methods and results of mechanistic data evaluations were compiled from eight recent IARC Monograph meetings. A systematic search, screening and evaluation procedure identified a broad literature encompassing multiple KCs for most (12/16) IARC Group 1 or 2A carcinogens identified in these meetings. Five carcinogens are genotoxic and induce oxidative stress, of which pentachlorophenol, hydrazine and malathion also showed additional KCs. Four others, including welding fumes, are immunosuppressive. The overall evaluation was upgraded to Group 2A based on mechanistic data for only two agents, tetrabromobisphenol A and tetrachloroazobenzene. Both carcinogens modulate receptor-mediated effects in combination with other KCs. Fewer studies were identified for Group 2B or 3 agents, with the vast majority (17/18) showing only one or no KCs. Thus, an objective approach to identify and evaluate mechanistic studies pertinent to cancer revealed strong evidence for multiple KCs for most Group 1 or 2A carcinogens but also identified opportunities for improvement. Further development and mapping of toxicological and biomarker endpoints and pathways relevant to the KCs can advance the systematic search and evaluation of mechanistic data in carcinogen hazard identification. PMID:29562322

Application of the key characteristics of carcinogens in cancer hazard identification.

PubMed

Guyton, Kathryn Z; Rusyn, Ivan; Chiu, Weihsueh A; Corpet, Denis E; van den Berg, Martin; Ross, Matthew K; Christiani, David C; Beland, Frederick A; Smith, Martyn T

2018-04-05

Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics (KCs), one or more of which are commonly exhibited by established human carcinogens. The KCs reflect the properties of a cancer-causing agent, such as 'is genotoxic,' 'is immunosuppressive' or 'modulates receptor-mediated effects,' and are distinct from the hallmarks of cancer, which are the properties of tumors. To assess feasibility and limitations of applying the KCs to diverse agents, methods and results of mechanistic data evaluations were compiled from eight recent IARC Monograph meetings. A systematic search, screening and evaluation procedure identified a broad literature encompassing multiple KCs for most (12/16) IARC Group 1 or 2A carcinogens identified in these meetings. Five carcinogens are genotoxic and induce oxidative stress, of which pentachlorophenol, hydrazine and malathion also showed additional KCs. Four others, including welding fumes, are immunosuppressive. The overall evaluation was upgraded to Group 2A based on mechanistic data for only two agents, tetrabromobisphenol A and tetrachloroazobenzene. Both carcinogens modulate receptor-mediated effects in combination with other KCs. Fewer studies were identified for Group 2B or 3 agents, with the vast majority (17/18) showing only one or no KCs. Thus, an objective approach to identify and evaluate mechanistic studies pertinent to cancer revealed strong evidence for multiple KCs for most Group 1 or 2A carcinogens but also identified opportunities for improvement. Further development and mapping of toxicological and biomarker endpoints and pathways relevant to the KCs can advance the systematic search and evaluation of mechanistic data in carcinogen hazard identification.

Mutagens and carcinogens in foods. Epidemiologic review.

PubMed Central

Hislop, T. G.

1993-01-01

Evidence that diet contributes to the development of cancer is strengthening. This paper examines mutagens and carcinogens, such as naturally occurring substances, products of cooking and food processing, intentional and unintentional additives, and contaminants, found in foods. Such substances are present in minute quantities in the diets of average Canadians. Indication of health risk is largely limited to experimental laboratory evidence. PMID:8499796

Release of asbestos fibers from weathered and corroded asbestos cement products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spurny, K.R.

The controversy on whether weathered and corroded asbestos cement products are emitting biologically significant asbestos fiber concentrations in ambient air has not been resolved. Nor is it known if the weathered and corroded asbestos cement products release asbestos fibers which have the same carcinogenic potency as standard chrysotile. The purpose of this research project was to develop a method for sampling and measuring asbestos fiber emissions from solid planar surfaces (i.e., roofs and facades) consisting of asbestos cement products and to develop methods for studying the physical and chemical changes and the carcinogenic potency of the emitted fibers. Using thismore » method asbestos fiber emissions in ambient air have been measured in the FRG during 1984/1986. The emissions of asbestos fibers longer than 5 microns were in the range 10(6) to 10(8) fibers/m2.hr. The ambient air concentrations of these asbestos fibers were for the most part less than 10(3) fibers/m3. It was shown that the emitted asbestos fibers were chemically changed and it was shown with animal experiments that their carcinogenic potency did not differ from the carcinogenicity of standard chrysotile fibers.« less

[Occupational exposure to carcinogens: analysis of the application of the CAREX information system to Catalonia].

PubMed

de Grado Andrés, Adolfo; Molinero Ruiz, Emilia; van der Haar, Rudolf

2014-01-01

The objective of this study is to estimate occupational exposures to human carcinogens in Catalonia in 2009, taking as a reference the CAREX ESP 2007 information system, and to evaluate the suitability of extrapolating these data to Catalonia. The reference population is the number of people registered with the Social Security system in Catalonia in 2009. Carcinogens considered are those which the International Agency for Research on Cancer (IARC) classified into groups 1 and 2A and are related to occupational exposures. The exposure prevalences from the CAREX ESP 2007, adapted to the Catalonian Industrial Classification (CCAE 09), were used. Technical survey reports from the Occupational Safety and Health Centers of the Catalonian local government, and related databases were consulted. The most frequent occupational exposures to human carcinogens were solar radiation, crystalline silica, diesel exhaust, radon and wood dust, although based mainly on data not considered adequate for extrapolation to Catalonia. Around 217 exposure situations for 25 carcinogens, not previously considered in CAREX ESP 2007, were identified. The estimated number of workers exposed to human carcinogens in Catalonia in 2009 based on the CAREX ESP 2007 system could differ from the real situation. Development of a CAREX CAT system that incorporates exposure data from Catalonia is recommended. Copyright belongs to the Societat Catalana de Seguretat i Medicina del Treball.

Reducing the use of carcinogens: the Massachusetts experience.

PubMed

Jacobs, Molly M; Massey, Rachel I; Tenney, Heather; Harriman, Elizabeth

2014-01-01

Toxics use reduction (TUR) is one part of a comprehensive cancer prevention strategy. TUR emphasizes reducing the use of cancer-causing chemicals by improving manufacturing processes and identifying and adopting safer alternatives. This analysis draws on 20 years of data collected from industries reporting to the Massachusetts Toxics Use Reduction Act (TURA) program to assess trends in the use and release of chemicals associated with cancer. We used a master list of known and suspected carcinogens developed from authoritative sources and a list of carcinogens grouped by their association with 11 cancer sites to analyze trends in use and release of chemicals by industrial facilities reporting to the TURA program from 1990 to 2010. The trend analysis shows that reported use and releases of carcinogens by these Massachusetts companies have decreased dramatically over time. Reported use declined 32% from 1990 to 2010, and reported releases declined 93% from 1991 to 2010 (1991 is when additional industrial sectors, including electric utilities, were phased into the program). Particularly large reductions were achieved in the use of trichloroethylene, perchloroethylene and cadmium and cadmium compounds. The analysis of groups of chemicals associated with specific cancer sites shows similar trends. Important opportunities for further reductions in many carcinogens, including formaldehyde, hexavalent chromium, and a variety of halogenated compounds are identified. Continued work to minimize the use of carcinogens can help to reduce the burden of cancer in Massachusetts and elsewhere.

Identifying and regulating carcinogens. Background paper

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1987-11-01

Contents include: Introduction and summary; policies for testing, assessing, and regulating carcinogens; federal agency assessment and regulation of carcinogens; the national toxicology program; agency responses to the annual report on carcinogens and NCI/NTP test results; statutory authority for regulating carcinogens; chemicals listed in annual report on carcinogens and NCI/NTP test results.

29 CFR 1990.121 - Candidate list of potential occupational carcinogens.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 9 2013-07-01 2013-07-01 false Candidate list of potential occupational carcinogens. 1990... OCCUPATIONAL CARCINOGENS Priority Setting § 1990.121 Candidate list of potential occupational carcinogens. (a... Potential Carcinogens or Category II Potential Carcinogens. For the purposes of this paragraph, “available...

29 CFR 1990.121 - Candidate list of potential occupational carcinogens.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 9 2012-07-01 2012-07-01 false Candidate list of potential occupational carcinogens. 1990... OCCUPATIONAL CARCINOGENS Priority Setting § 1990.121 Candidate list of potential occupational carcinogens. (a... Potential Carcinogens or Category II Potential Carcinogens. For the purposes of this paragraph, “available...

29 CFR 1990.121 - Candidate list of potential occupational carcinogens.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 9 2014-07-01 2014-07-01 false Candidate list of potential occupational carcinogens. 1990... OCCUPATIONAL CARCINOGENS Priority Setting § 1990.121 Candidate list of potential occupational carcinogens. (a... Potential Carcinogens or Category II Potential Carcinogens. For the purposes of this paragraph, “available...

Research Trends in Emerging Contaminants on the Aquatic Environments of Tanzania

PubMed Central

Miraji, H.; Othman, O. C.; Ngassapa, F. N.; Mureithi, E. W.

2016-01-01

The continuity for discovery and production of new chemicals, allied products, and uses has currently resulted into generation of recent form of contaminants known as Emerging Contaminants (ECs). Once in the aquatic environment ECs are carcinogenic and cause other threats to both human's and animals' health. Due to their effects this study was aimed at investigating research trends of ECs in Tanzania. Findings revealed that USA and EU countries were leading in ECs researches, little followed by Asia, South Africa, and then Zambia. Only few guidelines from USA-EPA, WHO, Canada, and Australia existed. Neither published guidelines nor regulations for ECs existed in Tanzania; rather only the occurrence of some disinfection by-products and antibiotics was, respectively, reported in Arusha and Dar es Salaam, Tanzania. As these reports had a limited coverage of ECs, henceforth, these findings constitute the first-line reference materials for ECs research in Tanzania which shall be useful for future monitoring and regulation planning. PMID:26998381

Recommendations for safety testing with the in vivo comet assay.

PubMed

Vasquez, Marie Z

2012-08-30

While the in vivo comet assay increases its role in regulatory safety testing, deliberations about the interpretation of comet data continue. Concerns can arise regarding comet assay publications with limited data from non-blind testing of positive control compounds and using protocols (e.g. dose concentrations, sample times, and tissues) known to give an expected effect. There may be a tendency towards bias when the validation or interpretation of comet assay data is based on results generated by widely accepted but non-validated assays. The greatest advantages of the comet assay are its sensitivity and its ability to detect genotoxicity in tissues and at sample times that could not previously be evaluated. Guidelines for its use and interpretation in safety testing should take these factors into account. Guidelines should be derived from objective review of data generated by blind testing of unknown compounds dosed at non-toxic concentrations and evaluated in a true safety-testing environment, where the experimental design and conclusions must be defensible. However, positive in vivo comet findings with such compounds are rarely submitted to regulatory agencies and this data is typically unavailable for publication due to its proprietary nature. To enhance the development of guidelines for safety testing with the comet assay, and with the permission of several sponsors, this paper presents and discusses relevant data from multiple GLP comet studies conducted blind, with unknown pharmaceuticals and consumer products. Based on these data and the lessons we have learned through the course of conducting these studies, I suggest significant adjustments to the current conventions, and I provide recommendations for interpreting in vivo comet assay results in situations where risk must be evaluated in the absence of carcinogenicity or clinical data. Copyright © 2012 Elsevier B.V. All rights reserved.

Past, present, and future of mutagens in cooked foods.

PubMed

Sugimura, T

1986-08-01

Mutation assay with Salmonella typhimurium enabled us to detect various types of mutagens in cooked foods. A series of mutagenic heterocyclic amines has been isolated and identified in broiled fish and meat and in pyrolyzates of amino acids and proteins. Feeding experiments showed these mutagens to be carcinogenic in mice and rats. The mechanism of formation and pathway of metabolic activation of these heterocyclic amines have been elucidated. Their contents in various cooked foods have been determined. The presence of mutagenic nitropyrenes (some of which were confirmed as carcinogens) in grilled chicken was also established. Roasted coffee beans also yield mutagens such as methylglyoxal. The formation of mutagen precursors, including beta-carboline derivatives and tyramine which become mutagens with nitrite treatment, was found during food processing. Oncogene activation in animal tumors induced by some of these food mutagens/carcinogens has been confirmed. The role of mutagens/carcinogens in cooked foods in human cancer development has not yet been exactly evaluated. In order to do this, more information on their carcinogenic potency, human intake, metabolism in the human body, and the effects of combined administration with other initiators, promoters and other modifying factors in food is required.

[The awareness of carcinogenic effect of tobacco smoke--a questionnaire survey of students and employees of Collegium Medicum of Nicolaus Copernicus University].

PubMed

Seget, Monika; Karolczak, Dominika; Wilk, Magdalena; Błaszczyk, Agata; Szylberg, Łukasz; Florek, Ewa; Marszałek, Andrzej

2012-01-01

Smoking is currently the most significant risk factor for health according to WHO statements. It has been proven that smoking is the cause of many diseases, for example cardiovascular and respiratory tract diseases as well as impaired fertility and decreased immunity. The adverse effects of cigarette smoking on pregnancy and health of children were also proved. However, special attention is laid on impact of smoking on the development of cancer. In tobacco smoke there are over 4,000 different chemical substances and compounds, of which more than 50 are carcinogens. The present study was aimed to assess the knowledge of students and employees of Collegium Medicum of Nicolaus Copernicus University in Torun (CM UMK), first on number and types of carcinogens contained in tobacco smoke and secondly on types of diseases caused by smoking. There were 480 responders included to the study(253 women and 227 men). Among them there were 416 students of CM UMK, 59 students of biomedical engineering at the University of Technology and Life Sciences in Bydgoszcz and 5 employees of CM UMK. Among the respondents there was considerable ignorance about the number of carcinogens contained in tobacco smoke with over 50% of them indicating the incorrect answer. Among the carcinogens there were mentioned mostly tar and nicotine, and among the diseases caused by tobacco smoke most often pointed response there were lung and larynx cancer and heart and blood vessels diseases and to reduce the weight of newborns. In summary, we can conclude that the awareness of students and employees of CM UMK about the carcinogenic properties of tobacco smoke was not sufficient. Respondents were aware of the dangers of smoking, they knew the basic carcinogenic substances and pointed a few diseases caused by smoking cigarettes. Unfortunately their knowledge does not refer to a number of diseases which in common believe are not connected to cigarette smoking, but in fact tobacco smoke is very important for their development.

Superficial bladder cancer.

PubMed Central

Hall, R. R.

1994-01-01

Bladder cancer is almost certainly a product of the industrial revolution and the cigarette smoking that has accompanied it. Exposure to a chemical bladder carcinogen such as beta naphthylamine, benzidine, or 4-diphenylaniline can be proved in only a small proportion of patients and only a handful obtain industrial diseases benefit after developing "Prescribed Industrial Disease C23." None the less, the continued use of known carcinogenic substances in British industry for many years after their identification, the wide range of industries with a known or suspected increased risk of bladder cancer, and our ignorance of the carcinogenic potential of many materials used in current manufacturing should be a cause for continuing concern. Images p912-a PMID:8173377

Qualitative and quantitative approaches in the dose-response assessment of genotoxic carcinogens.

PubMed

Fukushima, Shoji; Gi, Min; Kakehashi, Anna; Wanibuchi, Hideki; Matsumoto, Michiharu

2016-05-01

Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The use of dose-response data in a margin of exposure approach to carcinogenic risk assessment for genotoxic chemicals in food.

PubMed

Benford, Diane J

2016-05-01

Genotoxic substances are generally not permitted for deliberate use in food production. However, an appreciable number of known or suspected genotoxic substances occur unavoidably in food, e.g. from natural occurrence, environmental contamination and generation during cooking and processing. Over the past decade a margin of exposure (MOE) approach has increasingly been used in assessing the exposure to substances in food that are genotoxic and carcinogenic. The MOE is defined as a reference point on the dose-response curve (e.g. a benchmark dose lower confidences limit derived from a rodent carcinogenicity study) divided by the estimated human intake. A small MOE indicates a higher concern than a very large MOE. Whilst the MOE cannot be directly equated to risk, it supports prioritisation of substances for further research or for possible regulatory action, and provides a basis for communicating to the public. So far, the MOE approach has been confined to substances for which carcinogenicity data are available. In the absence of carcinogenicity data, evidence of genotoxicity is used only in hazard identification. The challenge to the genetic toxicology community is to develop approaches for characterising risk to human health based on data from genotoxicity studies. In order to achieve wide acceptance, it would be important to further address the issues that have been discussed in the context of dose-response modelling of carcinogenicity data in order to assign levels of concern to particular MOE values, and also whether it is possible to make generic conclusions on how potency in genotoxicity assays relates to carcinogenic potency. © Crown copyright 2015.

Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DNA damage in rats.

PubMed

Wei, Min; Yamada, Takanori; Yamano, Shotaro; Kato, Minoru; Kakehashi, Anna; Fujioka, Masaki; Tago, Yoshiyuki; Kitano, Mistuaki; Wanibuchi, Hideki

2013-11-15

Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. © 2013.

Absence of multiplicative interactions between occupational lung carcinogens and tobacco smoking: a systematic review involving asbestos, crystalline silica and diesel engine exhaust emissions.

PubMed

El Zoghbi, Mohamad; Salameh, Pascale; Stücker, Isabelle; Brochard, Patrick; Delva, Fleur; Lacourt, Aude

2017-02-02

Tobacco smoking is the main cause of lung cancer, but it is not the sole causal factor. Significant proportions of workers are smokers and exposed to occupational lung carcinogens. This study aims to systematically review the statistical interaction between occupational lung carcinogens and tobacco smoking, in particular asbestos, crystalline silica and diesel engine exhaust emissions. Articles were identified using Scopus, PubMed, and Web of Science, and were limited to those published in English or French, without limitation of time. The reference list of selected studies was reviewed to identify other relevant papers. One reviewer selected the articles based on the inclusion and exclusion criteria. Two reviewers checked the eligibility of articles to be included in the systematic review. Data were extracted by one reviewer and revised by two other reviewers. Cohorts and case-control studies were analyzed separately. The risk of bias was evaluated for each study based on the outcome. The results of the interaction between the tobacco smoking and each carcinogen was evaluated and reported separately. Fifteen original studies were included for asbestos-smoking interaction, seven for silica-smoking interaction and two for diesel-smoking interaction. The results suggested the absence of multiplicative interaction between the three occupational lung carcinogens and smoking. There is no enough evidence from the literature to conclude for the additive interaction. We believe there is a limited risk of publication bias as several studies reporting negative results were published. There are no multiplicative interactions between tobacco smoking and occupational lung carcinogens, in particular asbestos, crystalline silica and diesel engine exhaust emissions. Even though, specific programs should be developed and promoted to reduce concomitantly the exposure to occupational lung carcinogens and tobacco smoking.

Threshold and non-threshold chemical carcinogens: A survey of the present regulatory landscape.

PubMed

Bevan, Ruth J; Harrison, Paul T C

2017-08-01

For the proper regulation of a carcinogenic material it is necessary to fully understand its mode of action, and in particular whether it demonstrates a threshold of effect. This paper explores our present understanding of carcinogenicity and the mechanisms underlying the carcinogenic response. The concepts of genotoxic and non-genotoxic and threshold and non-threshold carcinogens are fully described. We provide summary tables of the types of cancer considered to be associated with exposure to a number of carcinogens and the available evidence relating to whether carcinogenicity occurs through a threshold or non-threshold mechanism. In light of these observations we consider how different regulatory bodies approach the question of chemical carcinogenesis, looking in particular at the definitions and methodologies used to derive Occupational Exposure Levels (OELs) for carcinogens. We conclude that unless proper differentiation is made between threshold and non-threshold carcinogens, inappropriate risk management measures may be put in place - and lead also to difficulties in translating carcinogenicity research findings into appropriate health policies. We recommend that clear differentiation between threshold and non-threshold carcinogens should be made by all expert groups and regulatory bodies dealing with carcinogen classification and risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece - An ecological study

PubMed Central

2011-01-01

Background Hexavalent chromium is a known carcinogen when inhaled, but its carcinogenic potential when orally ingested remains controversial. Water contaminated with hexavalent chromium is a worldwide problem, making this a question of significant public health importance. Methods We conducted an ecological mortality study within the Oinofita region of Greece, where water has been contaminated with hexavalent chromium. We calculated gender, age, and period standardized mortality ratios (SMRs) for all deaths, cancer deaths, and specific cancer types of Oinofita residents over an 11-year period (1999 - 2009), using the greater prefecture of Voiotia as the standard population. Results A total of 474 deaths were observed. The SMR for all cause mortality was 98 (95% CI 89-107) and for all cancer mortality 114 (95% CI 94-136). The SMR for primary liver cancer was 1104 (95% CI 405-2403, p-value < 0.001). Furthermore, statistically significantly higher SMRs were identified for lung cancer (SMR = 145, 95% CI 100-203, p-value = 0.047) and cancer of the kidney and other genitourinary organs among women (SMR = 368, 95% CI 119-858, p-value = 0.025). Elevated SMRs for several other cancers were also noted (lip, oral cavity and pharynx 344, stomach 121, female breast 134, prostate 128, and leukaemias 168), but these did not reach statistical significance. Conclusions Elevated cancer mortality in the Oinofita area of Greece supports the hypothesis of hexavalent chromium carcinogenicity via the oral ingestion pathway of exposure. Further studies are needed to determine whether this association is causal, and to establish preventive guidelines and public health recommendations. PMID:21609468

Formation and Repair of Tobacco Carcinogen-Derived Bulky DNA Adducts

DOE PAGES

Hang, Bo

2010-01-01

DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N -nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O 6 -alkylguaninemore » DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made in the areas concerning formation and repair of bulky DNA adducts in the context of tobacco carcinogen-associated genotoxic and carcinogenic effects.« less

Induction of mutagenesis and alterations in gene expression by tumorigenic chemicals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huberman, E.

1979-01-01

To determine the relationship between mutagenesis and carcinogenesis, a series of eleven polycyclic hydrocarbons with different degrees of carcinogenicity were tested in the cell-mediated mutagenesis assay for the induction of ouabain-resistant mutants. Four carcinogenic hydrocarbons induced ouabain-resistant mutants; five noncarcinogenic hydrocarbons were not mutagenic. Results indicated that there was a relationship between mutagenesis and the degree of carcinogenicity of polycyclic hydrocarbons after enhancement of their metabolism by aminophylline. To study liver carcinogens a system was developed for cocultivating primary liver cells and V79 hamster cells. In this system the nitrosamines and aflatoxins were metabolized by liver cells to intermediates thatmore » were mutagenic to the V79 cells. In experiments using human cells, tumor-promoting phorbol esters induced terminal differentiation while in other studies, in which avian and murine cells were employed, they inhibited differentiation. The results imply that human cells may respond differently from mouse and chicken cells to the biological effects of phorbol diesters. (HLW)« less

Epidemiology of virus infection and human cancer.

PubMed

Chen, Chien-Jen; Hsu, Wan-Lun; Yang, Hwai-I; Lee, Mei-Hsuan; Chen, Hui-Chi; Chien, Yin-Chu; You, San-Lin

2014-01-01

The International Agency for Research on Cancer (IARC) has comprehensively assessed the human carcinogenicity of biological agents. Seven viruses including Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), human immunodeficiency virus, type-1 (HIV-1), human T cell lymphotrophic virus, type-1 (HTLV-1), and human papillomavirus (HPV) have been classified as Group 1 human carcinogens by IARC. The conclusions are based on the findings of epidemiological and mechanistic studies. EBV, HPV, HTLV-1, and KSHV are direct carcinogens; HBV and HCV are indirect carcinogens through chronic inflammation; HIV-1 is an indirect carcinogen through immune suppression. Some viruses may cause more than one cancer, while some cancers may be caused by more than one virus. However, only a proportion of persons infected by these oncogenic viruses will develop specific cancers. A series of studies have been carried out to assess the viral, host, and environmental cofactors of EBV-associated nasopharyngeal carcinoma, HBV/HCV-associated hepatocellular carcinoma, and HPV-associated cervical carcinoma. Persistent infection and high viral load are important risk predictors of these virus-caused cancers. Risk calculators incorporating host and viral factors have also been developed for the prediction of long-term risk of hepatocellular carcinoma. These risk calculators are useful for the triage and clinical management of infected patients. Both clinical trials and national programs of immunization or antiviral therapy have demonstrated a significant reduction in the incidence of cancers caused by HBV, HCV, and HPV. Future researches on gene-gene and gene-environment interaction of oncogenic viruses and human host are in urgent need.

Development and application of non-invasive biomarkers for carcinogen-DNA adduct analysis in occupationally exposed populations.

PubMed

Talaska, G; Cudnik, J; Jaeger, M; Rothman, N; Hayes, R; Bhatnagar, V J; Kayshup, S J

1996-07-17

Biological monitoring of exposures to carcinogenic compounds in the workplace can be a valuable adjunct to environmental sampling and occupational medicine. Carcinogen-DNA adduct analysis has promise as a biomarker of effective dose if target organ samples can be obtained non-invasively. We have developed non-invasive techniques using exfoliated urothelial and bronchial cells collected in urine and sputum, respectively. First morning urine samples were collected from 33 workers exposed to benzidine or benzidine-based dyes and controls matched for age, education, and smoking status. Sufficient DNA for 32P-postlabelling analysis was obtained from every sample. Mean levels of a specific DNA adduct (which co-chromatographed with standard characterized by MS) were elevated significantly in the benzidine-exposed workers relative to controls. In addition, workers exposed to benzidine had higher adduct levels than those exposed to benzidine-based dyes. This study demonstrates the usefulness of these non-invasive techniques for exposure/effect assessment. To be useful in occupational studies, biomarkers must also be sensitive to exposure interventions. We have conducted topical application studies of used gasoline engine oils in mice and found that the levels of carcinogen-DNA adducts in skin and lung can be significantly lowered if skin cleaning is conducted in a timely manner. The combination of useful, non-invasive techniques to monitor exposure and effect and industrial hygiene interventions can be used to detect and prevent exposures to a wide range of carcinogens including those found in used gasoline engine oils and jet exhausts.

Occupational Burden of Cancer in Korea

PubMed Central

Lee, Hye-Eun; Kang, Seong-Kyu

2010-01-01

Objectives The extent of the occupational cancer burden has rarely been estimated in Korea. The aim of this study is to provide an estimation of the population attributable fraction (PAF) of occupational cancer in Korea. Methods Nine kinds of Group 1 carcinogens addressed by the International Agency for Research on Cancer (IARC) and 7 kinds of cancer were selected for the target carcinogens and diseases, respectively. The prevalence of carcinogen-exposed workers was estimated and correction factors were applied so that the value would be representative of the total population. Data on relative risk (RR) were taken from IARC reports and were compared with the RRs from the studies on Korean workers. The PAF was estimated according to Levin's formula. Results The proportion of the general Korean population exposed to carcinogens was 9.7%. The PAF of total cancer was 1.1% for incident cancer cases and 1.7% for cancer deaths. The PAFs of lung cancer and leukemia were 7.0% and 4.%, respectively. With the RRs reported from Korean studies, the PAF for lung cancer and leukemia were 3.7% and 3.4%, respectively. Conclusion The PAF in this study (1.1%) was lower than that reported in previous studies (2-4%) from developed countries. Considering that only 9 of the 29 kinds of Group 1 carcinogens were included in this study, the PAF might be underestimated. However, because the process of industrialization in Korea differs from that which occurred in other developed countries, 1.1% of the PAF might be appropriate for Korea. PMID:22953164

Cell-type-dependent activities of regulatory regions and E2 proteins derived from carcinogenic and non-carcinogenic human alphapapillomaviruses.

PubMed

Schenker, Astrid; Straub, Elke; Iftner, Thomas; Stubenrauch, Frank

2013-06-01

A large number of studies have revealed that persistent infections with certain human papillomavirus (HPV) types are necessary for the development of invasive cancer of the cervix. Recent studies have shown that not only do the major carcinogenic HPV types 16 and 18 encode E6 and E7 oncoproteins with immortalizing activity but also the very weakly or non-carcinogenic types 53, 66, 70 and 82. Currently, it is unknown whether transcriptional differences exist between these viruses that account for carcinogenicity in vivo. Therefore, we compared for the first time the activities of the upstream regulatory regions (URRs) that drive E6 and E7 expression derived from HPV16, -18, -31, -53, -66, -70 and -82 in the absence and presence of the viral E2 transcriptional regulator. URR activities in the absence of E2 varied widely and were further modulated by the cellular background. The co-expression of homologous E2 proteins resulted in repression of the URRs of only some HPV types and this varied with cell type. Activation by E2 proteins was less cell-type dependent but differed in an HPV-type-dependent manner. However, basal URR activity, repression of the URR by E2 and transcriptional activation by E2 did not correlate with HPV carcinogenicity in vivo. In summary, our data do not support the model that the transcriptional activity of human alphapapillomavirus types correlates with epidemiological risk classification.

MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells.

PubMed

Marrone, April K; Tryndyak, Volodymyr; Beland, Frederick A; Pogribny, Igor P

2016-02-01

Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose- and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanism of AFB1 and B[a]P carcinogenicity. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

Establishing a laboratory animal model from a transgenic animal: RasH2 mice as a model for carcinogenicity studies in regulatory science.

PubMed

Urano, K; Tamaoki, N; Nomura, T

2012-01-01

Transgenic animal models have been used in small numbers in gene function studies in vivo for a period of time, but more recently, the use of a single transgenic animal model has been approved as a second species, 6-month alternative (to the routine 2-year, 2-animal model) used in short-term carcinogenicity studies for generating regulatory application data of new drugs. This article addresses many of the issues associated with the creation and use of one of these transgenic models, the rasH2 mouse, for regulatory science. The discussion includes strategies for mass producing mice with the same stable phenotype, including constructing the transgene, choosing a founder mouse, and controlling both the transgene and background genes; strategies for developing the model for regulatory science, including measurements of carcinogen susceptibility, stability of a large-scale production system, and monitoring for uniform carcinogenicity responses; and finally, efficient use of the transgenic animal model on study. Approximately 20% of mouse carcinogenicity studies for new drug applications in the United States currently use transgenic models, typically the rasH2 mouse. The rasH2 mouse could contribute to animal welfare by reducing the numbers of animals used as well as reducing the cost of carcinogenicity studies. A better understanding of the advantages and disadvantages of the transgenic rasH2 mouse will result in greater and more efficient use of this animal model in the future.

The opinion of the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII) on silica-exposure and lung cancer risk.

PubMed

Piolatto, G; Pira, E

2011-01-01

The Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII) began a thorough overview of the silica-silicosis-lung cancer question starting in 2005. The body of informa tion obtained from a number of epidemiological studies, meta-analyses and reviews following the decision of the IARC to classify Respirable Crystalline Silica (RCS) as a human carcinogen (Group 1) led to different conclusions, which can be summarized as follows: basically an increased risk of developing lung cancer is demonstrated and generally accepted for silicotics; the association of lung cancer and exposure to silica per se is controversial, with some studies in favour of an association and some leading to contrary conclusions. Due to methodological problems affecting most studies and the difficulty in identifying the mechanism of action, we agree that the silica-lung cancer association is still unclear. The UE approach is more practical than scientific, in that it recommended the use of "good practices" subject to an agreement with the social partners, without any need to classify RCS as a human carcinogen. However, in 2008 the UE asked the Institute of Occupational Medicine (IOM) in Edinburgh to assess, as a primary objective, the impact of introducing a system for setting Occupational Exposure Limits (OELs) based on objective risk criteria. In the present state of the art SIMLII's conclusions are: a) There is no need to label RCS with phrase H350i (ex R.49); b) It is of utmost importance to enforce compliance with current OELs; c) Future guidelines specific for silicosis risk should include adequate health surveillance; d) For legal medicine purposes, only lung cancer cases with an unquestionable diagnosis of silicosis should be recognised as an occupational disease.

A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens.

PubMed

Schaap, Mirjam M; Wackers, Paul F K; Zwart, Edwin P; Huijskens, Ilse; Jonker, Martijs J; Hendriks, Giel; Breit, Timo M; van Steeg, Harry; van de Water, Bob; Luijten, Mirjam

2015-12-01

Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic.

29 CFR 1990.112 - Classification of potential carcinogens.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 9 2012-07-01 2012-07-01 false Classification of potential carcinogens. 1990.112 Section... CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria for identification, classification and regulation of potential occupational carcinogens will be...

29 CFR 1990.112 - Classification of potential carcinogens.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 9 2013-07-01 2013-07-01 false Classification of potential carcinogens. 1990.112 Section... CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria for identification, classification and regulation of potential occupational carcinogens will be...

29 CFR 1990.112 - Classification of potential carcinogens.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 9 2014-07-01 2014-07-01 false Classification of potential carcinogens. 1990.112 Section... CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria for identification, classification and regulation of potential occupational carcinogens will be...

Cadmium, Zinc, and Selenium Levels in Carcinoma of the Human Prostate

DTIC Science & Technology

2007-04-01

tissue (4-6). Cadmium (Cd) possesses carcinogenic effect that is hormonally mediated (7, 8), and is recognized as a risk factor in development of...in prostatic cells [28], and that the carcinogenic effect of Cd can be hormonally mediated [13, 29]. Protective Factors - Selenium and Zinc Se...studies have shown that this generation of Pacific Islands people have traditional diets, eating more taro, shellfish and fresh vegetables, and

Product stewardship and science: safe manufacture and use of fiber glass.

PubMed

Hesterberg, Thomas W; Anderson, Robert; Bernstein, David M; Bunn, William B; Chase, Gerald A; Jankousky, Angela Libby; Marsh, Gary M; McClellan, Roger O

2012-03-01

This paper describes a proactive product stewardship program for glass fibers. That effort included epidemiological studies of workers, establishment of stringent workplace exposure limits, liaison with customers on safe use of products and, most importantly, a research program to evaluate the safety of existing glass fiber products and guide development of new even safer products. Chronic inhalation exposure bioassays were conducted with rodents and hamsters. Amosite and crocidolite asbestos produced respiratory tract cancers as did exposure to "biopersistent" synthetic vitreous fibers. "less biopersistent" glass fibers did not cause respiratory tract cancers. Corollary studies demonstrated the role of slow fiber dissolution rates and biopersistence in cancer induction. These results guided development of safer glass fiber products and have been used in Europe to regulate fibers and by IARC and NTP in classifying fibers. IARC concluded special purpose fibers and refractory ceramic fibers are "possibly carcinogenic to humans" and insulation glass wool, continuous glass filament, rock wool and slag wool are "not classifiable as to their carcinogenicity to human." The NTP's 12th report on carcinogens lists "Certain Glass Wool Fibers (Inhalable)" as "reasonably anticipated to be a human carcinogen." "Certain" in the descriptor refers to "biopersistent" glass fibers and excludes "less biopersistent" glass fibers. Copyright © 2012 Elsevier Inc. All rights reserved.

The contribution of molecular epidemiology to the identification of human carcinogens: current status and future perspectives.

PubMed

Boffetta, P; Islami, F

2013-04-01

The use of biological-based markers of exposure, intermediate effect, outcome, and susceptibility has become standard practice in cancer epidemiology, which has contributed to identification of several carcinogenic agents. Nevertheless, with the exception of biological agents, this contribution, in terms of providing sufficiently strong evidence as required by the International Agency for Research on Cancer (IARC) monographs, has been modest. We discuss the overall contribution of molecular epidemiology to identification of carcinogens, with focus on IARC monographs. For many carcinogens, valid biological markers of exposure and mechanisms of actions are not available. Molecular markers are usually assessed in single biological samples, which may not represent the actual exposure or biological events related to carcinogens. The contribution of molecular epidemiology to identification of carcinogens has mainly been limited to the carcinogens acting through a genotoxic mechanism, i.e. when carcinogens induce DNA damage. A number of factors, including certain hormones and overweight/obesity, may show carcinogenic effects through nongenotoxic pathways, for which mechanisms of carcinogenicity are not well identified and their biomarkers are sparse. Longitudinal assessment of biomarkers may provide more informative data in molecular epidemiology studies. For many carcinogens and mechanistic pathways, in particular nongenotoxic carcinogenicity, valid biological markers still need to be identified.

Listing Occupational Carcinogens

PubMed Central

Siemiatycki, Jack; Richardson, Lesley; Straif, Kurt; Latreille, Benoit; Lakhani, Ramzan; Campbell, Sally; Rousseau, Marie-Claude; Boffetta, Paolo

2004-01-01

The occupational environment has been a most fruitful one for investigating the etiology of human cancer. Many recognized human carcinogens are occupational carcinogens. There is a large volume of epidemiologic and experimental data concerning cancer risks in different work environments. It is important to synthesize this information for both scientific and public health purposes. Various organizations and individuals have published lists of occupational carcinogens. However, such lists have been limited by unclear criteria for which recognized carcinogens should be considered occupational carcinogens, and by inconsistent and incomplete information on the occupations and industries in which the carcinogenic substances may be found and on their target sites of cancer. Based largely on the evaluations published by the International Agency for Research on Cancer, and augmented with additional information, the present article represents an attempt to summarize, in tabular form, current knowledge on occupational carcinogens, the occupations and industries in which they are found, and their target organs. We have considered 28 agents as definite occupational carcinogens, 27 agents as probable occupational carcinogens, and 113 agents as possible occupational carcinogens. These tables should be useful for regulatory or preventive purposes and for scientific purposes in research priority setting and in understanding carcinogenesis. PMID:15531427

Asphalt and risk of cancer in man.

PubMed Central

Chiazze, L; Watkins, D K; Amsel, J

1991-01-01

Epidemiological publications regarding the carcinogenic potential of asphalt (bitumen) are reviewed. In 1984 the International Agency for Research on Cancer (IARC) stated that there is "inadequate evidence that bitumens alone are carcinogenic to humans." They did, however, conclude that animal data provided sufficient evidence for the carcinogenicity of certain extracts of steam refined and air refined bitumens. In the absence of data on man, IARC considered it reasonable to regard chemicals with sufficient evidence of carcinogenicity in animals as if they presented a carcinogenic risk to man. Epidemiological data for man accumulated since the IARC report do not fulfil the criteria for showing a causal association between exposure to asphalt and development of cancer. The studies cited all suffer from a lack of data on exposure or potential confounders, which are necessary to establish whether or not such an association may or may not exist. In view of the evidence (or lack thereof) regarding asphalt today, an appropriate public health attitude suggests at least that action be taken to protect those working with asphalt by monitoring the workplace, taking whatever steps are possible to minimise exposures and to inform workers of potential hazards. At the same time, a need exists for well designed analytical epidemiological studies to determine whether a risk of cancer in man exists from exposure to asphalt. PMID:1878310

A proposal to improve clarity and communication in the EU Classification process for chemicals for carcinogenicity and reproductive and developmental toxicity.

PubMed

Doe, J E

2014-10-01

There is an issue in the EU classification of substances for carcinogenicity and for reproductive or developmental toxicity which has brought difficulties to those involved in the process. The issue lies in the inability of the classification system to distinguish between carcinogens and reproductive toxicants with different levels of concern. This has its origins in the early years of toxicology when it was thought that a relatively small number of chemicals would be either carcinogens or reproductive toxicants, but this has turned out not to be the case. This can cause problems in communicating to the users of chemicals, including the public, the nature of the hazard presented by chemicals. Processes have been developed within the classification system for setting specific concentration limits which assess the degree of hazard for carcinogens and reproductive toxicants as high, medium or low. However these categories are not otherwise used in classification. It is proposed that their wider use would bring the advantages of transparency, clarity of communication, certainty of the process and would allow chemicals with a high degree of hazard to be identified and managed in an appropriate way. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

Genotoxicity and carcinogenicity of cobalt-, nickel- and copper-based nanoparticles

PubMed Central

MAGAYE, RUTH; ZHAO, JINSHUN; BOWMAN, LINDA; DING, MIN

2012-01-01

The nanotechnology industry has matured and expanded at a rapid pace in the last decade, leading to the research and development of nanomaterials with enormous potential. The largest source of these nanomaterials is the transitional metals. It has been revealed that numerous properties of these nano-sized elements are not present in their bulk states. The nano size of these particles means they are easily transported into biological systems, thus, raising the question of their effects on the susceptible systems. Although advances have been made and insights have been gained on the effect of transitional metals on susceptible biological systems, there still is much ground to be covered, particularly with respect to our knowledge on the genotoxic and carcinogenic effects. Therefore, this review intends to summarize the current knowledge on the genotoxic and carcinogenic potential of cobalt-, nickel- and copper-based nanoparticles indicated in in vitro and in vivo mammalian studies. In the present review, we briefly state the sources, use and exposure routes of these nanoparticles and summarize the current literature findings on their in vivo and in vitro genotoxic and carcinogenic effects. Due to the increasing evidence of their role in carcinogenicity, we have also included studies that have reported epigenetic factors, such as abnormal apoptosis, enhanced oxidative stress and pro-inflammatory effects involving these nanoparticles. PMID:23170105

Modeling gene-environment interactions in oral cavity and esophageal cancers demonstrates a role for the p53 R72P polymorphism in modulating susceptibility.

PubMed

Sarkar, Jayanta; Dominguez, Emily; Li, Guojun; Kusewitt, Donna F; Johnson, David G

2014-08-01

A large number of epidemiological studies have linked a common single-nucleotide polymorphism (SNP) in the human p53 gene to risk for developing a variety of cancers. This SNP encodes either an arginine or proline at position 72 (R72P) of the p53 protein, which can alter the apoptotic activity of p53 via transcriptional and non-transcriptional mechanisms. This SNP has also been reported to modulate the development of human papilloma virus (HPV)-driven cancers through differential targeting of the p53 variant proteins by the E6 viral oncoprotein. Mouse models for the p53 R72P polymorphism have recently been developed but a role for this SNP in modifying cancer risk in response to viral and chemical carcinogens has yet to be established experimentally. Here, we demonstrate that the p53 R72P polymorphism modulates the hyperprolferative, apoptotic and inflammatory phenotypes caused by expression of the HPV16 E6 and E7 oncoproteins. Moreover, the R72P SNP also modifies the carcinogenic response to the chemical carcinogen 4NQO, in the presence and absence of the HPV16 transgene. Our findings confirm several human epidemiological studies associating the codon 72 proline variant with increased risk for certain cancers but also suggest that there are tissue-specific differences in how the R72P polymorphism influences the response to environmental carcinogens. © 2013 Wiley Periodicals, Inc.

Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days: relationship between cell cycle aberration and carcinogenesis.

PubMed

Taniai, Eriko; Hayashi, Hitomi; Yafune, Atsunori; Watanabe, Maiko; Akane, Hirotoshi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2012-09-01

Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28 days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen, p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex + OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα-immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G₂. OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G₂/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G₂ arrest in the target tubular cells.

Transplacental Arsenic Carcinogenesis in Mice

PubMed Central

Waalkes, Michael P.; Liu, Jie; Diwan, Bhalchandra A.

2007-01-01

Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from day 8 to 18 of gestation, and the offspring were observed for up to two years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and investigating a potential transplacental component of the human carcinogenic response to arsenic should be a research priority. PMID:17306315

Evidence of carcinogenicity in humans of water-soluble nickel salts

PubMed Central

2010-01-01

Background Increased risks of nasal cancer and lung cancer in nickel refiners have been investigated scientifically and discussed since they were detected in the 1930s. Nickel compounds are considered to be the main cause of the cancer excess. Parts of the nickel producing industry and their consultants oppose the classification of water-soluble nickel salts as human carcinogens, and argue that the risk in exposed workers should be ascribed to other occupational exposures and smoking. Discussion Respiratory cancer risks in Welsh, Finnish, and Norwegian nickel refiners add to the evidence of carcinogenicity of water-soluble nickel. In Norwegian refiners, the first epidemiological study in 1973 identified high risks of lung cancer and nasal cancer among long-term electrolysis workers. Risk analyses based on exposure estimates developed in the 1980s supported the view that water-soluble nickel compounds were central in the development of cancer. Recently, new exposure estimates were worked out for the same cohort based on personal monitoring of total nickel and chemical determination of four forms of nickel. Additional data have been collected on life-time smoking habits, and on exposure to arsenic, asbestos, sulphuric acid mists, cobalt, and occupational lung carcinogens outside the refinery. After adjustment for these potential confounding exposures in case-control analyses, the risk pattern added to the evidence of an important role of water-soluble nickel compounds as causes of lung cancer. These Norwegian cancer studies rely on national Cancer Registry data, considered close to complete from 1953 onwards; and on National Population Register data continuously updated with mortality and emigration. Canadian mortality studies--perceived to offer the strongest support to the industry position not to recognise carcinogenicity of water-soluble nickel--appear to suffer from limitations in follow-up time, loss to follow-up, absence of risk analysis with individual exposure estimates, no confounder control, and a likely underestimation of cancer mortality. Conclusions Rejection to recognise water-soluble nickel as a human carcinogen seems to contradict material epidemiological evidence that demonstrates a strong association between water-soluble nickel compounds and risks of lung cancer and nasal cancer. Independent international scientific bodies have classified nickel compounds as carcinogenic to humans, inclusive of water-soluble nickel. PMID:20377901

TOXNET: Toxicology Data Network

MedlinePlus

... 4. Supporting Data for Carcinogenicity Expand II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure II. ... of Confidence (Carcinogenicity, Oral Exposure) Expand II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure II. ...

Being more realistic about chemical carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilkinson, C.F.

1987-09-01

Public awareness and fear of cancer in the US intensified during the late 1960s as a result of widely publicized associations between human cancer and a number of environmental factors associated with modern technology. In particular, attention was focused on the possible carcinogenic risks associated with the many products and by-products of the chemical industry, and there was enormous public pressure for prompt legislative action to regulate human exposure to potential carcinogens. As a result, legislation directed toward the protection of human health and the environment has increased dramatically during the past two decades. Approximately 30 such laws have beenmore » enacted, and although they differ in their objectives and regulatory authority, most are designed to control the carcinogenic and other health risks of chemicals introduced into commerce, released into the environment, or encountered in the workplace. Despite substantial progress in the past few years, basic understanding of carcinogenic mechanisms and the major factors causing human cancer still leaves much to be desired. There remains considerable uncertainty in current procedures for identifying and regulating potential human carcinogens. Unfortunately, the development of an acceptable policy for the regulation of chemical carcinogens constitutes a particularly troublesome problem, because it seeks to match argument based on uncertain science against the deep-seated human fear of cancer. It is not surprising that the question of how to regulate cancer risks in the US has become a highly divisive issue in which the limited amount of good science that is available either is not used to maximum advantage or rapidly becomes lost in a tangle of emotions and subjective value judgments.« less

The use of genetically modified mice in cancer risk assessment: challenges and limitations.

PubMed

Eastmond, David A; Vulimiri, Suryanarayana V; French, John E; Sonawane, Babasaheb

2013-09-01

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53⁺/⁻, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program's conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.

The use of genetically modified mice in cancer risk assessment: Challenges and limitations*

PubMed Central

Eastmond, David A.; Vulimiri, Suryanarayana V.; French, John E.; Sonawane, Babasaheb

2015-01-01

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53+/−, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program’s conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals. PMID:23985072

Chemometric evaluation of heavy metal pollutions in Patna region of the Ganges alluvial plain, India: implication for source apportionment and health risk assessment.

PubMed

Devi, Ningombam Linthoingambi; Yadav, Ishwar Chandra

2018-03-28

While metal pollution and distribution in soil are well documented for many countries, the situation is more serious in developing countries because of the rapid increase in industrialization and urbanization during last decades. Although it is well documented in developed countries, data about substantial metal pollution in Indian soil, especially in eastern Ganges alluvial plain (GAP), are limited. In this study, eight different blocks of Patna district located in eastern GAP were selected to investigate the contamination, accumulation, and sources of metals in surface soil considering different land use types. Additionally, human health risk assessment was estimated to mark the potential carcinogenic and non-carcinogenic effect of metals in soil. The concentration of all metals (except Pb) in soil was below the Indian standard limit of the potential toxic element for agricultural soil. Pb was the most abundant in soil, followed by Zn and Cu, and accounted for 52, 33 and 8% of the total metal. In terms of land use types, roadside soil detected higher concentrations of all metals, followed by park/grassland soil. Principal component analysis results indicated traffic pollution and industrial emissions are the major sources of heavy metals in soil. This was further confirmed by strong inter-correlation of heavy metals (Cd, Cr, Ni, Cu and Pb). Human health risk assessment results indicated ingestion via soil as the primary pathway of heavy metal exposure to both adults and children population. The estimated hazard index was highest for Pb, suggesting significant non-carcinogenic effect to both adults and children population. The children were more prone to the non-carcinogenic effect of Pb than adults. However, relatively low cancer risk value estimated for all metals suggested non-significant carcinogenic risk in the soil.

Ionization in liquids. Progress report, September 1, 1977-April 30, 1981

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bakale, G.

1980-12-19

Quasifree electrons simulate the behavior of unsolvated or dry electrons in aqueous media including the special case of biological systems. A model of direct radiosensitization was developed based on dry charge-carriers having an extended lifetime in the sheath of structured water that surrounds polar biomolecules. In this model, the pre-solvation lifetimes of dry electrons increased with an increase in the rotational times of solvent molecules. During the development of this model, an increasing number of radiosensitizers were found to be carcinogenic. Measurement of the k/sub e/'s of known carcinogens and noncarcinogens revealed that carcinogens attached quasifree electrons at diffusion-controlled rates,more » whereas the k/sub e/'s of noncarcinogens were significantly less. To explore the k/sub e/-carcinogenicity correlation further, a study of quasifree electron attachment to the water pools of reversed micelles was conducted. The degree of structuredness of the water pools which determines the k/sub e/ of the reversed micellar systems was also controlled. Another approach to controlling the microenvironment of quasifree electrons in biological systems was done in studies of radiation-induced damage to DNA in concentrated DNA solutions. The high concentration of DNA introduces more structure into the solutions than that occurring in typical in vitro experiments. The structural enhancement by DNA extends the lifetime of unsolvated charge-carriers. The DNA-damaging effects of radiolyticaly produced charge-carriers were also determined in studies of synergistic mutagenesis in bacteria simultaneously exposed to ionizing radiation and electrophilic chemical carcinogens. The attachment-detachment equilibrium of nicotine in hexane solutions was also studied. Both the kinetics and the thermodynamics of electron reactions were studied. (ERB)« less

Green tea catechin intervention of reactive oxygen species-mediated ERK pathway activation and chronically induced breast cell carcinogenesis

PubMed Central

Rathore, Kusum; Choudhary, Shambhunath; Odoi, Agricola; Wang, Hwa-Chain R.

2012-01-01

Long-term exposure to low doses of environmental carcinogens contributes to sporadic human breast cancers. Epidemiologic and experimental studies indicate that green tea catechins (GTCs) may intervene with breast cancer development. We have been developing a chronically induced breast cell carcinogenesis model wherein we repeatedly expose non-cancerous, human breast epithelial MCF10A cells to bioachievable picomolar concentrations of environmental carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), to progressively induce cellular acquisition of cancer-associated properties, as measurable end points. The model is then used as a target to identify non-cytotoxic preventive agents effective in suppression of cellular carcinogenesis. Here, we demonstrate, for the first time, a two-step strategy that initially used end points that were transiently induced by short-term exposure to NNK and B[a]P as targets to detect GTCs capable of blocking the acquisition of cancer-associated properties and subsequently used end points constantly induced by long-term exposure to carcinogens as targets to verify GTCs capable of suppressing carcinogenesis. We detected that short-term exposure to NNK and B[a]P resulted in elevation of reactive oxygen species (ROS), leading to Raf-independent extracellular signal-regulated kinase (ERK) pathway activation and subsequent induction of cell proliferation and DNA damage. These GTCs, at non-cytotoxic levels, were able to suppress chronically induced cellular carcinogenesis by blocking carcinogen-induced ROS elevation, ERK activation, cell proliferation and DNA damage in each exposure cycle. Our model may help accelerate the identification of preventive agents to intervene in carcinogenesis induced by long-term exposure to environmental carcinogens, thereby safely and effectively reducing the health risk of sporadic breast cancer. PMID:22045026

Current status and associated human health risk of vanadium in soil in China.

PubMed

Yang, Jie; Teng, Yanguo; Wu, Jin; Chen, Haiyang; Wang, Guoqiang; Song, Liuting; Yue, Weifeng; Zuo, Rui; Zhai, Yuanzheng

2017-03-01

A detailed assessment of vanadium contamination characteristics in China was conducted based on the first national soil pollution survey. The map overlay analysis was used to evaluate the contamination level of vanadium and the non-carcinogenic risk assessment model was calculated to quantify the vanadium exposure risks to human health. The results showed that, due to the drastically increased mining and smelting activities, 26.49% of soils were contaminated by vanadium scattered in southwest of China. According to Canadian soil quality guidelines, about 8.6% of the national soil pollution survey samples were polluted, and pose high non-carcinogenic risks to the public, especially to children living in the vicinity of heavily polluted mining areas. We propose the area near the boundary of Yunnan, Guizhou, Guangxi, and Sichuan provinces as priority control areas due to their higher geochemical background or higher health risks posed to the public. Finally, recommendations for management are proposed, including minimization of contaminant inputs, establishing stringent monitoring program, using phytoremediation, and strengthening the enforcement of relevant laws. Therefore, this study provides a comprehensive assessment of soil vanadium contamination in China, and the results will provide valuable information for China's soil vanadium management and risk avoidance. Copyright © 2016 Elsevier Ltd. All rights reserved.

Potential occupational risk of amines in carbon capture for power generation.

PubMed

Gentry, P Robinan; House-Knight, Tamara; Harris, Angela; Greene, Tracy; Campleman, Sharan

2014-08-01

While CO2 capture and storage (CCS) technology has been well studied in terms of its efficacy and cost of implementation, there is limited available data concerning the potential for occupational exposure to amines, mixtures of amines, or degradation of by-products from the CCS process. This paper is a critical review of the available data concerning the potential effects of amines and CCS-degradation by-products. A comprehensive review of the occupational health and safety issues associated with exposure to amines and amine by-products at CCS facilities was performed, along with a review of the regulatory status and guidelines of amines, by-products, and CCS process vapor mixtures. There are no specific guidelines or regulations regarding permissible levels of exposure via air for amines and degradation products that could form atmospheric oxidation of amines released from post-combustion CO2 capture plants. While there has been a worldwide effort to develop legal and regulatory frameworks for CCS, none are directly related to occupational exposures. By-products of alkanolamine degradation may pose the most significant health hazard to workers in CCS facilities, with several aldehydes, amides, nitramines, and nitrosamines classified as either known or potential/possible human carcinogens. The absence of large-scale CCS facilities; absence and unreliability of reported data in the literature from pilot facilities; and proprietary amine blends make it difficult to estimate potential amine exposures and predict formation and exposure to degradation products.

Risk-based indicators of Canadians' exposures to environmental carcinogens.

PubMed

Setton, Eleanor; Hystad, Perry; Poplawski, Karla; Cheasley, Roslyn; Cervantes-Larios, Alejandro; Keller, C Peter; Demers, Paul A

2013-02-12

Tools for estimating population exposures to environmental carcinogens are required to support evidence-based policies to reduce chronic exposures and associated cancers. Our objective was to develop indicators of population exposure to selected environmental carcinogens that can be easily updated over time, and allow comparisons and prioritization between different carcinogens and exposure pathways. We employed a risk assessment-based approach to produce screening-level estimates of lifetime excess cancer risk for selected substances listed as known carcinogens by the International Agency for Research on Cancer. Estimates of lifetime average daily intake were calculated using population characteristics combined with concentrations (circa 2006) in outdoor air, indoor air, dust, drinking water, and food and beverages from existing monitoring databases or comprehensive literature reviews. Intake estimates were then multiplied by cancer potency factors from Health Canada, the United States Environmental Protection Agency, and the California Office of Environmental Health Hazard Assessment to estimate lifetime excess cancer risks associated with each substance and exposure pathway. Lifetime excess cancer risks in excess of 1 per million people are identified as potential priorities for further attention. Based on data representing average conditions circa 2006, a total of 18 carcinogen-exposure pathways had potential lifetime excess cancer risks greater than 1 per million, based on varying data quality. Carcinogens with moderate to high data quality and lifetime excess cancer risk greater than 1 per million included benzene, 1,3-butadiene and radon in outdoor air; benzene and radon in indoor air; and arsenic and hexavalent chromium in drinking water. Important data gaps were identified for asbestos, hexavalent chromium and diesel exhaust in outdoor and indoor air, while little data were available to assess risk for substances in dust, food and beverages. The ability to track changes in potential population exposures to environmental carcinogens over time, as well as to compare between different substances and exposure pathways, is necessary to support comprehensive, evidence-based prevention policy. We used estimates of lifetime excess cancer risk as indicators that, although based on a number of simplifying assumptions, help to identify important data gaps and prioritize more detailed data collection and exposure assessment needs.

Monitoring carcinogen actions on DNA by 32P-postlabeling.

PubMed

Randerath, K; Randerath, E

1990-01-01

Among several recently developed analytical methods, 32P-postlabeling analysis is a highly sensitive method for the detection and measurement of covalent carcinogen-DNA adducts and other DNA modifications. Since the method does not require radioactive carcinogens, it is suitable for DNA of humans exposed to environmental or occupational genotoxicants. The basic procedure entails the enzymatic incorporation of 32P-label into monomeric or dimeric hydrolysis products of DNA, followed by chromatographic mapping and autoradiography of the 32P-labeled digestion products and quantitation by scintillation spectrometry. Microgram amounts of DNA are analyzed; thus the assay is well suited for limited amounts of cells or tissue. Various versions of the assay afford different sensitivities of adduct detection. Under optimal conditions, one aromatic or bulky/hydrophobic adduct in 10(8)-10(10) nucleotides can be detected and measured (corresponding to 0.3-30 amol adduct/microgram DNA or 0.1-10 nmol adduct/mol DNA-P). The assay has been successfully applied to a variety of mutagenic (genotoxic) as well as non-mutagenic carcinogens. In humans, the 32P-postlabeling assay has been applied to DNA specimens from cigarette smokers, iron foundry workers, and coke oven workers. Estimation of total aromatic adduct levels in exposed individuals gave values of 1 adduct in 10(6)-10(8) DNA nucleotides. These values are similar to the total levels of persistent adducts in tissues of animals after exposure to initiating or carcinogenic doses of authentic aromatic genotoxicants. Among the non-mutagenic carcinogens investigated are estrogens, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), choline-devoid diet, carbon tetrachloride, and peroxisome proliferators. In addition, age-dependent DNA modifications (I-compounds) are being detected by 32P-postlabeling in animals that have not been knowingly exposed to mutagens/carcinogens. I-compound profiles and levels are dependent on species, tissue, sex, and diet. Reduced levels of I-compounds have been consistently noted in the target organ of carcinogen-exposed animals and in resulting neoplasms, suggesting that I-compound loss may play a role in carcinogenesis.

Oral carcinogenesis is not achieved in different carcinogen-treated PAI-1 transgenic and wild-type mouse models.

PubMed

Avgoustidis, Dimitris; Nisyrios, Themistoklis; Nkenke, Emeka; Lijnen, Roger; Ragos, Vassilis; Perrea, Despina; Donta, Ismini; Vaena, Apostolia; Yapijakis, Christos; Vairaktaris, Eleftherios

2012-01-01

In an effort to assess the role of plasminogen activator inhibitor-1 (PAI-1) in oral squamous cancer development and progression, two different carcinogen treatment protocols were conducted. Protocol I included mice from a PAI-1 transgenic (Tg) breed (n=56) and their wild-type (WT) counterparts (n=56), divided into one control group and two main experimental groups, treated with 7,12-dimethylbenz[a]anthracene (DMBA) for 8 and 16 weeks, respectively. Protocol II included the same number and types of animals and groups, which were similarly treated with 4-Nitroquinoline 1-oxide (4-NQO) in drinking water. Two drugs that affect plasma PAI-1 levels, enalapril and pravastatin, were administered to certain subgroups of animals in both protocols. None of the animals developed macroscopically-visible oral cancer lesions. Eleven animals under Protocol I and 52 animals under Protocol II died. Skin lesions were noted only in DMBA-treated animals (n=9). Almost all animals administered with 4-NQO developed alopecia and lost weight, while two of them developed stomach tumours, and one female mouse developed a large ovarian cyst. Transgenic mice may respond differently when used in well-established carcinogen models and oral carcinogenesis is hard to achieve in these rodents.

EPA (Environmental Protection Agency) programs and the regulation of carcinogens: Methods and philosophies. Technical report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jackson, M.; Johnson, L.; Kelly, J.

1988-01-01

This paper discusses the manner in which the EPA identifies, assesses risk for, and regulates substances determined to cause cancer in humans. The report provides an overall perspective of the carcinogen standard-setting process as it is affected by scientific, legal, and political influences. Discussed are: history and methods of carcinogen regulation; toxicological methods for determining carcinogenicity; the use of human-exposure data to regulate carcinogens; an overview of the agency's system for classifying chemical agents suspected or known to cause cancer; significant Federal court cases and decisions that have influenced attempts by Federal agencies to regulate carcinogens; and factors affecting EPAsmore » regulation of carcinogens.« less

Induction of prophage lambda by chlorinated organics: Detection of some single-species/single-site carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeMarini, D.M.; Brooks, H.G.

1992-01-01

Twenty-eight chlorinated organic compounds were evaluated for their ability to induce DNA damage using the Microscreen prophage-induction assay in Escherichia coli. Comparison of the performance characteristics of the prophage-induction and Salmonella assays to rodent carcinogenicity assays showed that the prophage-induction assay had a somewhat higher specificity than did the Salmonella assay (70% vs. 50%); sensitivity, concordance, and positive and negative predictivity were similar for the two microbial assays. The Microscreen prophage-induction assay failed to detect eight carcinogens, perhaps due to toxicity or other unknown factors; five of these eight carcinogens were detected by the Salmonella assay. However, the prophage-induction assaymore » did detect six carcinogens that were not detected by the Salmonella assay, and five of these were single-species, single-site carcinogens, mostly mouse liver carcinogens. Some of these carcinogens, such as the chloroethanes, produce free radicals, which may be the basis for their carcinogenicity and ability to induce prophage. The prophage-induction (or other SOS) assay may be useful in identifying some genotoxic chlorinated carcinogens that induce DNA damage that do not revert the standard Salmonella tester strains.« less

Aberrant activation of ubiquitin D at G2 phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats.

PubMed

Taniai, Eriko; Yafune, Atsunori; Hayashi, Hitomi; Itahashi, Megu; Hara-Kudo, Yukiko; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2012-01-01

We have previously reported that renal carcinogens examined in rats increase tubular cell proliferation and topoisomerase (Topo) IIα(+) cells. The present study was aimed at identifying early prediction markers of carcinogens after 28-day treatment in rats. Following gene expression screening by microarrays in renal tubules with renal carcinogens, immunohistochemical analysis and TUNEL-assay were performed with carcinogens targeting different organs. All renal carcinogens tested (ferric nitrilotriacetic acid, ochratoxin A (OTA), monuron, tris(2-chloroethyl) phosphate, and potassium bromate) increased tubular cells immunoreactive for minichromosome maintenance 3 (Mcm3) or ubiquitin D (Ubd) or those showing apoptosis, compared with untreated controls or non-carcinogenic renal toxicants. Carcinogens targeting the liver (thioacetamide (TAA), fenbendazole, piperonyl butoxide (PBO) and methyleugenol), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole), glandular stomach (catechol), and colon (chenodeoxycholic acid and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) were examined for induction of Mcm3, Ubd, Topo IIα, Ki-67 and apoptosis using non-carcinogenic toxicants as negative controls. All carcinogens increased Mcm3(+), Ubd(+), Topo IIα(+), Ki-67(+) or TUNEL(+) cells, except for hepatocarcinogen PBO and both colon carcinogens, which did not increase cell proliferation. Ubd(+) cells co-expressing Topo IIα was increased without changing phospho-Histone H3-co-expressing cell population as examined with OTA and TAA. Results revealed cooperative responses of Topo IIα, Ubd and apoptosis by carcinogens inducing high proliferation activity, irrespective of target organs, examined here after a 28-day administration. Aberrant expression of Ubd at G(2) phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens.

The Role of Tobacco-Derived Carcinogens in Pancreas Cancer

PubMed Central

Lochan, Rajiv; Reeves, Helen L.; Daly, Anne K.; Charnley, Richard M.

2011-01-01

The extremely poor outcome from pancreas cancer is well known. However, its aetiology less well appreciated, and the molecular mechanisms underlying this are poorly understood. Tobacco usage is one of the strongest risk factors for this disease, and this is a completely avoidable hazard. In addition, there are well described hereditary diseases which predispose, and familial pancreas cancer. We have sought here to summarise the role of tobacco-derived carcinogens and the mode of their tumorigenic action on the pancreas. There is compelling evidence from animal and human studies (laboratory including cell line studies and epidemiologic) that tobacco derived carcinogens cause pancreas cancer. However, the manner in which they do so is not entirely apparent. There is also compelling evidence that synergism with genetic and other life-style factors—like diet obesity—results in a multifactorial causation of the disease. Ascertaining the role of tobacco carcinogens in the development of this cancer and their interaction with other risk factors will enable novel therapeutic and preventative strategies to improve outcome from this appalling malignancy. PMID:22084727

METABOLISM, GENOTOXICITY, AND CARCINOGENICITY OF COMFREY

PubMed Central

Mei, Nan; Guo, Lei; Fu, Peter P.; Fuscoe, James C.; Luan, Yang; Chen, Tao

2018-01-01

Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, comfrey is mutagenic in liver, and PA contained in comfrey appear to be responsible for comfrey-induced toxicity and tumor induction. PMID:21170807

Binding of environmental carcinogens to asbestos and mineral fibres.

PubMed Central

Harvey, G; Pagé, M; Dumas, L

1984-01-01

A rapid method has been developed for measuring the binding capacity of asbestos and other mineral fibres for environmental carcinogens. Benzo(alpha)pyrene (B(alpha)P), nitrosonornicotine (NNN), and N-acetyl-2-aminofluorene (NAAF) were assayed in the presence of Canadian grade 4T30 chrysotile, chrysotile A, amosite, crocidolite, glass microfibres, glasswool, attapulgite, and titanium dioxide. Chrysotile binds significantly more carcinogens than the other mineral fibres. This binding assay is reproducible with coefficients of variation of less than 8% and 6% respectively for inter and intra assay. The influence of pH was also studied, and there is good correlation between the carcinogen binding and the charge of the tested mineral fibres. The in vitro cytotoxicity on macrophage like cell line P388D1 and the haemolytic activity of various mineral fibres were also measured; a good correlation was found between the binding capacity and the cytotoxicity of tested mineral fibres on P388D1 cells. These results give some explanations for the reported synergism between exposure to asbestos and the smoking habits of workers. PMID:6331497

Development of a high-throughput enzyme-linked immunosorbent assay for the routine detection of the carcinogen acrylamide in food, via rapid derivatisation pre-analysis.

PubMed

Preston, Andrew; Fodey, Terence; Elliott, Christopher

2008-02-11

The spontaneous formation of the neurotoxic carcinogen acrylamide in a wide range of cooked foods has recently been discovered. These foods include bread and other bakery products, crisps, chips, breakfast cereals, and coffee. To date, the diminutive size of acrylamide (71.08 Da) has prevented the development of screening immunoassays for this chemical. In this study, a polyclonal antibody capable of binding the carcinogen was produced by the synthesis of an immunogen comprising acrylamide derivatised with 3-mercaptobenzoic acid (3-MBA), and its conjugation to the carrier protein bovine thyroglobulin. Antiserum from the immunised rabbit was harvested and fully characterised. It displayed no binding affinity for acrylamide or 3-MBA but had a high affinity for 3-MBA-derivitised acrylamide. The antisera produced was utilised in the development of an ELISA based detection system for acrylamide. Spiked water samples were assayed for acrylamide content using a previously published extraction method validated for coffee, crispbread, potato, milk chocolate and potato crisp matrices. Extracted acrylamide was then subjected to a rapid 1-h derivatisation with 3-MBA, pre-analysis. The ELISA was shown to have a high specificity for acrylamide, with a limit of detection in water samples of 65.7 microgkg(-1), i.e. potentially suitable for acrylamide detection in a wide range of food commodities. Future development of this assay will increase sensitivity further. This is the first report of an immunoassay capable of detecting the carcinogen, as its small size has necessitated current analytical detection via expensive, slower, physico-chemical techniques such as Gas or Liquid Chromatography coupled to Mass Spectrometry.

Carcinogenicity of Black Rock Harbor sediment to the eastern oyster and trophic transfer of Black Rock Harbor carcinogens from the blue mussel to the winter flounder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gardner, G.R.; Yevich, P.P.; Malcolm, A.R.

1991-01-01

The eastern oyster (Crassostrea virginica) developed neoplastic disorders when experimentally exposed both in the laboratory and field to chemically contaminated sediment from Black Rock Harbor (BRH), Bridgeport, Connecticut. Neoplasia was observed in oysters after 30 or 60 days of continuous exposure in a laboratory flow-through system to a 20 mg/L suspension of BRH sediment plus postexposure periods of 3, 30, or 60 days. Composite tumor incidence was 13.6% for both exposures. Tumor occurrence was highest in the renal excretory epithelium, followed in order by gill, gonad, gastrointestinal, heart, and embryonic neural tissue. Regression of experimental neoplasia was not observed whenmore » the stimulus was discontinued. In field experiments, gill neoplasms developed in oysters, deployed in cages for 30 days at BRH and 36 days at a BRH dredge material disposal area in Central Long Island Sound, and kidney and gastrointestinal neoplasms developed in caged oysters deployed 40 days in Quincy Bay, Boston Harbor. Oysters exposed to BRH sediment in the laboratory and in the field accumulated high concentrations of polychlorinated biphenyls (PCBs), polyaromatic hydrocarbons (PAHs), and chlorinated pesticides. Chemical analyses demonstrated high concentrations of PCBs, PAHs, chlorinated pesticides, and heavy metals in BRH sediment. Known genotoxic carcinogens, cocarcinogens, and tumor promoters were present as contaminants. The uptake of parent PAH and PCBs from BRH sediment observed in oysters also occurs in blue mussels (Mytilus edulis). Winter flounder fed BRH-contaminated blue mussels contained xenobiotic chemicals analyzed in mussels. The flounder developed renal and pancreatic neoplasms and hepatotoxic neoplastic precursor lesions, demonstrating trophic transfer of sediment-bound carcinogens up the food chain.« less

In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis.

PubMed

Kleinstreuer, Nicole C; Dix, David J; Houck, Keith A; Kavlock, Robert J; Knudsen, Thomas B; Martin, Matthew T; Paul, Katie B; Reif, David M; Crofton, Kevin M; Hamilton, Kerry; Hunter, Ronald; Shah, Imran; Judson, Richard S

2013-01-01

Thousands of untested chemicals in the environment require efficient characterization of carcinogenic potential in humans. A proposed solution is rapid testing of chemicals using in vitro high-throughput screening (HTS) assays for targets in pathways linked to disease processes to build models for priority setting and further testing. We describe a model for predicting rodent carcinogenicity based on HTS data from 292 chemicals tested in 672 assays mapping to 455 genes. All data come from the EPA ToxCast project. The model was trained on a subset of 232 chemicals with in vivo rodent carcinogenicity data in the Toxicity Reference Database (ToxRefDB). Individual HTS assays strongly associated with rodent cancers in ToxRefDB were linked to genes, pathways, and hallmark processes documented to be involved in tumor biology and cancer progression. Rodent liver cancer endpoints were linked to well-documented pathways such as peroxisome proliferator-activated receptor signaling and TP53 and novel targets such as PDE5A and PLAUR. Cancer hallmark genes associated with rodent thyroid tumors were found to be linked to human thyroid tumors and autoimmune thyroid disease. A model was developed in which these genes/pathways function as hypothetical enhancers or promoters of rat thyroid tumors, acting secondary to the key initiating event of thyroid hormone disruption. A simple scoring function was generated to identify chemicals with significant in vitro evidence that was predictive of in vivo carcinogenicity in different rat tissues and organs. This scoring function was applied to an external test set of 33 compounds with carcinogenicity classifications from the EPA's Office of Pesticide Programs and successfully (p = 0.024) differentiated between chemicals classified as "possible"/"probable"/"likely" carcinogens and those designated as "not likely" or with "evidence of noncarcinogenicity." This model represents a chemical carcinogenicity prioritization tool supporting targeted testing and functional validation of cancer pathways.

Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, Min; Yamada, Takanori; Yamano, Shotaro

2013-11-15

Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes inmore » the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA.« less

Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents.

PubMed

van den Brink, Willem; Emerenciana, Annette; Bellanti, Francesco; Della Pasqua, Oscar; van der Laan, Jan Willem

2017-04-01

Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessment of Carcinogenic and Non-Carcinogenic Risk Lead in Bottled Water in Different Age Groups in Bandar Abbas Ciry, Iran

PubMed Central

Fakhri, Yadolah; Mohseni, Seyed Mohsen; Jafarzadeh, Saeedeh; Langarizadeh, Ghazaleh; Moradi, Bigard; Zandsalimi, Yahya; Rahimizadeh, Aziz; Mirzaei, Maryam

2015-01-01

The presence of heavy metals such as lead in drinking water resources can be dangerous for human because of toxicity and biological accumulation. The consumption of water or food which contains lead in high concentration can lead to prevent from Hemoglobin Synthesis (Anemia) and Kidney diseases. In this present study, the researcher collected 432 samples of bottled water in the popular marks in summer and winter from the surface of Bandar Abbas. The lead concentration was measured by atomic absorption Spectrophotometer in model DR2800 through the Dithizone method. CDI, R and HQ which are caused by lead for adult men, women and children, have been calculated and evaluated through the equations of EPA and WHO. The mean concentration of lead, which is 3.46±0.47 µg/l, and its range, which is 1.9-17.6 µg/l, are lower than the guideline of WHO (10 µg/l) and MPC of EPA is (15 µg/l). But the 40 samples of the bottled water (9.2%) have the concentration higher than guideline WHO and 8 samples (1.85%) has the concentration higher than the permissible limits of the EPA. CDI in different age groups is as following manner: Children>adult men>adult women. CDI in children is more than twice as much as in the adult men and women. The R of lead for children (24E-7), adult men (11E-7) and for adult women (10E-7) are more than the acceptable level of R in EPA (1E-6) but less than the acceptable level of R in WHO (1E-4). Since HQ of adult men (34E-5), adult women (31E-5) and children (84E-5), is lower than 1, it can be said that the population of Bandar Abbas is in a safe area regarding the HQ of the bottled water’s lead. PMID:25946951

Health Risk Assessment of Cyanobacterial (Blue-green Algal) Toxins in Drinking Water

PubMed Central

Falconer, Ian R.; Humpage, Andrew R.

2005-01-01

Cyanobacterial toxins have caused human poisoning in the Americas, Europe and Australia. There is accumulating evidence that they are present in treated drinking water supplies when cyanobacterial blooms occur in source waters. With increased population pressure and depleted groundwater reserves, surface water is becoming more used as a raw water source, both from rivers and lakes/reservoirs. Additional nutrients in water which arise from sewage discharge, agricultural run-off or storm water result in overabundance of cyanobacteria, described as a ‘water bloom’. The majority of cyanobacterial water-blooms are of toxic species, producing a diversity of toxins. The most important toxins presenting a risk to the human population are the neurotoxic alkaloids (anatoxins and paralytic shellfish poisons), the cyclic peptide hepatotoxins (microcystins) and the cytotoxic alkaloids (cylindrospermopsins). At the present time the only cyanobacteral toxin family that have been internationally assessed for health risk by the WHO are the microcystins, which cause acute liver injury and are active tumour promoters. Based on sub-chronic studies in rodents and pigs, a provisional Guideline Level for drinking water of 1μg/L of microcystin-LR has been determined. This has been adopted in legislation in countries in Europe, South America and Australasia. This may be revised in the light of future teratogenicity, reproductive toxicity and carcinogenicity studies. The other cyanobacterial toxin which has been proposed for detailed health risk assessment is cylindrospermopsin, a cytotoxic compound which has marked genotoxicity, probable mutagenicity, and is a potential carcinogen. This toxin has caused human poisoning from drinking water, and occurs in water supplies in the USA, Europe, Asia, Australia and South America. An initial health risk assessment is presented with a proposed drinking water Guideline Level of 1μg/L. There is a need for both increased monitoring data for toxins in drinking water and epidemiological studies on adverse health effects in exposed populations to clarify the extent of the health risk. PMID:16705800

Health risk assessment of phthalate esters (PAEs) in drinking water sources of China.

PubMed

Wang, Wen-Long; Wu, Qian-Yuan; Wang, Chao; He, Tao; Hu, Hong-Ying

2015-03-01

Phthalate esters (PAEs) with endocrine disruption effects and carcinogenicity are widely detected in water environment. Occurrences of PAEs in source water and removal efficiencies of PAEs by drinking water treatment plants (DWTPs) in China were surveyed from publications in the last 10 years. Concentration of diethylhexyl phthalate (DEHP) in source water with median value of 1.3 μg/L was higher than that of dimethyl phthalate (DMP), diethyl phthalate (DEP), and di-n-butyl phthalate (DnBP). If the removal efficiencies of DEHP and DnBP reached 60 and 90 %, respectively, the calculated PAE concentration in drinking water can generally meet Standards for Drinking Water Quality in China. The health risks of PAEs, including non-carcinogenic and carcinogenic risks via the "water source-DWTP-oral ingestion/dermal permeation" pathway, were evaluated with Monte Carlo simulation and sensitivity analysis under certain removal efficiencies from 0 to 95 %. The carcinogenic risk of DEHP was lower than the upper acceptable carcinogenic risk level (10(-4)), while the probability of DEHP's carcinogenic risk between lower (10(-6)) and upper (10(-4)) acceptable carcinogenic risk level decreased from about 21.2 to 0.4 % through increasing DEHP removal efficiency from 0 to 95 %. The non-carcinogenic risk of DEHP was higher than that of DEP and DnBP. In all cases, the total non-carcinogenic risk of DEP, DnBP, and DEHP was lower than 1, indicating that there would be unlikely incremental non-carcinogenic risk to humans. Both carcinogenic risk and non-carcinogenic risk of PAEs in drinking water to female were a little higher than those to male.

Risk assessment for children exposed to DDT residues in various milk types from the Greek market.

PubMed

Tsakiris, Ioannis N; Goumenou, Marina; Tzatzarakis, Manolis N; Alegakis, Athanasios K; Tsitsimpikou, Christina; Ozcagli, Eren; Vynias, Dionysios; Tsatsakis, Aristidis M

2015-01-01

The occurrence of residues of DDT and its metabolites was monitored in 196 cow milk samples of various pasteurized commercial types collected from the Greek market. Residue levels were determined by GC-MS analysis. In 97.4% of the samples at least one DDT isomer or one of the DDT metabolites was detected, in levels not exceeding the maximum permitted residue level by the EU. Hazard Index for both carcinogenic and non-carcinogenic effects was estimated under two assumptions: a) using DDT concentrations from positive samples and b) imputing LOD/2 as an arbitrary concentration for negative samples. No statistically significant differences in detected or summed residue (p > 0.05) concentrations between different milk types were observed, with the exception of specific metabolites of DDT in some milk types. Exposure assessment scenarios were developed for children aged 1, 3, 5, 7 and 12 years old based on estimated body weights and daily milk consumption. Hazard Indices for non-carcinogenic effects were below 0.109 covering also carcinogenic effects according to WHO approach. The cancer risk values for carcinogenic effects according to the US EPA Cancer Benchmark Concentration approach, ranged from 0.4 to 18. For both effects the highest values were calculated for the 1- to 3-year-old age groups. Copyright © 2014 Elsevier Ltd. All rights reserved.

Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC.

PubMed

Tarazona, Jose V; Court-Marques, Daniele; Tiramani, Manuela; Reich, Hermine; Pfeil, Rudolf; Istace, Frederique; Crivellente, Federica

2017-08-01

Glyphosate is the most widely used herbicide worldwide. It is a broad spectrum herbicide and its agricultural uses increased considerably after the development of glyphosate-resistant genetically modified (GM) varieties. Since glyphosate was introduced in 1974, all regulatory assessments have established that glyphosate has low hazard potential to mammals, however, the International Agency for Research on Cancer (IARC) concluded in March 2015 that it is probably carcinogenic. The IARC conclusion was not confirmed by the EU assessment or the recent joint WHO/FAO evaluation, both using additional evidence. Glyphosate is not the first topic of disagreement between IARC and regulatory evaluations, but has received greater attention. This review presents the scientific basis of the glyphosate health assessment conducted within the European Union (EU) renewal process, and explains the differences in the carcinogenicity assessment with IARC. Use of different data sets, particularly on long-term toxicity/carcinogenicity in rodents, could partially explain the divergent views; but methodological differences in the evaluation of the available evidence have been identified. The EU assessment did not identify a carcinogenicity hazard, revised the toxicological profile proposing new toxicological reference values, and conducted a risk assessment for some representatives uses. Two complementary exposure assessments, human-biomonitoring and food-residues-monitoring, suggests that actual exposure levels are below these reference values and do not represent a public concern.

Concomitant consumption of marijuana, alcohol and tobacco in oral squamous cell carcinoma development and progression: recent advances and challenges.

PubMed

Lopes, Caio Fabio Baeta; de Angelis, Bruno Brandão; Prudente, Henrique Maciel; de Souza, Bernardo Vieira Goulart; Cardoso, Sérgio Vitorino; de Azambuja Ribeiro, Rosy Iara Maciel

2012-08-01

Oral squamous cell carcinoma (OSCC) corresponds to 95% of all malignant tumours of the mouth. The association between alcohol and tobacco is the major risk factor for this disease, increasing the chances for the development of OSCC by 35-fold. The plant, Cannabis sativa is smoked as cigarettes or blunts and is commonly used in association with tobacco and alcohol. Any type of smoking habit exposes individuals to a wide range of carcinogens or pro-carcinogens, such as polycyclic aromatic hydrocarbons, as well as some ethanol derived substances such as acetaldehyde (AA), and all are genotoxic in the same way. In addition, ethanol acts in the oral mucosa as a solvent and therefore increases the cellular membrane permeability to carcinogens. Carcinogens found in tobacco are also concentrated in marijuana, but the latter also contains high levels of cannabinoids, bioactive compounds responsible for several effects such as euphoria and analgesia. However, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the major psychotropic cannabinoid found in plants, causes a reduction of cellular metabolism and induction of apoptosis, both of which are anti-neoplastic properties. Apart from limited epidemiologic and experimental data, the effects of concomitant chronic exposure to marijuana (or Δ(9)-THC), tobacco and alcohol in OSCC development and progression is poorly known. This paper reviews the most recent findings on the effects of marijuana over cellular proliferation, as well as in the risk for OSCC, with emphasis on its interaction with tobacco and ethanol consumption. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide (Final Report)

EPA Science Inventory

EPA has finalized its Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide. This assessment addresses the potential carcinogenicity from long-term inhalation exposure to ethylene oxide. Now final, this assessment updates the carcinogenicity information in EPA’s 1985 Hea...

Moving forward in carcinogenicity assessment: Report of an EURL ECVAM/ESTIV workshop.

PubMed

Corvi, Raffaella; Madia, Federica; Guyton, Kathryn Z; Kasper, Peter; Rudel, Ruthann; Colacci, Annamaria; Kleinjans, Jos; Jennings, Paul

2017-12-01

There is an increased need to develop novel alternative approaches to the two-year rodent bioassay for the carcinogenicity assessment of substances where the rodent bioassay is still a basic requirement, as well as for those substances where animal use is banned or limited or where information gaps are identified within legislation. The current progress in this area was addressed in a EURL ECVAM- ESTIV workshop held in October 2016, in Juan les Pins. A number of initiatives were presented and discussed, including data-driven, technology-driven and pathway-driven approaches. Despite a seemingly diverse range of strategic developments, commonalities are emerging. For example, providing insight into carcinogenicity mechanisms is becoming an increasingly appreciated aspect of hazard assessment and is suggested to be the best strategy to drive new developments. Thus, now more than ever, there is a need to combine and focus efforts towards the integration of available information between sectors. Such cross-sectorial harmonisation will aid in building confidence in new approach methods leading to increased implementation and thus a decreased necessity for the two-year rodent bioassay. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Alert-QSAR. Implications for Electrophilic Theory of Chemical Carcinogenesis

PubMed Central

Putz, Mihai V.; Ionaşcu, Cosmin; Putz, Ana-Maria; Ostafe, Vasile

2011-01-01

Given the modeling and predictive abilities of quantitative structure activity relationships (QSARs) for genotoxic carcinogens or mutagens that directly affect DNA, the present research investigates structural alert (SA) intermediate-predicted correlations ASA of electrophilic molecular structures with observed carcinogenic potencies in rats (observed activity, A = Log[1/TD50], i.e., ASA=f(X1SA,X2SA,…)). The present method includes calculation of the recently developed residual correlation of the structural alert models, i.e., ARASA=f(A−ASA,X1SA,X2SA,…). We propose a specific electrophilic ligand-receptor mechanism that combines electronegativity with chemical hardness-associated frontier principles, equality of ligand-reagent electronegativities and ligand maximum chemical hardness for highly diverse toxic molecules against specific receptors in rats. The observed carcinogenic activity is influenced by the induced SA-mutagenic intermediate effect, alongside Hansch indices such as hydrophobicity (LogP), polarizability (POL) and total energy (Etot), which account for molecular membrane diffusion, ionic deformation, and stericity, respectively. A possible QSAR mechanistic interpretation of mutagenicity as the first step in genotoxic carcinogenesis development is discussed using the structural alert chemoinformation and in full accordance with the Organization for Economic Co-operation and Development QSAR guidance principles. PMID:21954348

Approaches to cancer prevention based on an understanding of N-nitrosamine carcinogenesis.

PubMed

Hecht, S S

1997-11-01

Understanding carcinogenesis is critical for development of rational approaches to cancer prevention. This paper uses N-nitrosamine carcinogenesis as an example. N-Nitrosamines are a large group of potent carcinogens. Approximately 300 different N-nitrosamines are carcinogenic. At least 30 animal species are responsive to their effects. There is little doubt that humans exposed to sufficient amounts of N-nitrosamines would also be susceptible to their carcinogenic effects. Human exposure to preformed N-nitrosamines occurs through the diet, in certain occupational settings, and through the use of tobacco products, cosmetics, pharmaceutical products, and agricultural chemicals. Diminishing human exposure to these carcinogens is one approach to prevention of cancer, and this has been accomplished in many instances, although exposure to N-nitrosamines in tobacco products is still unacceptably high. Human exposure to N-nitrosamines also occurs by nitrosation of amines in the body, via their acid or bacterial catalyzed reaction with nitrite, or by reaction with products of nitric oxide generated during inflammation or infection. A second approach toward prevention of N-nitrosamine carcinogenesis is inhibition of this endogenous N-nitrosamine formation. Substantial reductions have been achieved with ascorbic acid and other nitrite scavengers. N-Nitrosamines undergo a simple cytochrome P450-mediated metabolic activation step, which is critical for their carcinogenicity. The third approach involves the use of chemopreventive agents that block this step, or other steps in the carcinogenic process. A large number of potent chemopreventive agents against nitrosamine carcinogenesis have been identified. Chemoprevention of lung cancer induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is discussed as an example of this approach.

29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

Code of Federal Regulations, 2014 CFR

2014-07-01

... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

Code of Federal Regulations, 2013 CFR

2013-07-01

... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

Code of Federal Regulations, 2012 CFR

2012-07-01

... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

Code of Federal Regulations, 2011 CFR

2011-07-01

... carcinogens. 1990.131 Section 1990.131 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential...

An estimation of the carcinogenic risk associated with the intake of multiple relevant carcinogens found in meat and charcuterie products.

PubMed

Hernández, Ángel Rodríguez; Boada, Luis D; Almeida-González, Maira; Mendoza, Zenaida; Ruiz-Suárez, Norberto; Valeron, Pilar F; Camacho, María; Zumbado, Manuel; Henríquez-Hernández, Luis A; Luzardo, Octavio P

2015-05-01

Numerous epidemiological studies have demonstrated a link between excessive meat consumption and the incidence of various cancers, especially colorectal cancer, and it has been suggested that environmental carcinogens present in meat might be related to the increased risk of cancer associated with this food. However, there are no studies evaluating the carcinogenic potential of meat in relation to its content of carcinogens. Our purpose was to emphasize the relevance of environmental carcinogens existing in meat as a determinant of the association between cancer and meat consumption. Because within Europe, Spain shows high consumption of meat and charcuterie, we performed this study focusing on Spanish population. Based on the preferences of consumers we acquired 100 samples of meat and charcuterie that reflect the variety available in the European market. We quantified in these samples the concentration of 33 chemicals with calculated carcinogenic potential (PAHs, organochlorine pesticides, and dioxin-like PCBs). The carcinogenic risk of these contaminants was assessed for each food using a risk ratio based on the current consumption of meat and charcuterie and the maximum tolerable intake of these foods depending on the level of contamination by the carcinogens they contain. Our results indicate that the current consumption of beef, pork, lamb, chicken, and "chorizo", represents a relevant carcinogenic risk for consumers (carcinogenic risk quotient between 1.33 and 13.98). In order to reduce carcinogenic risk, the study population should halve the monthly consumption of these foods, and also not to surpass the number of 5 servings of beef/pork/chicken (considered together). Copyright © 2015 Elsevier B.V. All rights reserved.

Chicken Fetal Liver DNA Damage and Adduct Formation by Activation-Dependent DNA-Reactive Carcinogens and Related Compounds of Several Structural Classes

PubMed Central

Williams, Gary M.; Duan, Jian-Dong; Brunnemann, Klaus D.; Iatropoulos, Michael J.; Vock, Esther; Deschl, Ulrich

2014-01-01

The chicken egg genotoxicity assay (CEGA), which utilizes the liver of an intact and aseptic embryo-fetal test organism, was evaluated using four activation-dependent DNA-reactive carcinogens and four structurally related less potent carcinogens or non-carcinogens. In the assay, three daily doses of test substances were administered to eggs containing 9–11-day-old fetuses and the fetal livers were assessed for two endpoints, DNA breaks using the alkaline single cell gel electrophoresis (comet) assay and DNA adducts using the 32P-nucleotide postlabeling (NPL) assay. The effects of four carcinogens of different structures requiring distinct pathways of bioactivation, i.e., 2-acetylaminofluorene (AAF), aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), and diethylnitrosamine (DEN), were compared with structurally related non-carcinogens fluorene (FLU) and benzo[e]pyrene (B[e]P) or weak carcinogens, aflatoxin B2 (AFB2) and N-nitrosodiethanolamine (NDELA). The four carcinogens all produced DNA breaks at microgram or low milligram total doses, whereas less potent carcinogens and non-carcinogens yielded borderline or negative results, respectively, at higher doses. AAF and B[a]P produced DNA adducts, whereas none was found with the related comparators FLU or B[e]P, consistent with comet results. DEN and NDELA were also negative for adducts, as expected in the case of DEN for an alkylating agent in the standard NPL assay. Also, AFB1 and AFB2 were negative in NPL, as expected, due to the nature of ring opened aflatoxin adducts, which are resistant to enzymatic digestion. Thus, the CEGA, using comet and NPL, is capable of detection of the genotoxicity of diverse DNA-reactive carcinogens, while not yielding false positives for non-carcinogens. PMID:24973097

29 CFR 1990.147 - Final action.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.147 Final action. (a) Within one hundred twenty (120) days from the last day of... is classified as a Category I Potential Carcinogen or as a Category II Potential Carcinogen. If the...

29 CFR 1990.147 - Final action.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.147 Final action. (a) Within one hundred twenty (120) days from the last day of... is classified as a Category I Potential Carcinogen or as a Category II Potential Carcinogen. If the...

29 CFR 1990.147 - Final action.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.147 Final action. (a) Within one hundred twenty (120) days from the last day of... is classified as a Category I Potential Carcinogen or as a Category II Potential Carcinogen. If the...

29 CFR 1990.147 - Final action.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.147 Final action. (a) Within one hundred twenty (120) days from the last day of... is classified as a Category I Potential Carcinogen or as a Category II Potential Carcinogen. If the...

Integration of QSAR and SAR methods for the mechanistic interpretation of predictive models for carcinogenicity

PubMed Central

Fjodorova, Natalja; Novič, Marjana

2012-01-01

The knowledge-based Toxtree expert system (SAR approach) was integrated with the statistically based counter propagation artificial neural network (CP ANN) model (QSAR approach) to contribute to a better mechanistic understanding of a carcinogenicity model for non-congeneric chemicals using Dragon descriptors and carcinogenic potency for rats as a response. The transparency of the CP ANN algorithm was demonstrated using intrinsic mapping technique specifically Kohonen maps. Chemical structures were represented by Dragon descriptors that express the structural and electronic features of molecules such as their shape and electronic surrounding related to reactivity of molecules. It was illustrated how the descriptors are correlated with particular structural alerts (SAs) for carcinogenicity with recognized mechanistic link to carcinogenic activity. Moreover, the Kohonen mapping technique enables one to examine the separation of carcinogens and non-carcinogens (for rats) within a family of chemicals with a particular SA for carcinogenicity. The mechanistic interpretation of models is important for the evaluation of safety of chemicals. PMID:24688639

Identification of potential fish carcinogens in sediment from Hamilton Harbour, Ontario, Canada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balch, G.C.; Metcalfe, C.D.; Huestis, S.Y.

1995-01-01

A carcinogenicity- and mutagenicity-directed fractionation approach was used to identify the carcinogenic compounds in contaminated sediments that are putatively responsible for the high prevalence of tumors in bottom-dwelling fish from Hamilton Harbour, Ontario. Mutagenic activity was detected with Ames tester strains (TA98, TA100) in relatively nonpolar fractions of sediment extract containing PAHs and nitrogen-containing aromatic compounds (NCACs). These fractions were also carcinogenic in an in vivo carcinogenicity bioassay with rainbow trout (Oncorhynchus mykiss). When a more polar extract fraction was tested for mutagenicity and carcinogenicity, weak mutagenic activity was detected with an O-acetyltransferase-enriched Ames tester strain (YG1024), and weak carcinogenicmore » activity was detected in the rainbow trout assay. These data indicate that PAHs in contaminated Hamilton Harbour sediments are potent fish carcinogens, but it is also evident that other organic compounds in the sediment, such as NCACs and nitroarenes, may contribute to carcinogenicity.« less

MOUSE LIVER TUMOR DATA: ASSESSMENT OF CARCINOGENIC ACTIVITY

EPA Science Inventory

A significant number of chemicals have been shown to be carcinogenic in mouse liver while lacking carcinogenic activity in other organs or tissues of mice or rats. The review focus on the reasons for the unique susceptibility of the mouse liver to these carcinogens, and the exten...

78 FR 68849 - Draft Current Intelligence Bulletin “Update of NIOSH Carcinogen Classification and Target Risk...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-15

...; Docket Number NIOSH 240-A] Draft Current Intelligence Bulletin ``Update of NIOSH Carcinogen... document for public comment entitled ``Current Intelligence Bulletin: Update of NIOSH Carcinogen... obtain comments on the draft document, ``Current Intelligence Bulletin: Update of NIOSH Carcinogen...

Source apportionment and health risk assessment among specific age groups during haze and non-haze episodes in Kuala Lumpur, Malaysia.

PubMed

Sulong, Nor Azura; Latif, Mohd Talib; Khan, Md Firoz; Amil, Norhaniza; Ashfold, Matthew J; Wahab, Muhammad Ikram Abdul; Chan, Kok Meng; Sahani, Mazrura

2017-12-01

This study aims to determine PM 2.5 concentrations and their composition during haze and non-haze episodes in Kuala Lumpur. In order to investigate the origin of the measured air masses, the Numerical Atmospheric-dispersion Modelling Environment (NAME) and Global Fire Assimilation System (GFAS) were applied. Source apportionment of PM 2.5 was determined using Positive Matrix Factorization (PMF). The carcinogenic and non-carcinogenic health risks were estimated using the United State Environmental Protection Agency (USEPA) method. PM 2.5 samples were collected from the centre of the city using a high-volume air sampler (HVS). The results showed that the mean PM 2.5 concentrations collected during pre-haze, haze and post-haze periods were 24.5±12.0μgm -3 , 72.3±38.0μgm -3 and 14.3±3.58μgm -3 , respectively. The highest concentration of PM 2.5 during haze episode was five times higher than World Health Organisation (WHO) guidelines. Inorganic compositions of PM 2.5 , including trace elements and water soluble ions were determined using inductively coupled plasma-mass spectrometry (ICP-MS) and ion chromatography (IC), respectively. The major trace elements identified were K, Al, Ca, Mg and Fe which accounted for approximately 93%, 91% and 92% of the overall metals' portions recorded during pre-haze, haze and post-haze periods, respectively. For water-soluble ions, secondary inorganic aerosols (SO 4 2- , NO 3 - and NH 4 + ) contributed around 12%, 43% and 16% of the overall PM 2.5 mass during pre-haze, haze and post-haze periods, respectively. During haze periods, the predominant source identified using PMF was secondary inorganic aerosol (SIA) and biomass burning where the NAME simulations indicate the importance of fires in Sumatra, Indonesia. The main source during pre-haze and post-haze were mix SIA and road dust as well as mineral dust, respectively. The highest non-carcinogenic health risk during haze episode was estimated among the infant group (HI=1.06) while the highest carcinogenic health risk was estimated among the adult group (2.27×10 -5 ). Copyright © 2017 Elsevier B.V. All rights reserved.

Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats.

PubMed

Yafune, Atsunori; Taniai, Eriko; Morita, Reiko; Hayashi, Hitomi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2013-06-07

We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1α (HP1α)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1α responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

29 CFR 1910.1003 - 13 Carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2010 CFR

2010-07-01

.... Disposal means the safe removal of the carcinogens addressed by this section from the work environment... in an environment free of the 13 carcinogens addressed by this section. The clean change room shall... external environment. Decontamination means the inactivation of a carcinogen addressed by this section or...

Aspartame and Risk of Cancer: A Meta-analytic Review.

PubMed

Mallikarjun, Sreekanth; Sieburth, Rebecca McNeill

2015-01-01

Aspartame (APM) is the most commonly used artificial sweetener and flavor enhancer in the world. There is a rise in concern that APM is carcinogenic due to a variation in the findings of the previous APM carcinogenic bioassays. This article conducts a meta-analytic review of all previous APM carcinogenic bioassays on rodents that were conducted before 31 December 2012. The search yielded 10 original APM carcinogenic bioassays on rodents. The aggregate effect sizes suggest that APM consumption has no significant carcinogenic effect in rodents.

Maté: a risk factor for oral and oropharyngeal cancer.

PubMed

Goldenberg, David

2002-10-01

Maté is a tea-like beverage consumed mainly in Argentina, Uruguay, Paraguay, southern Brazil and to a lesser degree in other areas of the world such as Germany, Syria, Lebanon and Northern Israel. It is brewed from the dried leaves and stemlets of the perennial tree Ilex paraguarensis ("yerba mate") a species that belongs to the Aquifoliaceae family. Maté consumption has been associated with an increased rate of oral and oropharyngeal cancers. The purpose of this study is to review the literature and discuss the role of Maté consumption in the development of oral and oropharyngeal cancer and the potential carcinogenic mechanisms. A review of the relevant literature linking Maté consumption with oral and oropharyngeal cancer and the carcinogenicity of Maté was performed. The search was performed using Medline, library catalogues, OCLC first search and ISI web of science databases. Case control studies on Maté drinking populations and, in vivo and in vitro studies on the carcinogenicity of Maté were reviewed. The populations reviewed in many of these studies also used alcohol and tobacco products confounding the influence of Maté as an independent risk factor. There is evidence in the literature that Maté consumption is in itself carcinogenic and plays a role in the development of cancers of the oral cavity and oropharynx. Although the exact mechanism of carcinogenesis is still unknown, available information suggests that Maté drinking should be considered one of the risk factors for oral and oropharyngeal cancer.

Prediction of Chemical Carcinogenicity in Rodents from in vitro Genetic Toxicity Assays

NASA Astrophysics Data System (ADS)

Tennant, Raymond W.; Margolin, Barry H.; Shelby, Michael D.; Zeiger, Errol; Haseman, Joseph K.; Spalding, Judson; Caspary, William; Resnick, Michael; Stasiewicz, Stanley; Anderson, Beth; Minor, Robert

1987-05-01

Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays. To help put this project into its proper context, we emphasize certain features of the study: 1) Standard protocols were used to mimic the major use of STTs worldwide--screening for mutagens and carcinogens; no attempt was made to optimize protocols for specific chemicals. 2) The 73 NTP chemicals and their 60% incidence of carcinogenicity are probably not representative of the universe of chemicals but rather reflect the recent chemical selection process for the NTP carcinogenicity assay. 3) The small, diverse group of chemicals precludes a meaningful evaluation of the predictive utility of chemical structure information. 4) The NTP is currently testing these same 73 chemicals in two in vivo STTs for chromosomal effects. 5) Complete data for an additional group of 30 to 40 NTP chemicals will be gathered on carcinogenicity and the four in vitro STTs to attempt to confirm the current findings. The standard against which the performance of STTs is measured has changed dramatically in the past decade. The high levels of concordance published in the early 1970s were accurate at the time. Nearly all known carcinogens tested were genotoxic, and there was little experimental evidence on which to base a judgment of noncarcinogenicity which, taken together, restricted assessment of test performances with noncarcinogens. With the increasing availability of results from NCI and NTP 2-year carcinogenicity studies in rodents, higher frequencies of nongenotoxic carcinogens and genotoxic noncarcinogens have been observed; this has resulted in the reduced concordance of the STT results with carcinogenicity results. It is clear that even with a battery of assays, not all rodent carcinogens are in vitro mutagens nor are all in vitro mutagens rodent carcinogens. If current in vitro STTs are expected to replace long-term rodent studies for the identification of chemical carcinogens, then that expectation should be abandoned. STTs do, however, continue to offer an economical, rapid, and dependable means to detect genotoxic chemicals. There is a range of applications in which STTs have been used successfully, from the identification of mutagenic fractions in complex mixtures such as cooked meat (32, 33) or air pollutants (34) to the early identification of genetic toxicity in the development of new chemical products (35). Requirements for the use of STT have not been consistent in both the national and international regulatory agencies. This is evident in the variety of testing requirements (8) and the different impacts that positive test results have on the registration or further testing requirements of chemicals. Consensus on these matters is not likely to occur in the near future, but agreement should be possible in certain areas. For instance, any time a new test or strategy is proposed, it is imperative that there be documentation by a substantial set of systematically acquired test results on well-defined rodent carcinogens and noncarcinogens (36). The current study represents a prototype of the evaluative effort needed for such documentation. Results of the current study focus attention on two questions involving discordances between carcinogenicity and genotoxicity test results: (i) Do nongenotoxic rodent carcinogens pose the same carcinogenic risk to humans as those that are genotoxic? (ii) Can the apparent high frequency of in vitro genotoxic rodent noncarcinogens be explained as a combination of artifacts arising from extremely high dosing in in vitro tests or the failure of many bona fide in vitro genotoxins to express their genetic toxicity in whole animals? Until these questions are resolved, chemicals that show mutagenic effects, particularly if such effects are observed in vivo, must be initially considered to pose human health risks as long as the somatic mutation theory of cancer remains a viable explanation for the etiology of some chemically induced cancers.

Health-hazard evaluation report HETA 90-390-2065 and mHETA 86-012-2065, R. T. Vanderbilt Company, Gouverneur, New York and NIOSH comments to OSHA on Variations in the Carcinogenicity of Tremolite Dust Samples of Differing Morphology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, D.P.; Sanderson, W.; Fine, L.J.

1990-09-01

The testimony concerned the comments of NIOSH on a manuscript entitled Variations in the Carcinogenicity of Tremolite (77536686) Dust Samples of Differing Morphology. In general the results presented in the publication have not been peer reviewed or published in the scientific literature and therefore NIOSH suggested they be viewed with caution. Appropriate controls were not included in the study, the material and methods section lacked sufficient detail to evaluate the results, and the results were presented in an awkward and confusing way. The interpretation of results for the evidence of carcinogenicity in two of the samples was questionable. Mineralogic classificationmore » of the various samples, particularly three of the samples, was unclear. To what degree the nonasbestiform varieties of tremolite used in the study represent other varieties in the world was not clear. Dose-response relationships associated with fibers from these tremolite samples were not able to be developed. In general, the results appeared to demonstrate that all forms of tremolite asbestos should be considered carcinogenic.« less

Occurrence of Pineal Gland Tumors in Combined Chronic Toxicity/Carcinogenicity Studies in Wistar Rats.

PubMed

Treumann, Silke; Buesen, Roland; Gröters, Sibylle; Eichler, Jens-Olaf; van Ravenzwaay, Bennard

2015-08-01

Pineal gland tumors are very rare brain lesions in rats as well as in other species including humans. A total of 8 (out of 1,360 examined) Wistar rats from 3 different combined chronic toxicity/carcinogenicity or mere carcinogenicity studies revealed pineal gland tumors. The tumors were regarded to be spontaneous and unrelated to treatment. The morphology and immunohistochemical evaluation led to the diagnosis malignant pinealoma. The main characteristics that were variably developed within the tumors were the following: cellular atypia, high mitotic index, giant cells, necrosis, Homer Wright rosettes, Flexner-Wintersteiner rosettes and pseudorosettes, positive immunohistochemical reaction for synaptophysin, and neuron-specific enolase. The pineal gland is not a protocol organ for histopathological examination in carcinogenicity studies. Nevertheless, the pineal gland can occasionally be encountered on the routine brain section or if it is the origin of a tumor protruding into the brain, the finding will be recorded. Therefore, although known to be a rare tumor in rats, pineal neoplasms should be included in the list of possible differential diagnoses for brain tumors, especially when the tumor is located in the region of the pineal body. © 2015 by The Author(s).

Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review.

PubMed

Demeyer, Daniel; Mertens, Birgit; De Smet, Stefaan; Ulens, Michèle

2016-12-09

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The vast majority of CRC cases have been linked to environmental causes rather than to heritable genetic changes. Over the last decades, epidemiological evidence linking the consumption of red and, more convincingly, of processed red meat to CRC has accumulated. In parallel, hypotheses on carcinogenic mechanisms underlying an association between CRC and the intake of red and processed red meat have been proposed and investigated in biological studies. The hypotheses that have received most attention until now include (1) the presence of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, two groups of compounds recognized as carcinogenic, (2) the enhancing effect of (nitrosyl)heme on the formation of carcinogenic N-nitroso compounds and lipid peroxidation. However, none of these hypotheses completely explains the link between red and processed red meat intake and the CRC risk. Consequently, scientists have proposed additional mechanisms or refined their hypotheses. This review first briefly summarizes the development of CRC followed by an in-depth overview and critical discussion of the different potential carcinogenic mechanisms underlying the increased CRC risk associated with the consumption of red and processed red meat.

A Systematic Review of Carcinogenic Outcomes and Potential Mechanisms from Exposure to 2,4-D and MCPA in the Environment

PubMed Central

von Stackelberg, Katherine

2013-01-01

Chlorophenoxy compounds, particularly 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxy)acetic acid (MCPA), are amongst the most widely used herbicides in the United States for both agricultural and residential applications. Epidemiologic studies suggest that exposure to 2,4-D and MCPA may be associated with increased risk non-Hodgkins lymphoma (NHL), Hodgkin's disease (HD), leukemia, and soft-tissue sarcoma (STS). Toxicological studies in rodents show no evidence of carcinogenicity, and regulatory agencies worldwide consider chlorophenoxies as not likely to be carcinogenic or unclassifiable as to carcinogenicity. This systematic review assembles the available data to evaluate epidemiologic, toxicological, pharmacokinetic, exposure, and biomonitoring studies with respect to key cellular events noted in disease etiology and how those relate to hypothesized modes of action for these constituents to determine the plausibility of an association between exposure to environmentally relevant concentrations of 2,4-D and MCPA and lymphohematopoietic cancers. The combined evidence does not support a genotoxic mode of action. Although plausible hypotheses for other carcinogenic modes of action exist, a comparison of biomonitoring data to oral equivalent doses calculated from bioassay data shows that environmental exposures are not sufficient to support a causal relationship. Genetic polymorphisms exist that are known to increase the risk of developing NHL. The potential interaction between these polymorphisms and exposures to chlorophenoxy compounds, particularly in occupational settings, is largely unknown. PMID:23533401

Indoor air-assessment: Indoor concentrations of environmental carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gold, K.W.; Naugle, D.F.; Berry, M.A.

1991-01-01

In the report, indoor concentration data are presented for the following general categories of air pollutants: radon-222, environmental tobacco smoke (ETS), asbestos, gas phase organic compounds, formaldehyde, polycyclic aromatic hydrocarbons (PAH), pesticides, and inorganic compounds. These pollutants are either known or suspect carcinogens (i.e., radon-222, asbestos) or more complex mixtures or classes of compounds which contain known or suspect carcinogens. Concentration data for individual carcinogenic compounds in complex mixtures are usually far from complete. The data presented for complex mixtures often include compounds which are not carcinogenic or for which data are insufficient to evaluate carcinogenicity. Their inclusion is justified,more » however, by the possibility that further work may show them to be carcinogens, cocarcinogens, initiators or promotors, or that they may be employed as markers (e.g., nicotine, acrolein) for the estimation of exposure to complex mixtures.« less

40 CFR 266.106 - Standards to control metals emissions.

Code of Federal Regulations, 2013 CFR

2013-07-01

...-specific doses (RSDs) are listed for the carcinogenic metals. The RSD for a metal is the acceptable ambient... RSD as described in paragraph (d)(3) of this section. (3) Carcinogenic metals. For the carcinogenic... person resides on site) to the risk-specific dose (RSD) for all carcinogenic metals emitted shall not...

40 CFR 266.106 - Standards to control metals emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

...-specific doses (RSDs) are listed for the carcinogenic metals. The RSD for a metal is the acceptable ambient... RSD as described in paragraph (d)(3) of this section. (3) Carcinogenic metals. For the carcinogenic... person resides on site) to the risk-specific dose (RSD) for all carcinogenic metals emitted shall not...

40 CFR 266.106 - Standards to control metals emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

...-specific doses (RSDs) are listed for the carcinogenic metals. The RSD for a metal is the acceptable ambient... RSD as described in paragraph (d)(3) of this section. (3) Carcinogenic metals. For the carcinogenic... person resides on site) to the risk-specific dose (RSD) for all carcinogenic metals emitted shall not...

Small fish models for identifying carcinogens in the aqueous environment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hawkins, W.E.; Overstreet, R.M.; Walker, W.W.

1988-10-01

Contaminants in water and sediments can be carcinogenic to aquatic wildlife as well as humans. Identifying those carcinogens, however, is difficult because they often occur in low concentrations and exert their effects over a large part of the life span of affected organisms. Furthermore, the carcinogens are often components of complex mixtures. Recent studies suggest that laboratory-reared fish species might be well suited for testing water-associated and other carcinogens. Here, we review the principal carcinogen exposure methods that utilize small fish species or can be adapted to utilize small fish species to detect carcinogens in aqueous environments. Emphasis is placedmore » on methods for which the end-point is tumor induction. The methods discussed are dietary exposures, skin painting, embryo microinjection, early life stage (pulse) exposures, static water exposures, flow-through exposures, and controlled field exposures. Early life stage exposures seem to have the greatest utility with regard to carcinogen sensitivity, ease of administration, disposal of test compounds, and economy of materials and effort. For certain types of carcinogens, however, long-term flow-through exposures are probably required. In summary, small fish carcinogenesis models offer an array of methodologies that can be utilized in a variety of combinations depending on compounds tested, exposure parameters employed, and end point sought.« less

Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry.

PubMed

El-Bayoumy, Karam; Chen, Kun-Ming; Zhang, Shang-Min; Sun, Yuan-Wan; Amin, Shantu; Stoner, Gary; Guttenplan, Joseph B

2017-01-17

Worldwide, cancers of the oral cavity and pharynx comprise the sixth most common malignancies. Histologically, more than 90% of oral cancers are squamous cell carcinoma (SCC). Epidemiologic data strongly support the role of exogenous factors such as tobacco, alcohol, and human papilloma virus infection as major causative agents. Avoidance of risk factors has only been partially successful, and survival rates have not improved despite advances in therapeutic approaches. Therefore, new or improved approaches to prevention and/or early detection are critical. Better understanding of the mechanisms of oral carcinogenesis can assist in the development of novel biomarkers for early detection and strategies for disease prevention. Toward this goal, several animal models for carcinogenesis in the oral cavity have been developed. Among these are xenograft, and transgenic animal models, and others employing the synthetic carcinogens such as 7,12-dimethylbenz[a]anthracene in hamster cheek pouch and 4-nitroquinoline-N-oxide in rats and mice. Additional animal models employing environmental carcinogens such as benzo[a]pyrene and N'-nitrosonornicotine have been reported. Each model has certain advantages and disadvantages. Models that (1) utilize environmental carcinogens, (2) reflect tumor heterogeneity, and (3) accurately represent the cellular and molecular changes involved in the initiation and progression of oral cancer in humans could provide a realistic platform. To achieve this goal, we introduced a novel nonsurgical mouse model to study oral carcinogenesis induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and tobacco smoke constituent, and its diol epoxide metabolite (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene [(±)-anti-DB[a,l]PDE]. On the basis of a detailed comparison of oral cancer induced by DB[a,l]P with that induced by the other above-mentioned oral carcinogens with respect to dose, duration, species and strain, cellular and molecular targets, and relative carcinogenic potency, our animal model may offer a more realistic platform to study oral carcinogenesis. In this perspective, we also discuss our preclinical studies to demonstrate the potential of black raspberry extracts on the prevention of OSCC. Specifically, we were the first to demonstrate that black raspberry inhibited DB[a,l]P-DNA binding and of particular importance its capacity to enhance the repair of DB[a,l]P-induced bulky lesions in DNA. We believe that the information presented in this perspective will stimulate further research on the impact of environmental carcinogens in the development of oral cancer and may lead to novel strategies toward the control and prevention of this disease.

Target organs in chronic bioassays of 533 chemical carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gold, L.S.; Slone, T.H.; Manley, N.B.

1991-06-01

A compendium of carcinogenesis bioassay results organized by target organ is presented for 533 chemicals that are carcinogenic in at least one species. This compendium is based primarily on experiments in rats or mice; results in hamsters, nonhuman primates, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites, and to determine whether target sites are the same for chemicals positive in more than one species. The Carcinogenic Potency Database (CPDB), which includes results of 3969 experiments, is used in the analysis. The published CPDB includes details on each test, andmore » literature references. Chemical carcinogens are reported for 35 different target organs in rats or mice. More than 80% of the carcinogens in each of these species are positive in at least one of the 8 most frequent target sites; liver, lung, mammary gland, stomach, vascular system, kidney, hematopoietic system, and urinary bladder. An analysis is presented of how well one can predict the carcinogenic response in mice from results in rats, or vice versa. Among chemicals tested in both species, 76% of rat carcinogens are positive in mice, and 71% of mouse carcinogens are positive in rats. Prediction is less accurate to the same target site: 52% of rat carcinogens are positive in the same site in mice, and 48% of mouse carcinogens are positive in the same site in rats. The liver is the most frequent site in common between rats and mice.« less

Chicken fetal liver DNA damage and adduct formation by activation-dependent DNA-reactive carcinogens and related compounds of several structural classes.

PubMed

Williams, Gary M; Duan, Jian-Dong; Brunnemann, Klaus D; Iatropoulos, Michael J; Vock, Esther; Deschl, Ulrich

2014-09-01

The chicken egg genotoxicity assay (CEGA), which utilizes the liver of an intact and aseptic embryo-fetal test organism, was evaluated using four activation-dependent DNA-reactive carcinogens and four structurally related less potent carcinogens or non-carcinogens. In the assay, three daily doses of test substances were administered to eggs containing 9-11-day-old fetuses and the fetal livers were assessed for two endpoints, DNA breaks using the alkaline single cell gel electrophoresis (comet) assay and DNA adducts using the (32)P-nucleotide postlabeling (NPL) assay. The effects of four carcinogens of different structures requiring distinct pathways of bioactivation, i.e., 2-acetylaminofluorene (AAF), aflatoxin B1 (AFB1), benzo[a]pyrene (B[a]P), and diethylnitrosamine (DEN), were compared with structurally related non-carcinogens fluorene (FLU) and benzo[e]pyrene (B[e]P) or weak carcinogens, aflatoxin B2 (AFB2) and N-nitrosodiethanolamine (NDELA). The four carcinogens all produced DNA breaks at microgram or low milligram total doses, whereas less potent carcinogens and non-carcinogens yielded borderline or negative results, respectively, at higher doses. AAF and B[a]P produced DNA adducts, whereas none was found with the related comparators FLU or B[e]P, consistent with comet results. DEN and NDELA were also negative for adducts, as expected in the case of DEN for an alkylating agent in the standard NPL assay. Also, AFB1 and AFB2 were negative in NPL, as expected, due to the nature of ring opened aflatoxin adducts, which are resistant to enzymatic digestion. Thus, the CEGA, using comet and NPL, is capable of detection of the genotoxicity of diverse DNA-reactive carcinogens, while not yielding false positives for non-carcinogens. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Using the Hill viewpoints from 1965 for evaluating strengths of evidence of the risk for brain tumors associated with use of mobile and cordless phones.

PubMed

Hardell, Lennart; Carlberg, Michael

2013-01-01

Wireless phones, i.e., mobile phones and cordless phones, emit radiofrequency electromagnetic fields (RF-EMF) when used. An increased risk of brain tumors is a major concern. The International Agency for Research on Cancer (IARC) at the World Health Organization (WHO) evaluated the carcinogenic effect to humans from RF-EMF in May 2011. It was concluded that RF-EMF is a group 2B, i.e., a "possible", human carcinogen. Bradford Hill gave a presidential address at the British Royal Society of Medicine in 1965 on the association or causation that provides a helpful framework for evaluation of the brain tumor risk from RF-EMF. All nine issues on causation according to Hill were evaluated. Regarding wireless phones, only studies with long-term use were included. In addition, laboratory studies and data on the incidence of brain tumors were considered. The criteria on strength, consistency, specificity, temporality, and biologic gradient for evidence of increased risk for glioma and acoustic neuroma were fulfilled. Additional evidence came from plausibility and analogy based on laboratory studies. Regarding coherence, several studies show increasing incidence of brain tumors, especially in the most exposed area. Support for the experiment came from antioxidants that can alleviate the generation of reactive oxygen species involved in biologic effects, although a direct mechanism for brain tumor carcinogenesis has not been shown. In addition, the finding of no increased risk for brain tumors in subjects using the mobile phone only in a car with an external antenna is supportive evidence. Hill did not consider all the needed nine viewpoints to be essential requirements. Based on the Hill criteria, glioma and acoustic neuroma should be considered to be caused by RF-EMF emissions from wireless phones and regarded as carcinogenic to humans, classifying it as group 1 according to the IARC classification. Current guidelines for exposure need to be urgently revised.

Chemical carcinogens: a review of the science and its associated principles. U.S. Interagency Staff Group on Carcinogens.

PubMed Central

1986-01-01

In order to articulate a view of chemical carcinogenesis that scientists generally hold in common today and to draw upon this understanding to compose guiding principles that can be used as a bases for the efforts of the regulatory agencies to establish guidelines for assessing carcinogenic risk to meet the specific requirements of the legislative acts they are charged to implement, the Office of Science and Technology Policy, Executive Office, the White House drew on the expertise of a number of regulatory agencies to elucidate present scientific views in critical areas of the major disciplines important to the process of risk assessment. The document is composed of two major sections, Principles and the State-of-the-Science. The latter consists of subsections on the mechanisms of carcinogenesis, short-term and long-term testing, and epidemiology, which are important components in the risk assessment step of hazard identification. These subsections are followed by one on exposure assessment, and a final section which includes analyses of dose-response (hazard) assessment and risk characterization. The principles are derived from considerations in each of the subsections. Because of present gaps in understanding, the principles contain judgmental (science policy) decisions on major unresolved issues as well as statements of what is generally accepted as fact. These judgments are basically assumptions which are responsible for much of the uncertainty in the process of risk assessment. There was an attempt to clearly distinguish policy and fact. The subsections of the State-of-the-Science portion provide the underlying support to the principles articulated, and to read the "Principles" section without a full appreciation of the State-of-the-Science section is to invite oversimplification and misinterpretation. Finally, suggestions are made for future research efforts which will improve the process of risk assessment. PMID:3530737

[Carcinogenic efficacy of the transuranium elements americium-241 and curium-244].

PubMed

Rudnitskaia, E I

1984-01-01

Albino female rats were used in the experiments. After a single intraperitoneal administration of 241Am and 244Cm chloride is doses ranging from 0.37 to 185 kBq/kg (14 doses were used) it was established that the doses applied had different effect on the average life of animals. The largest doses shortened and the lowest increased the life span of experimental animals as compared to the controls. The carcinogenic effect of the studied radionuclides and the development of malignant tumors were detected at sufficiently low doses absorbed. Malignant tumors developed in the experimental and control animals were different not only in their incidence but also their localization and spectrum.

Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling.

PubMed Central

Yang, R S; Thomas, R S; Gustafson, D L; Campain, J; Benjamin, S A; Verhaar, H J; Mumtaz, M M

1998-01-01

Systematic toxicity testing, using conventional toxicology methodologies, of single chemicals and chemical mixtures is highly impractical because of the immense numbers of chemicals and chemical mixtures involved and the limited scientific resources. Therefore, the development of unconventional, efficient, and predictive toxicology methods is imperative. Using carcinogenicity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to environmental contamination. Central to the approaches presented is the integration of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) and quantitative structure--activity relationship (QSAR) modeling with focused mechanistically based experimental toxicology. In this development, molecular and cellular biomarkers critical to the carcinogenesis process are evaluated quantitatively between different chemicals and/or chemical mixtures. Examples presented include the integration of PBPK/PD and QSAR modeling with a time-course medium-term liver foci assay, molecular biology and cell proliferation studies. Fourier transform infrared spectroscopic analyses of DNA changes, and cancer modeling to assess and attempt to predict the carcinogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixtures using in vitro cell culture (Syrian hamster embryo cell transformation assay and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully applied, these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemical mixtures. Images Figure 6 PMID:9860897

Studies on promoting action in skin carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saffiotti, U.; Shubik, P.

1963-01-01

A number of substances were tested for carcinogenic promoting activity in Swiss mice by applying them twice weekly to the clipped dorsal skin, beginning 1 wk after a single application of 9,10-dimethyl-1, 2-benzanthracene (DMBA; 1 to 1.5% in mineral oil). Tests with silver nitrate (10% aqueous), iodoacetic acid (0.9% in acetone, fumaric acid (1% in acetone), ethylphenylpropiolate (5% in acetone), trihydroxymethylanthraquinone. (Emodin; 0.5% in acetone), oleic alcohol, monostearin (5% in acetone) and sorbitan monolaurate were essentially negative; when a single application of croton oil (5% in mineral oil) was interspersed between the carcinogen and silver nitrate, 6/20 mice developed 14more » benign tumors and 1 carcinoma. N-Dodecane showed moderate promoting activity (26 tumors, with 2 carcinomas, in 12/30 mice). Tests of several petroleum fractions showed high initial promoting activity (404 tumors, with 31 carcinomas, in 36/50 mice), but the activity disappeared on storage; while there was no carcinogenic activity in mice, in New Zealand albino rabbits the petroleum fractions alone produced considerable numbers of tumors. One application of DMBA, however, did increase tumor incidence and shorten the latent period. The hexane-eluted fraction of a methanolic extract of croton seeds (which had little vesicant activity), had all the promoting activity of the original croton oil; this could be demonstrated with uethan (20 mg/day ip for 5 days) as the initiator as well as with DMBA. In conclusion, the authors distinguish sharply between the promoting activity of compounds such as croton oil, which lead mostly to benign tumors (many of which regress spontaneously), and the additive effects of carcinogenic substances which may have a stimulatory effect on the second stage of carcinogenesis; for this additive carcinogenic effect, they suggest the term developing action. Other studies on croton oil are also reviewed.« less

The influence of thresholds on the risk assessment of carcinogens in food.

PubMed

Pratt, Iona; Barlow, Susan; Kleiner, Juliane; Larsen, John Christian

2009-08-01

The risks from exposure to chemical contaminants in food must be scientifically assessed, in order to safeguard the health of consumers. Risk assessment of chemical contaminants that are both genotoxic and carcinogenic presents particular difficulties, since the effects of such substances are normally regarded as being without a threshold. No safe level can therefore be defined, and this has implications for both risk management and risk communication. Risk management of these substances in food has traditionally involved application of the ALARA (As Low as Reasonably Achievable) principle, however ALARA does not enable risk managers to assess the urgency and extent of the risk reduction measures needed. A more refined approach is needed, and several such approaches have been developed. Low-dose linear extrapolation from animal carcinogenicity studies or epidemiological studies to estimate risks for humans at low exposure levels has been applied by a number of regulatory bodies, while more recently the Margin of Exposure (MOE) approach has been applied by both the European Food Safety Authority and the Joint FAO/WHO Expert Committee on Food Additives. A further approach is the Threshold of Toxicological Concern (TTC), which establishes exposure thresholds for chemicals present in food, dependent on structure. Recent experimental evidence that genotoxic responses may be thresholded has significant implications for the risk assessment of chemicals that are both genotoxic and carcinogenic. In relation to existing approaches such as linear extrapolation, MOE and TTC, the existence of a threshold reduces the uncertainties inherent in such methodology and improves confidence in the risk assessment. However, for the foreseeable future, regulatory decisions based on the concept of thresholds for genotoxic carcinogens are likely to be taken case-by-case, based on convincing data on the Mode of Action indicating that the rate limiting variable for the development of cancer lies on a critical pathway that is thresholded.

[Carcinogenic effects of diesel emission: an epidemiological review].

PubMed

Szadkowska-Stańczyk, I; Ruszkowska, J

2000-01-01

The results of recent epidemiological studies and meta-analysis relating to carcinogenic effects of diesel emissions in exposed populations were reviewed. Statistical, but still not causal association between risk of lung cancer and occupational exposure to diesel emissions was found in a great number of studies under review. Long-term exposure to diesel exhausts (> 20 years) increases by 30-40% lung cancer risk in workers of the transport industry: truck drivers, diesel engine mechanics, locomotive engineers and brakesmen. The results are inconsistent among heavy equipment operators, bus drivers and miners. Relative risk of lung cancer among workers occupationally exposed to diesel emission may be comparable with that of environmental tobacco smoke. Further research is also needed in the area of carcinogenic mechanisms, and biomarkers of exposure should be developed and validated before reliable quantitative estimates of risk of harmful effects to the human health in occupational setting are made.

The Temporal Structure of Scientific Consensus Formation

PubMed Central

Shwed, Uri; Bearman, Peter S.

2011-01-01

This article engages with problems that are usually opaque: What trajectories do scientific debates assume, when does a scientific community consider a proposition to be a fact, and how can we know that? We develop a strategy for evaluating the state of scientific contestation on issues. The analysis builds from Latour’s black box imagery, which we observe in scientific citation networks. We show that as consensus forms, the importance of internal divisions to the overall network structure declines. We consider substantive cases that are now considered facts, such as the carcinogenicity of smoking and the non-carcinogenicity of coffee. We then employ the same analysis to currently contested cases: the suspected carcinogenicity of cellular phones, and the relationship between vaccines and autism. Extracting meaning from the internal structure of scientific knowledge carves a niche for renewed sociological commentary on science, revealing a typology of trajectories that scientific propositions may experience en route to consensus. PMID:21886269

Overexpression of Transcription Factor Sp2 Inhibits Epidermal Differentiation and Increases Susceptibility to Wound and Carcinogen-Induced Tumorigenesis

PubMed Central

Kim, Tae-Hyung; Chiera, Shannon L.; Linder, Keith E.; Trempus, Carol S.; Smart, Robert C.; Horowitz, Jonathan M.

2010-01-01

Sp proteins are evolutionarily-conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell-cycle progression. De-regulated expression of certain Sp proteins is associated with the formation of a variety of human tumors, however direct evidence that any given Sp protein is oncogenic has been lacking. Here we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen-induced murine squamous cell carcinomas. Transgenic mice specifically overexpressing murine Sp2 in epidermal basal keratinocytes were highly susceptible to wound- and carcinogen-induced papillomagenesis. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within two weeks of birth. Our results directly support the likelihood that Sp2 overexpression occurring in various human cancers has significant functional impact. PMID:20959487

An epidemiological and toxicological evaluation of the carcinogenicity of man-made vitreous fiber, with a consideration of coexposures.

PubMed

Wong, O; Musselman, R P

1994-01-01

Exposure to man-made mineral (or vitreous) fiber (MMMF or MMVF) is a potential health concern in both occupational and environmental settings. Previous epidemiologic studies have reported a small increase of lung cancer among workers exposed to MMVF. Most of these studies were cohort studies and lacked information on fiber concentration, occupational coexposures, and cigarette smoking. Some of the coexposures were known human lung carcinogens and could have accounted for the small lung cancer excess. In a recently completed epidemiologic case-control study of lung cancer in MMVF workers exposed to slag wool fibers, we analyzed lung cancer risk in relation to cumulative fiber exposure (concentration and duration) and smoking history and controlled for other coexposures such as asbestos contamination. No increased lung cancer risk with exposure to slag wool fibers was found. As expected, however, we detected a strong confounding effect of smoking. The findings from this epidemiologic study were consistent with the results of recently completed toxicologic studies, which found that slag wool fibers of dimension classically associated with tumor induction ("Stanton" fibers) do not stay in the lung in sufficient quantity or time to induce tumors in animals. In this paper we emphasize the importance of confounding effects due to coexposures and provide guidelines to estimate the magnitude of potential confounding effects of coexposures such as smoking.

Evaluation of potential human health risk and investigation of drinking water quality in Isparta city center (Turkey).

PubMed

Varol, Simge; Davraz, Aysen

2016-06-01

Isparta city center is selected as a work area in this study because the public believes that the tap water is dirty and harmful. In this study, the city's drinking water in the distribution system and other spring waters which are used as drinking water in this region were investigated from the point of water quality and health risk assessment. Water samples were collected from major drinking water springs, tap waters, treatment plants and dam pond in the Isparta province center. Ca-Mg-HCO3, Mg-Ca-HCO3, Ca-Na-HCO3, Ca-HCO3, Ca-HCO3-SO4 and Ca-Mg-HCO3-SO4 are dominant water types. When compared to drinking water guidelines established by World Health Organization and Turkey, much greater attention should be paid to As, Br, Fe, F, NH4, PO4 through varied chemicals above the critical values. The increases of As, Fe, F, NH4 and PO4 are related to water-rock interaction. In tap waters, the increases of As and Fe are due to corrosion of pipes in drinking water distribution systems. The major toxic and carcinogenic chemicals within drinking water are As and Br for both tap water and spring water. Also, F is the non-carcinogenic chemical for only spring waters in the study area.

Spatial distribution variation and probabilistic risk assessment of exposure to chromium in ground water supplies; a case study in the east of Iran.

PubMed

Fallahzadeh, Reza Ali; Khosravi, Rasoul; Dehdashti, Bahare; Ghahramani, Esmail; Omidi, Fariborz; Adli, Abolfazl; Miri, Mohammad

2018-05-01

A high concentration of chromium (VI) in groundwater can threaten the health of consumers. In this study, the concentration of chromium (VI) in 18 drinking water wells in Birjand, Iran, s was investigated over a period of two yearsNon-carcinogenic risk assessment, sensitivity, and uncertainty analysis as well as the most important variables in determining the non-carcinogenic risk for three age groups including children, teens, and adults, were performed using the Monte Carlo simulations technique. The northern and southern regions of the study area had the highest and lowest chromium concentrations, respectively. The chromium concentrations in 16.66% of the samples in an area of 604.79 km2 were more than World Health Organization (WHO) guideline (0.05 mg/L). The Moran's index analysis showed that the distribution of contamination is a cluster. The Hazard Index (HI) values for the children and teens groups were 1.02 and 2.02, respectively, which was more than 1. A sensitivity analysis indicated that the most important factor in calculating the HQ was the concentration of chromium in the consumed water. HQ values higher than 1 represent a high risk for the children group, which should be controlled by removing the chromium concentration of the drinking water. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Determining health policy for sensible mobile phone use--current world status].

PubMed

Sagi, Omer Itzhak; Sadetzki, Siegal

2011-03-01

Mobile phones have become the leading communication system, with more than 4.5 billions users around the world. The sharp increase in the number of users, and its penetration to all populations, including children, has raised concern about possible adverse health effects, particularly cancer This article reviews the public health policies introduced in Israel and several other countries regarding mobile phone use in view of the lack of clarity concerning the safety of this new technology. The data show that most countries have adopted the precautionary principle as the leading guideline, recommending the use of simple and low-cost safety measures which could substantially reduce exposure to the brain and other body organs from mobile phones. These include the use of text messages, hands-free kits, and/or the loud-speaker mode of the phone. Accordingly, recommendations, guidelines, standards, and legislation aimed at the general population, drivers, state institutions and the industry have been formulated. For children, who are considered to be more susceptible to cancer development following exposure to carcinogens, there is widespread consensus for a stricter approach. In some countries, measures such as banning use of mobile phones in schools, prohibiting sales/advertisements targeted at young age groups, expanding warnings on phones/ packages, and encouraging educational campaigns have been adopted for this population. Regulations regarding phone use while driving have been instituted in most countries. In conclusion, many public health practitioners have moved from the theoretical level (adoption of the precautionary principle) to an active phase of introducing regulations, with specific emphasis to various populations.

Index analysis and human health risk model application for evaluating ambient air-heavy metal contamination in Chemical Valley Sarnia.

PubMed

Olawoyin, Richard; Schweitzer, Linda; Zhang, Kuangyuan; Okareh, Oladapo; Slates, Kevin

2018-02-01

The impacts of air emissions as a consequence of industrial activities around communities of human habitation have been extensively reported. This study is the first to assess potential adverse human health effects in the Chemical Valley Sarnia (CVS) area, around the St. Clair River, using health risk models, ecological and pollution indices. Large quantities of particulate matters (PM) are generated from anthropogenic activities, which contain several heavy metals in trace quantities with potentially adverse effects to humans and environmental health. The distribution, and human health impact assessment of trace element concentrations in PM fractions were examined. Elemental concentrations of As, Cd, Cr (VI), Cu, Fe, Mn, Pb, Ni, Zn were determined in the PM size-segregated samples collected from the CVS area between 2014 and 2017. The results showed relatively high concentration of PM <2.5 (87.19±8.1(mgm 3 )) which is approximately 4 times the WHO air quality guidelines. Pb concentration (143.03 ± 46.87ηg/m 3 ) was 3.6 times higher than the air quality standards of NAAQS. Cr (VI) showed moderate to considerable contamination ( C f =4) in the CVS while Cr (VI), Pb, and Ni had enrichment factor E f < 3 (minimal), signifying contributions from anthropogenic activities. Pollution load index (P Li ) value observed was 1.4 indicating human health risk from the PM, especially for the children in the area. The deposition fluxes (DΦ) showed that PM-bound metals could potentially bypass the head airways and cause damages to the tracheobronchial tree, increasing the human health risks of nephroblastomasis development. The main route of entry for the heavy metal bound PM in humans were observed as through ingestion and inhalation. The highest total excess cancer risks observed for children (6.7×10 -4 ) and adult (1.0×10 -4 ) indicating potential cancer effects. The Incremental Lifetime Cancer Risk (ILCR) increased from Pb < Ni < Cd < Cr (VI) < As. Overall, children are more likely to develop carcinogenic and non-carcinogenic health effects from exposures to elemental concentrations of airborne PM in the study area. Copyright © 2017 Elsevier Inc. All rights reserved.

Inter-laboratory comparison of turkey in ovo carcinogenicity assessment (IOCA) of hepatocarcinogens.

PubMed

Enzmann, H; Brunnemann, K; Iatropoulos, M; Shpyleva, S; Lukyanova, N; Todor, I; Moore, M; Spicher, K; Chekhun, V; Tsuda, H; Williams, G

2013-09-01

In three independent laboratories carcinogens (diethylnitrosamine, DEN, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) and non-carcinogens (N-nitrosoproline, nicotine) were evaluated in turkey eggs for in ovo carcinogenicity assessment (IOCA). Compounds were injected into aseptic fertilized eggs. After incubation for 24 days, foci of altered hepatocytes (FAH), some with a pseudoglandular structure and/or signs of compression of the surrounding tissue were observed in the fetal liver. All laboratories were able to distinguish unequivocally the hepatocarcinogen-exposed groups from those exposed to non-carcinogens or the vehicle controls, based on the pre-specified evaluation parameters: tumor-like lesions, pseudoglandular areas and FAH. In addition to focal changes, only the carcinogens induced hepatocellular karyomegaly. Lower doses of the carcinogens, which did not induce FAH, were sufficient to induce hepatocellular karyomegaly. After exposure to 4 mg DEN, gall bladder agenesis was observed in all fetuses. The IOCA may be a valuable tool for early investigative studies on carcinogenicity and since it does not use rodents may complement chronic rat or mouse bioassays. Test substances that are positive in both rodents and fertilized turkey eggs are most probably trans-species carcinogens with particular significance for humans. The good concordance observed among the three laboratories demonstrates that the IOCA is a reliable and robust method. Copyright © 2012 Elsevier GmbH. All rights reserved.

Dissecting modes of action of non-genotoxic carcinogens in primary mouse hepatocytes.

PubMed

Schaap, Mirjam M; Zwart, Edwin P; Wackers, Paul F K; Huijskens, Ilse; van de Water, Bob; Breit, Timo M; van Steeg, Harry; Jonker, Martijs J; Luijten, Mirjam

2012-11-01

Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity and chronic bioassays are no longer regularly performed, this class of carcinogens will go undetected. Therefore, test systems detecting non-genotoxic carcinogens, or even better their modes of action, are required. Here, we investigated whether gene expression profiling in primary hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens. For this, primary mouse hepatocytes were exposed to 16 non-genotoxic carcinogens with diverse modes of action. Upon profiling, pathway analysis was performed to obtain insight into the biological relevance of the observed changes in gene expression. Subsequently, both a supervised and an unsupervised comparison approach were applied to recognize the modes of action at the transcriptomic level. These analyses resulted in the detection of three of eight compound classes, that is, peroxisome proliferators, metalloids and skin tumor promotors. In conclusion, gene expression profiles in primary hepatocytes, at least in rodent hepatocytes, appear to be useful to detect some, certainly not all, modes of action of non-genotoxic carcinogens.

Identification of EBP50 as a Specific Biomarker for Carcinogens Via the Analysis of Mouse Lymphoma Cellular Proteome

PubMed Central

Lee, Yoen Jung; Choi, In-Kwon; Sheen, Yhun Yhong; Park, Sue Nie; Kwon, Ho Jeong

2012-01-01

To identify specific biomarkers generated upon exposure of L5178Y mouse lymphoma cells to carcinogens, 2-DE and MALDI-TOF MS analysis were conducted using the cellular proteome of L5178Y cells that had been treated with the known carcinogens, 1,2-dibromoethane and O-nitrotoluene and the noncarcinogens, emodin and D-mannitol. Eight protein spots that showed a greater than 1.5-fold increase or decrease in intensity following carcinogen treatment compared with treatment with noncarcinogens were selected. Of the identified proteins, we focused on the candidate biomarker ERM-binding phosphoprotein 50 (EBP50), the expression of which was specifically increased in response to treatment with the carcinogens. The expression level of EBP50 was determined by western analysis using polyclonal rabbit anti-EBP50 antibody. Further, the expression level of EBP50 was increased in cells treated with seven additional carcinogens, verifying that EBP50 could serve as a specific biomarker for carcinogens. PMID:22434383

Identification of EBP50 as a specific biomarker for carcinogens via the analysis of mouse lymphoma cellular proteome.

PubMed

Lee, Yoen Jung; Choi, In-Kwon; Sheen, Yhun Yhong; Park, Sue Nie; Kwon, Ho Jeong

2012-03-01

To identify specific biomarkers generated upon exposure of L5178Y mouse lymphoma cells to carcinogens, 2-DE and MALDI-TOF MS analysis were conducted using the cellular proteome of L5178Y cells that had been treated with the known carcinogens, 1,2-dibromoethane and O-nitrotoluene and the noncarcinogens, emodin and D-mannitol. Eight protein spots that showed a greater than 1.5-fold increase or decrease in intensity following carcinogen treatment compared with treatment with noncarcinogens were selected. Of the identified proteins, we focused on the candidate biomarker ERM-binding phosphoprotein 50 (EBP50), the expression of which was specifically increased in response to treatment with the carcinogens. The expression level of EBP50 was determined by western analysis using polyclonal rabbit anti-EBP50 antibody. Further, the expression level of EBP50 was increased in cells treated with seven additional carcinogens, verifying that EBP50 could serve as a specific biomarker for carcinogens.

QSAR Study for Carcinogenic Potency of Aromatic Amines Based on GEP and MLPs

PubMed Central

Song, Fucheng; Zhang, Anling; Liang, Hui; Cui, Lianhua; Li, Wenlian; Si, Hongzong; Duan, Yunbo; Zhai, Honglin

2016-01-01

A new analysis strategy was used to classify the carcinogenicity of aromatic amines. The physical-chemical parameters are closely related to the carcinogenicity of compounds. Quantitative structure activity relationship (QSAR) is a method of predicting the carcinogenicity of aromatic amine, which can reveal the relationship between carcinogenicity and physical-chemical parameters. This study accessed gene expression programming by APS software, the multilayer perceptrons by Weka software to predict the carcinogenicity of aromatic amines, respectively. All these methods relied on molecular descriptors calculated by CODESSA software and eight molecular descriptors were selected to build function equations. As a remarkable result, the accuracy of gene expression programming in training and test sets are 0.92 and 0.82, the accuracy of multilayer perceptrons in training and test sets are 0.84 and 0.74 respectively. The precision of the gene expression programming is obviously superior to multilayer perceptrons both in training set and test set. The QSAR application in the identification of carcinogenic compounds is a high efficiency method. PMID:27854309

Sucralose Non-Carcinogenicity: A Review of the Scientific and Regulatory Rationale

PubMed Central

Berry, Colin; Brusick, David; Cohen, Samuel M.; Hardisty, Jerry F.; Grotz, V. Lee; Williams, Gary M.

2016-01-01

ABSTRACT Regulatory authorities worldwide have found the nonnutritive sweetener, sucralose, to be noncarcinogenic, based on a range of studies. A review of these and other studies found through a comprehensive search of electronic databases, using appropriate key terms, was conducted and results of that review are reported here. An overview of the types of studies relied upon by regulatory agencies to assess carcinogenicity potential is also provided as context. Physiochemical and pharmacokinetic/toxicokinetic studies confirm stability under conditions of use and reveal no metabolites of carcinogenic potential. In vitro and in vivo assays reveal no confirmed genotoxic activity. Long-term carcinogenicity studies in animal models provide no evidence of carcinogenic potential for sucralose. In studies in healthy adults, sucralose was well-tolerated and without evidence of toxicity or other changes that might suggest a potential for carcinogenic effects. In summary, sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels. PMID:27652616

Sucralose Non-Carcinogenicity: A Review of the Scientific and Regulatory Rationale.

PubMed

Berry, Colin; Brusick, David; Cohen, Samuel M; Hardisty, Jerry F; Grotz, V Lee; Williams, Gary M

2016-01-01

Regulatory authorities worldwide have found the nonnutritive sweetener, sucralose, to be noncarcinogenic, based on a range of studies. A review of these and other studies found through a comprehensive search of electronic databases, using appropriate key terms, was conducted and results of that review are reported here. An overview of the types of studies relied upon by regulatory agencies to assess carcinogenicity potential is also provided as context. Physiochemical and pharmacokinetic/toxicokinetic studies confirm stability under conditions of use and reveal no metabolites of carcinogenic potential. In vitro and in vivo assays reveal no confirmed genotoxic activity. Long-term carcinogenicity studies in animal models provide no evidence of carcinogenic potential for sucralose. In studies in healthy adults, sucralose was well-tolerated and without evidence of toxicity or other changes that might suggest a potential for carcinogenic effects. In summary, sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels.

Prevalence of occupational exposure to carcinogens among workers of Arabic, Chinese and Vietnamese ancestry in Australia.

PubMed

Boyle, Terry; Carey, Renee N; Glass, Deborah C; Peters, Susan; Fritschi, Lin; Reid, Alison

2015-09-01

Although job-related diseases result in more deaths per year than job-related injuries, most research concerning ethnic minority workers has concerned accidents and injuries rather than disease-causing exposures such as carcinogens. We conducted a telephone-based cross-sectional survey to estimate the prevalence of occupational exposure to carcinogens among a sample of ethnic minority workers in Australia, and compared their exposure prevalence to that of a sample of the general Australian-born working population ('Australian workers'). One-third of the ethnic minority workers were exposed to at least one carcinogen at work. The likelihood of exposure to carcinogens was not significantly different from that of Australian workers, although the likelihood of exposure to individual carcinogens varied by ethnicity. Knowing the prevalence of exposure to carcinogens in the workplace in different ethnic groups will allow better targeted and informed occupational health and safety measures to be implemented where necessary. © 2015 Wiley Periodicals, Inc.

Carcinogens in the Schools

ERIC Educational Resources Information Center

Block, J. Bradford

1976-01-01

Reports the presence and use of known carcinogens in Kentucky colleges, junior colleges, and high schools. Includes a listing of known carcinogens and the synonym names under which each may be labeled. (SL)

An opportune and unique research to evaluate the public health impact of electronic cigarettes.

PubMed

Besaratinia, Ahmad; Tommasi, Stella

2017-10-01

In response to the growing public health concern regarding the risks or benefits of electronic cigarettes (e-cig) use relative to smoking, the National Institute on Drug Abuse (NIDA) has recently introduced the first standardized- and well- characterized e-cig device to the research community (see, https://www.drugabuse.gov/funding/supplemental-information-nida-e-cig ). E-cig are promoted as safe alternatives to conventional tobacco cigarettes and/or as aides to smoking cessation. E-cig are highly popular among cigarette smokers who are unable/unwilling to quit but are willing to switch to putatively less-harmful tobacco substitutes. E-cig are also becoming increasingly popular among youth who have never experimented with combustible cigarettes. However, chemical analyses of e-cig juices (both in liquid form and after being heated into vapor) have shown that many carcinogens present in cigarette smoke are also found in a range of e-cig products. To date, the cancer-causing potential of e-cig has not been investigated in e-cig users (i.e., vapers). Use of e-cig without a prior history of smoking is currently a rare phenomenon in adults, but is increasingly common among youth. Consequently, investigating the carcinogenic potential of e-cig in nonsmoking youth provides a unique opportunity to verify the health impact of e-cig use, without the confounding effects of cigarette smoking. Within this context, the availability of the NIDA Standard Research e-cig offers a unique research opportunity with tremendous public health implications. Comparing and contrasting the cancer-causing potentials of standard vaping and smoking in youth will help determine the health risks or benefits of e-cig use relative to cigarette smoking. This information will be instrumental in making scientifically based decisions on the development and evaluation of policies and regulations on e-cig manufacture, marketing, and distribution. Ultimately, evidence-based guidelines and legislations on e-cig will help reduce the burden of tobacco-related diseases, particularly on minors and vulnerable populations.

Risk assessment for carcinogens under California's Proposition 65

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pease, W.S.; Zeise, L.; Kelter, A.

1990-06-01

Risk assessments for carcinogens are being developed through an accelerated process in California as a part of the state's implementation of Proposition 65, the Safe Drinking Water and Toxic Enforcement Act. Estimates of carcinogenic potency made by the California Department of Health Services (CDHS) are generally similar to estimates made by the U.S. Environmental Protection Agency (EPA). The largest differences are due to EPA's use of the maximum likelihood estimate instead of CDHS' use of the upper 95% confidence bounds on potencies derived from human data and to procedures used to correct for studies of short duration or with earlymore » mortality. Numerical limits derived from these potency estimates constitute no significant risk levels, which govern exemption from Proposition 65's discharge prohibition and warning requirements. Under Proposition 65 regulations, lifetime cancer risks less than 10(-5) are not significant and cumulative intake is not considered. Following these regulations, numerical limits for a number of Proposition 65 carcinogens that are applicable to the control of toxic discharges are less stringent than limits under existing federal water pollution control laws. Thus, existing federal limits will become the Proposition 65 levels for discharge. Chemicals currently not covered by federal and state controls will eventually be subject to discharge limitations under Proposition 65. No significant risk levels (expressed in terms of daily intake of carcinogens) also trigger warning requirements under Proposition 65 that are more extensive than existing state or federal requirements. A variety of chemical exposures from multiple sources are identified that exceed Proposition 65's no significant risk levels.« less

[The evaluation of biological effects of exposure to respirable crystalline silica in building industry].

PubMed

Pira, E; Piolatto, P G

2012-01-01

The building industry entails the exposure to Respirable Crystalline Silica (RCS), though there is a large variability among different sectors. The environmental values reported for the current conditions seem to be relatively low. For example the mean exposure estimated by IOM for all industrial sectors in the EU is 0.07 mg/m3. There are few studies in the building sector which show similar values. This is obviously not representative of past exposure. Moreover, the problems of sampling and analysis techniques are still at issue. The well known effect of RCS exposure is silicosis. The carcinogenicity of RCS is still under debate, especially regarding the question of whether RCS is carcinogenic "per se" or whether the risk of developing lung cancer is mediated by silicosis. Although the IARC includes RCS in the Group I (human carcinogen), the reference should be the CLP regulation, of which carcinogen definition criteria allow to state that today there are not sufficient data to classify RCS as a carcinogen and that it seems more appropriate to include RCS in different STOT.RE categories. This is valid for building industry as well as for the other industrial sectors. In Italy the recommended exposure limit is the ACGIH value of 0.025 mg/m3. At EU level it is still debated which is the best choice, based on cost/benefits evaluation, among the following limit values: 0.2, 0.1 and 0.05 respectively. The authors obviously believe that the most protective value should be adopted.

Investigating the different mechanisms of genotoxic and non-genotoxic carcinogens by a gene set analysis.

PubMed

Lee, Won Jun; Kim, Sang Cheol; Lee, Seul Ji; Lee, Jeongmi; Park, Jeong Hill; Yu, Kyung-Sang; Lim, Johan; Kwon, Sung Won

2014-01-01

Based on the process of carcinogenesis, carcinogens are classified as either genotoxic or non-genotoxic. In contrast to non-genotoxic carcinogens, many genotoxic carcinogens have been reported to cause tumor in carcinogenic bioassays in animals. Thus evaluating the genotoxicity potential of chemicals is important to discriminate genotoxic from non-genotoxic carcinogens for health care and pharmaceutical industry safety. Additionally, investigating the difference between the mechanisms of genotoxic and non-genotoxic carcinogens could provide the foundation for a mechanism-based classification for unknown compounds. In this study, we investigated the gene expression of HepG2 cells treated with genotoxic or non-genotoxic carcinogens and compared their mechanisms of action. To enhance our understanding of the differences in the mechanisms of genotoxic and non-genotoxic carcinogens, we implemented a gene set analysis using 12 compounds for the training set (12, 24, 48 h) and validated significant gene sets using 22 compounds for the test set (24, 48 h). For a direct biological translation, we conducted a gene set analysis using Globaltest and selected significant gene sets. To validate the results, training and test compounds were predicted by the significant gene sets using a prediction analysis for microarrays (PAM). Finally, we obtained 6 gene sets, including sets enriched for genes involved in the adherens junction, bladder cancer, p53 signaling pathway, pathways in cancer, peroxisome and RNA degradation. Among the 6 gene sets, the bladder cancer and p53 signaling pathway sets were significant at 12, 24 and 48 h. We also found that the DDB2, RRM2B and GADD45A, genes related to the repair and damage prevention of DNA, were consistently up-regulated for genotoxic carcinogens. Our results suggest that a gene set analysis could provide a robust tool in the investigation of the different mechanisms of genotoxic and non-genotoxic carcinogens and construct a more detailed understanding of the perturbation of significant pathways.

Investigating the Different Mechanisms of Genotoxic and Non-Genotoxic Carcinogens by a Gene Set Analysis

PubMed Central

Lee, Won Jun; Kim, Sang Cheol; Lee, Seul Ji; Lee, Jeongmi; Park, Jeong Hill; Yu, Kyung-Sang; Lim, Johan; Kwon, Sung Won

2014-01-01

Based on the process of carcinogenesis, carcinogens are classified as either genotoxic or non-genotoxic. In contrast to non-genotoxic carcinogens, many genotoxic carcinogens have been reported to cause tumor in carcinogenic bioassays in animals. Thus evaluating the genotoxicity potential of chemicals is important to discriminate genotoxic from non-genotoxic carcinogens for health care and pharmaceutical industry safety. Additionally, investigating the difference between the mechanisms of genotoxic and non-genotoxic carcinogens could provide the foundation for a mechanism-based classification for unknown compounds. In this study, we investigated the gene expression of HepG2 cells treated with genotoxic or non-genotoxic carcinogens and compared their mechanisms of action. To enhance our understanding of the differences in the mechanisms of genotoxic and non-genotoxic carcinogens, we implemented a gene set analysis using 12 compounds for the training set (12, 24, 48 h) and validated significant gene sets using 22 compounds for the test set (24, 48 h). For a direct biological translation, we conducted a gene set analysis using Globaltest and selected significant gene sets. To validate the results, training and test compounds were predicted by the significant gene sets using a prediction analysis for microarrays (PAM). Finally, we obtained 6 gene sets, including sets enriched for genes involved in the adherens junction, bladder cancer, p53 signaling pathway, pathways in cancer, peroxisome and RNA degradation. Among the 6 gene sets, the bladder cancer and p53 signaling pathway sets were significant at 12, 24 and 48 h. We also found that the DDB2, RRM2B and GADD45A, genes related to the repair and damage prevention of DNA, were consistently up-regulated for genotoxic carcinogens. Our results suggest that a gene set analysis could provide a robust tool in the investigation of the different mechanisms of genotoxic and non-genotoxic carcinogens and construct a more detailed understanding of the perturbation of significant pathways. PMID:24497971

Evaluation of the sensitivity and specificity of in vivo erythrocyte micronucleus and transgenic rodent gene mutation tests to detect rodent carcinogens.

PubMed

Morita, Takeshi; Hamada, Shuichi; Masumura, Kenichi; Wakata, Akihiro; Maniwa, Jiro; Takasawa, Hironao; Yasunaga, Katsuaki; Hashizume, Tsuneo; Honma, Masamitsu

2016-05-01

Sensitivity and/or specificity of the in vivo erythrocyte micronucleus (MN) and transgenic rodent mutation (TGR) tests to detect rodent carcinogens and non-carcinogens were investigated. The Carcinogenicity and Genotoxicity eXperience (CGX) dataset created by Kirkland et al. was used for the carcinogenicity and in vitro genotoxicity data, i.e., Ames and chromosome aberration (CA) tests. Broad literature surveys were conducted to gather in vivo MN or TGR test data to add to the CGX dataset. Genotoxicity data in vitro were also updated slightly. Data on 379 chemicals (293 carcinogens and 86 non-carcinogens) were available for the in vivo MN test; sensitivity, specificity or concordances were calculated as 41.0%, 60.5% or 45.4%, respectively. For the TGR test, data on 80 chemicals (76 carcinogens and 4 non-carcinogens) were available; sensitivity was calculated as 72.4%. Based on the recent guidance on genotoxicity testing strategies, performance (sensitivity/specificity) of the following combinations was calculated; Ames+in vivo MN (68.7%/45.3%), Ames+TGR (83.8%/not calculated (nc)), Ames+in vitro CA+in vivo MN (80.8%/21.3%), Ames+in vitro CA+TGR (89.1%/nc), Ames+in vivo MN+TGR (87.5%/nc), Ames+in vitro CA+in vivo MN+TGR (89.3%/nc). Relatively good balance in performance was shown by the Ames+in vivo MN in comparison with Ames+in vitro CA (74.3%/37.5%). Ames+TGR and Ames+in vivo MN+TGR gave even higher sensitivity, but the specificity could not be calculated (too few TGR data on non-carcinogens). This indicates that in vivo MN and TGR tests are both useful as in vivo tests to detect rodent carcinogens. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

29 CFR 1990.141 - Advance notice of proposed rulemaking.

Code of Federal Regulations, 2014 CFR

2014-07-01

... CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.141 Advance notice of proposed rulemaking... carcinogen, the Secretary will normally publish, in the Federal Register, a notice which includes at least...

29 CFR 1990.141 - Advance notice of proposed rulemaking.

Code of Federal Regulations, 2013 CFR

2013-07-01

... CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.141 Advance notice of proposed rulemaking... carcinogen, the Secretary will normally publish, in the Federal Register, a notice which includes at least...

29 CFR 1990.141 - Advance notice of proposed rulemaking.

Code of Federal Regulations, 2012 CFR

2012-07-01

... CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.141 Advance notice of proposed rulemaking... carcinogen, the Secretary will normally publish, in the Federal Register, a notice which includes at least...

Ethyl carbamate in alcoholic beverages from Mexico (tequila, mezcal, bacanora, sotol) and Guatemala (cuxa): market survey and risk assessment.

PubMed

Lachenmeier, Dirk W; Kanteres, Fotis; Kuballa, Thomas; López, Mercedes G; Rehm, Jürgen

2009-01-01

Ethyl carbamate (EC) is a recognized genotoxic carcinogen, with widespread occurrence in fermented foods and beverages. No data on its occurrence in alcoholic beverages from Mexico or Central America is available. Samples of agave spirits including tequila, mezcal, bacanora and sotol (n=110), and of the sugarcane spirit cuxa (n=16) were purchased in Mexico and Guatemala, respectively, and analyzed for EC. The incidence of EC contamination was higher in Mexico than in Guatemala, however, concentrations were below international guideline levels (<0.15 mg/L). Risk assessment found the Margin of Exposure (MOE) in line with that of European spirits. It is therefore unlikely that EC plays a role in high rates of liver cirrhosis reported in Mexico.

Ethyl Carbamate in Alcoholic Beverages from Mexico (Tequila, Mezcal, Bacanora, Sotol) and Guatemala (Cuxa): Market Survey and Risk Assessment

PubMed Central

Lachenmeier, Dirk W.; Kanteres, Fotis; Kuballa, Thomas; López, Mercedes G.; Rehm, Jürgen

2009-01-01

Ethyl carbamate (EC) is a recognized genotoxic carcinogen, with widespread occurrence in fermented foods and beverages. No data on its occurrence in alcoholic beverages from Mexico or Central America is available. Samples of agave spirits including tequila, mezcal, bacanora and sotol (n=110), and of the sugarcane spirit cuxa (n=16) were purchased in Mexico and Guatemala, respectively, and analyzed for EC. The incidence of EC contamination was higher in Mexico than in Guatemala, however, concentrations were below international guideline levels (<0.15 mg/L). Risk assessment found the Margin of Exposure (MOE) in line with that of European spirits. It is therefore unlikely that EC plays a role in high rates of liver cirrhosis reported in Mexico. PMID:19440288

Identifying occupational carcinogens: an update from the IARC Monographs.

PubMed

Loomis, Dana; Guha, Neela; Hall, Amy L; Straif, Kurt

2018-05-16

The recognition of occupational carcinogens is important for primary prevention, compensation and surveillance of exposed workers, as well as identifying causes of cancer in the general population. This study updates previously published lists of known occupational carcinogens while providing additional information on cancer type, exposure scenarios and routes, and discussing trends in the identification of carcinogens over time. Data were extracted from International Agency for Research on Cancer (IARC) Monographs covering the years 1971-2017, using specific criteria to ensure occupational relevance and provide high confidence in the causality of observed exposure-disease associations. Selected agents were substances, mixtures or types of radiation classified in IARC Group 1 with 'sufficient evidence of carcinogenicity' in humans from studies of exposed workers and evidence of occupational exposure documented in the pertinent monograph. The number of known occupational carcinogens has increased over time: 47 agents were identified as known occupational carcinogens in 2017 compared with 28 in 2004. These estimates are conservative and likely underestimate the number of carcinogenic agents present in workplaces. Exposure to these agents causes a wide range of cancers; cancers of the lung and other respiratory sites, followed by skin, account for the largest proportion. The dominant routes of exposure are inhalation and dermal contact. Important progress has been made in identifying occupational carcinogens; nevertheless, there is an ongoing need for research on the causes of work-related cancer. Most workplace exposures have not been evaluated for their carcinogenic potential due to inadequate epidemiologic evidence and a paucity of quantitative exposure data. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide ...

EPA Pesticide Factsheets

In December 2016, EPA finalized its Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide. EPA’s evaluation was reviewed internally by EPA and by other federal agencies and White House Offices in October 2016, before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science discussion materials provided to other agencies, including interagency review drafts of the EPA’s Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide, are posted on this site. Note: No major science comments were received on the Interagency Science Discussion Draft. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science consultation materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Ammonia and the charge to external peer reviewers, are posted on this site.

Availability of epidemiologic data on humans exposed to animal carcinogens. II. Chemical uses and production volume

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karstadt, M.; Bobal, R.

1982-01-01

We report further findings of a survey of manufacturers, processors, and importers of chemicals determined by the International Agency for Research on Cancer (IARC) to be animal carcinogens, but whose carcinogenicity in humans was considered uncertain because of inadequate epidemiologic data. We requested epidemiologic studies from the companies marketing or using any of the 75 IARC animal carcinogens in commerce in the United States. Eighteen of the 75 IARC animal carcinogens had volumes listed of 10(6) lb/year or greater, with 8 of the 13 chemicals for which studies had been completed or are in progress in this ''high volume'' category.more » The use category with the largest number of chemicals was drugs--19 of the 75 IARC animal carcinogens were in this category. However, none of the 13 chemicals included in epidemiologic studies was a drug. Seven of the 13 chemicals included in studies were used primarily as pesticides. We received little information on dyes and dye intermediates, experimental carcinogens, and drugs, all of which are produced in relatively low volumes; these categories represent 42 of the 75 IARC animal carcinogens. Low volumes and declining usage/production appear to be barriers to performance of epidemiologic studies. Information we received suggests that sometimes the problem of low production volume may be avoided by studying users rather than production workers. Overall, however, we expect few additional epidemiologic studies of the 75 IARC animal carcinogens.« less

Quantification of the carcinogenic effect of polycyclic aromatic hydrocarbons in used engine oil by topical application onto the skin of mice.

PubMed

Grimmer, G; Dettbarn, G; Brune, H; Deutsch-Wenzel, R; Misfeld, J

1982-01-01

The purpose of this investigation was to identify the substances mainly responsible for the carcinogenic effect of used engine oil from gasoline engines using topical application as a carcinogen-specific bioassay. This was performed by comparison of the tumorigenic effect of single fractions with that of an unseparated sample of the lubricating oil. The probit analysis of the results shows: 1) The used engine oil, from gasoline-driven automobiles, investigated provoked local tumors after long-term application to the dorsal skin of mice. The incidence of carcinoma depended on the dose of the oil. 2) The fraction of the polycyclic aromatic hydrocarbons (PAH) containing more than three rings accounts for about 70% of the total carcinogenicity in the case of crankcase oil. This fraction constitutes only up to 1.14% by weight of the total oil sample. 3) The content of benzo(a)pyrene (216.8 mg/kg) accounts for 18% of the total carcinogenicity of the used oil. 4) Regarding the reduced carcinogenicity of the oil sample, which was reconstituted from all fractions, it seems possible that some of the carcinogenic substances were lost due to volatility, with evaporation of the solvents from the oil-fractionation processes. 5) Regarding the small effect of the PAH-free fraction, as well as the equal carcinogenic effects of the PAH-fraction (containing more than three rings) and the reconstituted oil sample, no hints for a co-carcinogenic activity were obtained.

An Evaluation of Transplacental Carcinogenesis for Human ...

EPA Pesticide Factsheets

Risk assessments take into account the sensitivity of the postnatal period to carcinogens through the application of age-dependent adjustment factors (ADAFs) (Barton et al. 2005). The prenatal period is also recognized to be sensitive but is typically not included into risk assessments (NRC, 2009). An analysis by California OEHHA (2008) contrasted prenatal, postnatal and adult sensitivity to 23 different carcinogens across 37 studies. That analysis found a wide range of transplacental sensitivity with some agents nearly 100 fold more potent in utero than in adults while others had an in utero/adult ratio adult only exposure). Five carcinogens had more modest ratios to adult potency in both pre- and postnatal testing (vinyl chloride, ethylnitroso biuret, 3-methylcholanthrene, urethane, diethylnitrosamine, 3-10 fold). Only one chemical showed a pre- vs postnatal divergence (butylnitrosourea, prenataladult). Based upon this limited set of genotoxic carcinogens, it appears that the prenatal period often has a sensitivity that approximates what has been found for postnatal, and the maternal system does not offer substantial protection against transplacental carcinogenesis in most cases. This suggests that the system of ADAFs developed for postnatal exposure may be considered for prenatal exposures as well. An alternative approach may be to calculate cancer risk for the period of pregnancy rather than blend this risk into the calculation of lifetime risk. This

Mechanisms of carcinogensis: dose response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gehring, P.J.; Blau, G.E.

There is great controversy whether the carcinogenicity of chemicals is dose-dependent and whether a threshold dose exists below which cancer will not be induced by exposure. Evidence for dose-dependency exists and is believed to be accepted generally if extricated as it should be from the threshold concept. The threshold concept conflict is not likely to be resolved in the foreseeable future; proponents and opponents argue their case in a manner similar to those arguing religion. In this paper the various arguments are reviewed. Subsequently, a chemical process model for carcinogenesis is developed based on the generally accepted evidence that themore » carcinogenic activity of many chemicals can be related to electrophilic alkylation of DNA. Using this model, some incidence of cancer, albeit negligible, will be predicted regardless how low the dose. However, the model revelas that the incidence of cancer induced by real-life exposures is likely to be greatly overestimated by currently used stochastic statistical extrapolations. Even more important, modeling of the chemical processes involved in the fate of a carcinogenic chemical in the body reveals experimental approaches to elucidating the mechanism(s) of carcinogenesis and ultimately a more scientifically sound basis for assessing the hazard of low-level exposure to a chemical carcinogen.« less

CORRELATION OF CARCINOGENIC POTENCY WITH MOUSE SKIN 32P-POSTLABELING AND LAC Z-MUTATION DATE FOR DMBA AN ITS K-REGION SULPHUR ISOSTERE: COMPARISON WITH ACTIVITIES OBSERVED IN STANDARD GENOTOXICITY ASSAYS

EPA Science Inventory

6,11-Dimethylbenzo(b]naphtho[2,3-d]thiophene (S-DMBA) is one of several carcinogenic analogs of the reference mouse skin carcinogen 7,12-dimethylbenz[alanthracene (OMBA)Demonstration of the weak carcinogenicity of S-DMBA by Tilak in 1946 established at that early stage the inadeq...

IARC classes 1 and 2 carcinogens are successfully identified by an alternative strategy that detects DNA-reactivity and cell transformation ability of chemicals.

PubMed

Benigni, Romualdo; Bossa, Cecilia; Battistelli, Chiara Laura; Tcheremenskaia, Olga

2013-12-12

For decades, traditional toxicology has been the ultimate source of information on the carcinogenic potential of chemicals; however with increasing demand on regulation of chemicals and decreasing resources for testing, opportunities to accept "alternative" approaches have dramatically expanded. The need for tools able to identify carcinogens in shorter times and at a lower cost in terms of animal lives and money is still an open issue, and the present strategies and regulations for carcinogenicity pre-screening do not adequately protect human health. In previous papers, we have proposed an integrated in vitro/in silico strategy that detects DNA-reactivity and tissue disorganization/disruption by chemicals, and we have shown that the combination of Salmonella and Structural Alerts for the DNA-reactive carcinogens, and in vitro cell transformation assays for nongenotoxic carcinogens permits the identification of a very large proportion (up to 95%) of rodent carcinogens, while having a considerable specificity with the rodent noncarcinogens. In the present paper we expand the previous investigation and show that this alternative strategy identifies correctly IARC Classes 1 and 2 carcinogens. If implemented, this alternative strategy can contribute to improve the protection of human health while decreasing the use of animals. Copyright © 2013 Elsevier B.V. All rights reserved.

Approaches to the risk assessment of genotoxic carcinogens in food: a critical appraisal.

PubMed

O'Brien, J; Renwick, A G; Constable, A; Dybing, E; Müller, D J G; Schlatter, J; Slob, W; Tueting, W; van Benthem, J; Williams, G M; Wolfreys, A

2006-10-01

The present paper examines the particular difficulties presented by low levels of food-borne DNA-reactive genotoxic carcinogens, some of which may be difficult to eliminate completely from the diet, and proposes a structured approach for the evaluation of such compounds. While the ALARA approach is widely applicable to all substances in food that are both carcinogenic and genotoxic, it does not take carcinogenic potency into account and, therefore, does not permit prioritisation based on potential risk or concern. In the absence of carcinogenicity dose-response data, an assessment based on comparison with an appropriate threshold of toxicological concern may be possible. When carcinogenicity data from animal bioassays are available, a useful analysis is achieved by the calculation of margins of exposure (MOEs), which can be used to compare animal potency data with human exposure scenarios. Two reference points on the dose-response relationship that can be used for MOE calculation were examined; the T25 value, which is derived from linear extrapolation, and the BMDL10, which is derived from mathematical modelling of the dose-response data. The above approaches were applied to selected food-borne genotoxic carcinogens. The proposed approach is applicable to all substances in food that are DNA-reactive genotoxic carcinogens and enables the formulation of appropriate semi-quantitative advice to risk managers.

The JaCVAM international validation study on the in vivo comet assay: Selection of test chemicals.

PubMed

Morita, Takeshi; Uno, Yoshifumi; Honma, Masamitsu; Kojima, Hajime; Hayashi, Makoto; Tice, Raymond R; Corvi, Raffaella; Schechtman, Leonard

2015-07-01

The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and genotoxic data, differences in chemical class or genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 genotoxic carcinogens, 6 genotoxic non-carcinogens, 7 non-genotoxic carcinogens and 8 non-genotoxic non-carcinogens. "Genotoxicity" was defined as positive in the Ames mutagenicity test or in one of the standard in vivo genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Mechanisms of Chemical Carcinogenesis in the Kidneys

PubMed Central

Radford, Robert; Frain, Helena; Ryan, Michael P.; Slattery, Craig; McMorrow, Tara

2013-01-01

Chemical carcinogens are substances which induce malignant tumours, increase their incidence or decrease the time taken for tumour formation. Often, exposure to chemical carcinogens results in tissue specific patterns of tumorigenicity. The very same anatomical, biochemical and physiological specialisations which permit the kidney to perform its vital roles in maintaining tissue homeostasis may in fact increase the risk of carcinogen exposure and contribute to the organ specific carcinogenicity observed with numerous kidney carcinogens. This review will address the numerous mechanisms which play a role in the concentration, bioactivation, and uptake of substances from both the urine and blood which significantly increase the risk of cancer in the kidney. PMID:24071941

[The National Registry of Occupational Exposures to Carcinogens (SIREP): information system and results].

PubMed

Scarselli, Alberto

2011-01-01

The recording of occupational exposure to carcinogens is a fundamental step in order to assess exposure risk factors in workplaces. The aim of this paper is to describe the characteristics of the Italian register of occupational exposures to carcinogen agents (SIREP). The core data collected in the system are: firm characteristics, worker demographics, and exposure information. Statistical descriptive analyses were performed by economic activity sector, carcinogen agent and geographic location. Currently, the information recorded regard: 12,300 firms, 130,000 workers, and 250,000 exposures. The SIREP database has been set up in order to assess, control and reduce the carcinogen risk at workplace.

Investigating palygorskite's role in the development of mesothelioma in southern Nevada: Insights into fiber-induced carcinogenicity.

PubMed

Larson, David; Powers, Amy; Ambrosi, Jean-Paul; Tanji, Mika; Napolitano, Andrea; Flores, Erin G; Baumann, Francine; Pellegrini, Laura; Jennings, Cormac J; Buck, Brenda J; McLaurin, Brett T; Merkler, Doug; Robinson, Cleo; Morris, Paul; Dogan, Meral; Dogan, A Umran; Pass, Harvey I; Pastorino, Sandra; Carbone, Michele; Yang, Haining

2016-01-01

Similar to asbestos fibers, nonregulated mineral fibers can cause malignant mesothelioma (MM). Recently, increased proportions of women and young individuals with MM were identified in southern Nevada, suggesting that environmental exposure to carcinogenic fibers was causing the development of MM. Palygorskite, a fibrous silicate mineral with a history of possible carcinogenicity, is abundant in southern Nevada. In this study, our aim was to determine whether palygorskite was contributing to the development of MM in southern Nevada. While palygorskite, in vitro, displayed some cytotoxicity toward primary human mesothelial (HM) cells and reduced their viability, the effects were roughly half of those observed when using similar amounts of crocidolite asbestos. No Balb/c (0/19) or MexTAg (0/18) mice injected with palygorskite developed MM, while 3/16 Balb/c and 13/14 MexTAg mice injected with crocidolite did. Lack of MM development was associated with a decreased acute inflammatory response, as injection of palygorskite resulted in lower percentages of macrophages (p = .006) and neutrophils (p = .02) in the peritoneal cavity 3 d after exposure compared to injection of crocidolite. Additionally, compared to mice injected with crocidolite, palygorskite-injected mice had lower percentages of M2 (tumor-promoting) macrophages (p = .008) in their peritoneal cavities when exposed to fiber for several weeks. Our study indicates that palygorskite found in the environment in southern Nevada does not cause MM in mice, seemingly because palygorskite, in vivo, fails to elicit inflammation that is associated with MM development. Therefore, palygorskite is not a likely contributor to the MM cases observed in southern Nevada.

Best practices for clinical pathology testing in carcinogenicity studies.

PubMed

Young, Jamie K; Hall, Robert L; O'Brien, Peter; Strauss, Volker; Vahle, John L

2011-02-01

The Society of Toxicologic Pathology (STP) and American Society for Veterinary Clinical Pathology (ASCVP) convened a Clinical Pathology in Carcinogenicity Studies Working Group to recommend best practices for inclusion of clinical pathology testing in carcinogenicity studies. Regulatory guidance documents and literature were reviewed, and veterinary pathologists from North America, Japan, and Europe were surveyed regarding current practices, perceived value, and recommendations for clinical pathology testing in carcinogenicity studies. For two-year rodent carcinogenicity studies, the Working Group recommends that clinical pathology testing be limited to collection of blood smears at scheduled and unscheduled sacrifices to be examined only if indicated to aid in the diagnosis of possible hematopoietic neoplasia following histopathologic evaluation. Additional clinical pathology testing is most appropriately used to address specific issues from prior toxicity studies or known test article-related class effects. Inadequate data were available to make a recommendation concerning clinical pathology testing for alternative six-month carcinogenicity assays using genetically modified mice, although the Working Group suggests that it may be appropriate to use the same approach as for two-year carcinogenicity studies since the study goal is the same.

Carcinogenicity and Mutagenicity Data: New Initiatives to ...

EPA Pesticide Factsheets

Currents models for prediction of chemical carcinogenicity and mutagenicity rely upon a relatively small number of publicly available data resources, where the data being modeled are highly summarized and aggregated representations of the actual experimental results. A number of new initiatives are underway to improve access to existing public carcinogenicity and mutagenicity data for use in modeling, as well as to encourage new approaches to the use of data in modeling. Rodent bioassay results from the NIEHS National Toxicology Program (NTP) and the Berkeley Carcinogenic Potency Database (CPDB) have provided the largest public data resources for building carcinogenicity prediction models to date. However, relatively few and limited representations of these data have actually informed existing models. Initiatives, such as EPA's DSSTox Database Network, offer elaborated and quality reviewed presentations of the CPDB and expanded data linkages and coverage of chemical space for carcinogenicity and mutagenicity. In particular the latest published DSSTox CPDBAS structure-data file includes a number of species-specific and summary activity fields, including a species-specific normalized score for carcinogenic potency (TD50) and various weighted summary activities. These data are being incorporated into PubChem to provide broad

Reducing carcinogens in public schools: A non-regulatory approach by a regulatory agency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roche, L.M.

1995-05-01

The New Jersey Public Employees` Occupational Safety and Health Program identified 318 public school districts that reported any of 10 selected carcinogens on their 1990 New Jersey Right to Know Survey of hazardous substances. After obtaining more information about the school districts` use of these carcinogens from a 10% random sample phone survey, a letter recommending substitution of less hazardous substances was sent to the 318 school districts. Individualized to reflect information provided by the schools in the 1990 survey, a form requesting additional information on the status of containers holding the carcinogens was also sent. There were 1,303 reportsmore » of the 10 carcinogens from the 272 (86%) school districts that completed the form. Most were disposed of (668, 51%), used completely (65, 5%), or were slated for disposal (287, 22%). This is an example of a successful project by a regulatory agency to reduce potential exposure to carcinogens in public schools. The 10 most reported carcinogens were arsenic, arsenic trioxide, asbestos, benzene, benzidine, lead chromate, sodium arsenate, sodium arsenite, sodium dichromate, and vinyl chloride.« less

Carcinogenicity of 4-methoxyphenol and 4-methylcatechol in F344 rats.

PubMed

Asakawa, E; Hirose, M; Hagiwara, A; Takahashi, S; Ito, N

1994-01-02

The carcinogenic potentials of 4-methoxyphenol (4-MP) and 4-methylcatechol (4-MC), phenolic compounds which are structurally similar to the known forestomach carcinogen BHA and the glandular stomach carcinogen catechol respectively, and cause considerably enhanced cell proliferation and cytotoxicities in rat forestomach and/or glandular stomach epithelium, were examined in male and female F344 rats. Groups of 30 male and female animals were administered diets containing 2% 4-MP or 2% 4-MC for 104 weeks. Histopathological findings in the 4-MP case included atypical hyperplasias (male, 67%, female, 37%), papillomas (50%, 23%) and squamous-cell carcinomas (77%, 20%) in the forestomach. 4-MC induced forestomach papillomas (70%, 93%) and squamous-cell carcinomas (53%, 37%), also glandular stomach submucosal hyperplasias (90%, 93%), adenomas (100%, 100%) and adenocarcinomas (57%, 47%), with ulceration or erosion. The degree of differentiation of the squamous-cell carcinomas induced by 4-MP was less than with 4-MC. The present study demonstrated unequivocal forestomach carcinogenicity for 4-MP and forestomach and glandular stomach carcinogenicity for 4-MC, with cytotoxicity and cell proliferation both appearing as important factors for these non-genotoxic carcinogens.

Emission from open burning of municipal solid waste in India.

PubMed

Kumari, Kanchan; Kumar, Sunil; Rajagopal, Vineel; Khare, Ankur; Kumar, Rakesh

2017-07-27

Open burning of Municipal Solid Waste (MSW) is a potential non-point source of emission, which causes greater concern especially in developing countries such as India. Lack of awareness about environmental impact of open burning, and ignorance of the fact, i.e. 'Open burning is a source of emission of carcinogenic substances' are major hindrances towards an appropriate municipal solid waste management system in India. The paper highlights the open burning of MSW practices in India, and the current and projected emission of 10 major pollutants (dioxin, furans, particulate matter, carbon monoxide, sulphur oxides, nitrogen oxides, benzene, toluene, ethyl benzene and 1-hexene) emitted due to the open burning of MSW. Waste to Energy potential of MSW was also estimated adopting effective biological and thermal techniques. Statistical techniques were applied to analyse the data and current and projected emission of various pollutants were estimated. Data pertaining to population, MSW generation and its collection efficiency were compiled for 29 States and 7 Union Territories. Thereafter, emission of 10 pollutants was measured following methodology prescribed in Intergovernmental Panel on Climate Change guideline for National Greenhouse Gas Inventories, 2006. The study revealed that people living in Metropolitan cities are more affected by emissions from open burning.

Approaches to evaluating the toxicity and carcinogenicity of man-made fibers: summary of a workshop held November 11-13, 1991, Durham, North Carolina.

PubMed

McClellan, R O; Miller, F J; Hesterberg, T W; Warheit, D B; Bunn, W B; Kane, A B; Lippmann, M; Mast, R W; McConnell, E E; Reinhardt, C F

1992-12-01

The Workshop on Approaches to Evaluating the Toxicity and Carcinogenicity of Man-Made Fibers (MMF) was held in Durham, North Carolina, on November 11-13, 1991. The goal of the workshop was to reach a consensus, or to determine the extent to which a consensus existed, in two areas. Participants were asked to identify scientifically sound approaches for evaluating the toxicity and carcinogenicity of man-made fibers based on today's science and to determine research appropriate for study during the next 5 years that can provide an improved scientific basis for future revisions of approaches used to evaluate man-made fiber toxicity and carcinogenicity. During the first day, a series of "state of knowledge" presentations were made to provide all participants with a common data base from which to interact and discuss scientific issues. The workshop participants were assigned to one of four discussion groups, which met separately in three half-day sessions following the first day of presentations. All groups discussed the same topics: exposure assessment, hazard identification, and dose-response information needed to integrate to characterize risk in the first session; approaches to obtaining the needed information in the second session; and recommended approaches and guidelines for evaluating the toxicity and carcinogenicity of MMF and research needs in the third session. The workshop participants reconvened as a whole after each discussion session, and one member from each group reported the group's conclusions. A closure period was also included at the end of the workshop for review and discussion of items that had been considered during the workshop. The primary conclusions reached were the following: -All fiber types capable of depositing in the thorax are not alike in their pathogenic potential. -Only fiber samples with dimensions similar to those to which humans can inhale should be tested. -A complete characterization (i.e., dimensions, fiber number, mass, and aerodynamic diameter) of the fiber aerosol and retained dose is essential. -Appropriate aerosol generation methods must be used for inhalation studies in order to preserve fiber lengths. -A tiered approach to toxicity evaluation is recommended that includes: 1. In vitro screening for durability, surface properties, cytotoxicity, and similar properties, etc; 2. Short-term inhalation or other in vivo studies; 3. That chronic inhalation studies are the "gold standard" (i.e., provide most appropriate data for risk characterization). -The rat is the most appropriate species for inhalation studies. -In chronic inhalation studies, animals should be retained to at least 20% survival after 2-year exposure. -Serial lung burden analyses are an essential component of inhalation studies and are essential for understanding exposure-dose-response relationships. -Studies oriented to understanding mechanisms of toxicity and carcinogenicity are important adjuncts to traditional toxicity studies. -Histopathological analyses of tissues of the respiratory tract represent primary endpoints for evaluating effects of inhaled fibers. Major effects include pulmonary fibrosis, lung tumors, and mesotheliomas. Experimental tissues should be archived for future studies; wherever possible, handling and preservation of tissues should be done in a way that maximizes their future use in mechanistic studies. -Potential human exposures throughout the entire life-cycle of the fiber must be considered and fibrous material for toxicologic studies prepared accordingly. -Intracavity studies are inappropriate for risk characterization but can play a useful screening role in assessing fiber toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

29 CFR 1990.142 - Initiation of a rulemaking.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.142 Initiation of a rulemaking. Where the Secretary decides to regulate a potential occupational carcinogen, the Secretary shall initiate a rulemaking...

29 CFR 1990.142 - Initiation of a rulemaking.

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.142 Initiation of a rulemaking. Where the Secretary decides to regulate a potential occupational carcinogen, the Secretary shall initiate a rulemaking...

29 CFR 1990.142 - Initiation of a rulemaking.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.142 Initiation of a rulemaking. Where the Secretary decides to regulate a potential occupational carcinogen, the Secretary shall initiate a rulemaking...

29 CFR 1990.142 - Initiation of a rulemaking.

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS Regulation of Potential Occupational Carcinogens § 1990.142 Initiation of a rulemaking. Where the Secretary decides to regulate a potential occupational carcinogen, the Secretary shall initiate a rulemaking...

Moesin Is a Biomarker for the Assessment of Genotoxic Carcinogens in Mouse Lymphoma

PubMed Central

Lee, Yoen Jung; Choi, In-Kwon; Sheen, Yhun Yhong; Park, Sue Nie; Kwon, Ho Jeong

2012-01-01

1,2-Dibromoethane and glycidol are well known genotoxic carcinogens, which have been widely used in industry. To identify a specific biomarker for these carcinogens in cells, the cellular proteome of L5178Y mouse lymphoma cells treated with these compounds was analyzed by 2-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry (MS). Of 50 protein spots showing a greater than 1.5-fold increase or decrease in intensity compared to control cells on a 2-D gel, we focused on the candidate biomarker moesin. Western analysis using monoclonal rabbit anti-moesin confirmed the identity of the protein and its increased level of expression upon exposure to the carcinogenic compounds. Moesin expression also increased in cells treated with six additional genotoxic carcinogens, verifying that moesin could serve as a biomarker to monitor phenotypic change upon exposure to genotoxic carcinogens in L5178Y mouse lymphoma cells. PMID:22358511

[Health risk assessment of coke oven PAHs emissions].

PubMed

Bo, Xin; Wang, Gang; Wen, Rou; Zhao, Chun-Li; Wu, Tie; Li, Shi-Bei

2014-07-01

Polycyclic aromatic hydrocarbons (PAHs) produced by coke oven are with strong toxicity and carcinogenicity. Taken typical coke oven of iron and steel enterprises as the case study, the dispersion and migration of 13 kinds of PAHs emitted from coke oven were analyzed using AERMOD dispersion model, the carcinogenic and non-carcinogenic risks at the receptors within the modeling domain were evaluated using BREEZE Risk Analyst and the Human Health Risk Assessment Protocol for Hazardous Waste Combustion (HHRAP) was followed, the health risks caused by PAHs emission from coke oven were quantitatively evaluated. The results indicated that attention should be paid to the non-carcinogenic risk of naphthalene emission (the maximum value was 0.97). The carcinogenic risks of each single pollutant were all below 1.0E-06, while the maximum value of total carcinogenic risk was 2.65E-06, which may have some influence on the health of local residents.

Consequences of synergy between environmental carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berenbaum, M.C.

1985-12-01

As it is generally impossible to determine dose-response relationships for carcinogens at the low concentrations in which they occur in the environment, risk-benefit considerations are by consensus based on the linear, no-threshold model, on the assumption that this represents the worst case. However, this assumption does not take into account the possibility of synergistic interactions between carcinogens. It is shown here that, as a result of such interactions, the dose-response curve for added risk due to any individual carcinogen will generally be steeper at lower doses than at higher doses, and consequently the risk at low environmental levels will bemore » higher than would be expected from a linear response. Moreover, this excess risk at low doses is shown to increase as the general level of environmental carcinogens rises and, independently of this effect, it may also increase with the number of carcinogens present.« less

Moesin is a biomarker for the assessment of genotoxic carcinogens in mouse lymphoma.

PubMed

Lee, Yoen Jung; Choi, In-Kwon; Sheen, Yhun Yhong; Park, Sue Nie; Kwon, Ho Jeong

2012-02-01

1,2-Dibromoethane and glycidol are well known genotoxic carcinogens, which have been widely used in industry. To identify a specific biomarker for these carcinogens in cells, the cellular proteome of L5178Y mouse lymphoma cells treated with these compounds was analyzed by 2-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry (MS). Of 50 protein spots showing a greater than 1.5-fold increase or decrease in intensity compared to control cells on a 2-D gel, we focused on the candidate biomarker moesin. Western analysis using monoclonal rabbit anti-moesin confirmed the identity of the protein and its increased level of expression upon exposure to the carcinogenic compounds. Moesin expression also increased in cells treated with six additional genotoxic carcinogens, verifying that moesin could serve as a biomarker to monitor phenotypic change upon exposure to genotoxic carcinogens in L5178Y mouse lymphoma cells.

Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke

PubMed Central

Hecht, S

2004-01-01

Objective: To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts. Method: Published reviews and the current literature were searched for relevant articles. Results: The most consistently elevated biomarker in people exposed to SHS was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc), urinary metabolites of the tobacco specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The tobacco specificity of this biomarker as well as its clear relation to an established lung carcinogen are particularly appropriate for its application in studies of SHS exposure. Conclusion: The results of the available carcinogen derived biomarker studies provide biochemical data which support the conclusion, based on epidemiologic investigations, that SHS causes lung cancer in non-smokers. PMID:14985617

[Application of quantum-chemical methods to prediction of the carcinogenicity of chemical substances].

PubMed

Zholdikova, Z I; Kharchevnikova, N V

2006-01-01

A version of logical-combinatorial JSM type intelligent system was used to predict the presence and the degree of a carcinogenic effect. This version was based on combined description of chemical substances including both structural and numeric parameters. The new version allows for the fact that the toxicity and danger caused by chemical substances often depend on their biological activation in the organism. The authors substantiate classifying chemicals according to their carcinogenic activity, and illustrate the use of the system to predict the carcinogenicity of polycyclic aromatic hydrocarbons using a model of bioactivation via the formation of diolepoxides, and the carcinogenicity of halogenated alkanes using a model of bioactivation via oxidative dehalogenation. The paper defined the boundary level of an energetic parameter, the exceeding of which correlated with the inhibition of halogenated alkanes's metabolism and the absence of carcinogenic activity.

Father's occupational exposure to carcinogenic agents and childhood acute leukemia: a new method to assess exposure (a case-control study)

PubMed Central

Perez-Saldivar, Maria Luisa; Ortega-Alvarez, Manuel Carlos; Fajardo-Gutierrez, Arturo; Bernaldez-Rios, Roberto; del Campo-Martinez, Maria de los Angeles; Medina-Sanson, Aurora; Palomo-Colli, Miguel Angel; Paredes-Aguilera, Rogelio; Martínez-Avalos, Armando; Borja-Aburto, Victor Hugo; Rodriguez-Rivera, Maria de Jesus; Vargas-Garcia, Victor Manuel; Zarco-Contreras, Jesus; Flores-Lujano, Janet; Mejia-Arangure, Juan Manuel

2008-01-01

Background Medical research has not been able to establish whether a father's occupational exposures are associated with the development of acute leukemia (AL) in their offspring. The studies conducted have weaknesses that have generated a misclassification of such exposure. Occupations and exposures to substances associated with childhood cancer are not very frequently encountered in the general population; thus, the reported risks are both inconsistent and inaccurate. In this study, to assess exposure we used a new method, an exposure index, which took into consideration the industrial branch, specific position, use of protective equipment, substances at work, degree of contact with such substances, and time of exposure. This index allowed us to obtain a grade, which permitted the identification of individuals according to their level of exposure to known or potentially carcinogenic agents that are not necessarily specifically identified as risk factors for leukemia. The aim of this study was to determine the association between a father's occupational exposure to carcinogenic agents and the presence of AL in their offspring. Methods From 1999 to 2000, a case-control study was performed with 193 children who reside in Mexico City and had been diagnosed with AL. The initial sample-size calculation was 150 children per group, assessed with an expected odds ratio (OR) of three and a minimum exposure frequency of 15.8%. These children were matched by age, sex, and institution with 193 pediatric surgical patients at secondary-care hospitals. A questionnaire was used to determine each child's background and the characteristics of the father's occupation(s). In order to determine the level of exposure to carcinogenic agents, a previously validated exposure index (occupational exposure index, OEI) was used. The consistency and validity of the index were assessed by a questionnaire comparison, the sensory recognition of the work area, and an expert's opinion. Results The adjusted ORs and 95% confidence intervals (CI) were 1.69 (0.98, 2.92) during the preconception period; 1.98 (1.13, 3.45) during the index pregnancy; 2.11 (1.17, 3.78) during breastfeeding period; 2.17 (1.28, 3.66) after birth; and 2.06 (1.24, 3.42) for global exposure. Conclusion This is the first study in which an OEI was used to assess a father's occupational exposure to carcinogenic agents as a risk factor for the development of childhood AL in his offspring. From our results, we conclude that children whose fathers have been exposed to a high level of carcinogenic agents seem to have a greater risk of developing acute leukemia. However, confounding factors cannot be disregarded due to an incomplete control for confounding. PMID:18194546

[Health Risk Assessment of Drinking Water Quality in Tianjin Based on GIS].

PubMed

Fu, Gang; Zeng, Qiang; Zhao, Liang; Zhang, Yue; Feng, Bao-jia; Wang, Rui; Zhang, Lei; Wang, Yang; Hou, Chang-chun

2015-12-01

This study intends to assess the potential health hazards of drinking water quality and explore the application of geographic information system( GIS) in drinking water safety in Tianjin. Eight hundred and fifty water samples from 401 sampling points in Tianjin were measured according to the national drinking water standards. The risk assessment was conducted using the environmental health risk assessment model recommended by US EAP, and GIS was combined to explore the information visualization and risk factors simultaneously. The results showed that the health risks of carcinogens, non-carcinogens were 3.83 x 10⁻⁵, 5.62 x 10⁻⁹ and 3.83 x 10⁻⁵ for total health risk respectively. The rank of health risk was carcinogen > non-carcinogen. The rank of carcinogens health risk was urban > new area > rural area, chromium (VI) > cadmium > arsenic > trichlormethane > carbon tetrachloride. The rank of non-carcinogens health risk was rural area > new area > urban, fluoride > cyanide > lead > nitrate. The total health risk level of drinking water in Tianjin was lower than that of ICRP recommended level (5.0 x 10⁻⁵), while was between US EPA recommended level (1.0 x 10⁻⁴-1.0 x 10⁻⁶). It was at an acceptable level and would not cause obvious health hazards. The main health risks of drinking water came from carcinogens. More attentions should be paid to chromium (VI) for carcinogens and fluoride for non-carcinogens. GIS can accomplish information visualization of drinking water risk assessment and further explore of risk factors.

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

PubMed Central

Chappell, Grace; Pogribny, Igor P.; Guyton, Kathryn Z.; Rusyn, Ivan

2016-01-01

Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. PMID:27234561

Tumor initiating activities of various derivatives of benz(a)anthracene and 7, 12-dimethyl-benz(a)anthracene in mouse skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slaga, T.J.; Gleason, G.L.; DiGiovanni, J.

Current information indicates that polycyclic aromatic hydrocarbons (PAH) exert their toxic, mutagenic, and carcinogenic activities after they have been metabolically activated by target cells to reactive epoxides. The results obtained from IN VIVO and IN VITRO binding, mutagenicity, metabolism, and carcinogenicity studies have led to the conclusion that BP-7, 8-diol is a proximate carcinogenic metabolite of BP, and the BP-diol-epoxide is an ultimate carcinogenic metabolite of BP. Recent results concerning the strong carcinogenicity of BP-7..beta.., 8..cap alpha..-diol-9..cap alpha..,10..cap alpha..-epoxide in newborn mice and in mouse skin strongly indicate that it is the ultimate carcinogenic metabolite of BP. Since diol-epoxides maymore » be responsible for the carcinogenicity of PAH other than BP, diols and diol-epoxides as well as other derivatives of PAH were tested for skin tumor-initiation in a two-stage system of tumorigenesis. In addition, since activation of methylated PAH may involve the side-chain methyl group, the skin tumor-initiating activity of various side-chain derivatives of methylated PA were determined. In this report, the skin tumor initiation of various derivatives of a nonmethylated PAH, BA as well as a methylated PAH, DMBA are compared. The data suggest that bay region diol-epoxides may be important in BA and DMBA carcinogenicity in mice which is supportive of the theory proposed by Jerina and co-workers which predicts that diol-epoxides in the bay region are the major determinants of PAH carcinogenicity.« less

EPA's evaluation of the carcinogenic potential of glyphosate

EPA Science Inventory

Recently, several international agencies have evaluated the carcinogenic potential of glyphosate. In March 2015, the International Agency for Research on Cancer (IARC), a subdivision of the World Health Organization (WHO), determined that glyphosate was a probable carcinogen (gro...

PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC

EPA Science Inventory

PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC.

Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. In contrast,
there is no accepted experimental animal model of inorganic arsenic carcinogenesis.
Proposed mechanisms/modes of action for a...

Arsenic Is A Genotoxic Carcinogen

EPA Science Inventory

Arsenic is a recognized human carcinogen; however, there is controversy over whether or not it should be considered a genotoxic carcinogen. Many possible modes of action have been proposed on how arsenic induces cancer, including inhibiting DNA repair, altering methylation patter...

29 CFR 1990.101 - Scope.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS General § 1990.101 Scope... potential occupational carcinogens found in each workplace in the United States regulated by the... occupational carcinogens. This part may be referred to as “The OSHA Cancer Policy.” ...

29 CFR 1990.101 - Scope.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS General § 1990.101 Scope... potential occupational carcinogens found in each workplace in the United States regulated by the... occupational carcinogens. This part may be referred to as “The OSHA Cancer Policy.” ...

29 CFR 1990.101 - Scope.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS General § 1990.101 Scope... potential occupational carcinogens found in each workplace in the United States regulated by the... occupational carcinogens. This part may be referred to as “The OSHA Cancer Policy.” ...

29 CFR 1990.112 - Classification of potential carcinogens.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 1990.112 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria...

29 CFR 1990.112 - Classification of potential carcinogens.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 1990.112 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) IDENTIFICATION, CLASSIFICATION, AND REGULATION OF POTENTIAL OCCUPATIONAL CARCINOGENS The Osha Cancer Policy § 1990.112 Classification of potential carcinogens. The following criteria...

Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Auerbach, Scott S.; Shah, Ruchir R.; Mav, Deepak

Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination ofmore » exposures (2 + 14, 2 + 90, 14 + 90 and 2 + 14 + 90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these chemicals should be a higher priority relative to other untested alkenylbenzenes for evaluation in the carcinogenicity bioassay. The results of the study indicate that gene expression-based predictive models are an effective tool for identifying hepatocarcinogens. Furthermore, we find that exposure duration is a critical variable in the success or failure of such an approach, particularly when evaluating chemicals with unknown carcinogenic potency.« less

Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning.

PubMed

Auerbach, Scott S; Shah, Ruchir R; Mav, Deepak; Smith, Cynthia S; Walker, Nigel J; Vallant, Molly K; Boorman, Gary A; Irwin, Richard D

2010-03-15

Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination of exposures (2+14, 2+90, 14+90 and 2+14+90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these chemicals should be a higher priority relative to other untested alkenylbenzenes for evaluation in the carcinogenicity bioassay. The results of the study indicate that gene expression-based predictive models are an effective tool for identifying hepatocarcinogens. Furthermore, we find that exposure duration is a critical variable in the success or failure of such an approach, particularly when evaluating chemicals with unknown carcinogenic potency. Published by Elsevier Inc.

A proposed framework for consistent regulation of public exposures to radionuclides and other carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kocher, D.C.; Hoffman, F.O.

1991-12-31

This paper discusses a proposed framework for consistent regulation of carcinogenic risks to the public based on establishing de manifestis (i.e., unacceptable) and de minimis (i.e., trivial) lifetime risks from exposure to any carcinogens at levels of about 10{sup {minus}1}--10{sup {minus}3} and 10{sup {minus}4}--10{sup {minus}6}, respectively, and reduction of risks above de minimis levels as low as reasonably achievable (ALARA). We then discuss certain differences in the way risks from exposure to radionuclides and other carcinogens currently are regulated or assessed which would need to be considered in implementing the proposed regulatory framework for all carcinogens.

A proposed framework for consistent regulation of public exposures to radionuclides and other carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kocher, D.C.; Hoffman, F.O.

1991-01-01

This paper discusses a proposed framework for consistent regulation of carcinogenic risks to the public based on establishing de manifestis (i.e., unacceptable) and de minimis (i.e., trivial) lifetime risks from exposure to any carcinogens at levels of about 10{sup {minus}1}--10{sup {minus}3} and 10{sup {minus}4}--10{sup {minus}6}, respectively, and reduction of risks above de minimis levels as low as reasonably achievable (ALARA). We then discuss certain differences in the way risks from exposure to radionuclides and other carcinogens currently are regulated or assessed which would need to be considered in implementing the proposed regulatory framework for all carcinogens.

[Risk assessment and countermeasures of BTEX contamination in soils of typical pesticide factory].

PubMed

Tan, Bing; Wang, Tie-Yu; Li, Qi-Feng; Zhang, Hai-Yan; Pang, Bo; Zhu, Zhao-Yun; Wang, Dao-Han; Lü, Yong-Long

2014-06-01

Soil samples around three representative pesticide factories were collected in Zhangjiakou City, Hebei Province, and analyzed to identify their pollution characteristics and health risk of BTEX by purge-and trap and gas chromatography/mass spectroscopy method. Total concentrations of BTEX in soils in Plant A, B and C ranged from 673.50 to 32 363.50 ng x g(-1), nd to 6 461.80 ng x g(-1) and 461.70 to 8 740.80 ng x g(-1), respectively. Concentrations of detected toluene (4 619.50-7 234.30 ng x g(-1)) and ethylbenzene (364.60-7 944.60 ng x g(-1)) had exceeded the Canadian guidelines for industrial land (370 ng x g(-1) and 82 ng x g(-1)), and concentration of xylene (19 799.40 ng x g(-1)) in dust in production area of Plant A was larger than the Dutch soil intervention value (17 000 ng x g(-1)). While concentrationsn of BTEX around Plant A (Region I ) and Plant B and C (Region II) ranged from nd to 645.81 ng x g(-1), and nd to 309.13 ng x g(-1), respectively, which were below the Canadian guidelines for agricultural land. The non-carcinogenic risk of BTEX in Plant A (2.90E-06 -1.32E-04), B (nd -4.30E-05) and C (1.29E-06 -5.64E-05) were all below 1, which suggested that no obvious health risk existed in each plant. The non-carcinogenic risks in Region I (nd -2.02E-06) and Region II (nd -1.10E-06) were below than 1, and also lower than those in factories. High risk areas were mainly concentrated in the downwind, moreover, soils around villages and towns were also with higher risk. In conclusion, soils and dusts in each factory had been polluted and the quality of agricultural land had been partly deteriorated. Finally, environmental management and occupational protection countermeasures were proposed based on the research results.

Installation Restoration Program. Phase 2. Confirmation/Quantification. Stage 1. Reese Air Force Base, Lubbock, Texas. Volume 2. Appendices

DTIC Science & Technology

1988-04-01

epidemiological studies ; pending resolution of essentiality in human diet; EPA has not regulated arsenic as a carcinogen in drinking water 3ICadmium B1...Probable human carcinogen based upon sufficient evidence in epidemiological studies ; not regulated as a carcinogen in drinking water because there is...Carcinogenic in animal studies ; because of the extensive negative epidemiological evidence, EPA has proposed to regu- late lead in drinking water based on

Uterine adenocarcinoma in mice treated neonatally with genistein.

PubMed

Newbold, R R; Banks, E P; Bullock, B; Jefferson, W N

2001-06-01

The developing fetus is uniquely sensitive to perturbation with estrogenic chemicals. The carcinogenic effect of prenatal exposure to diethylstilbestrol (DES) is the classic example. Because phytoestrogen use in nutritional and pharmaceutical applications for infants and children is increasing, we investigated the carcinogenic potential of genistein, a naturally occurring plant estrogen in soy, in an experimental animal model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal DES exposure. Outbred female CD-1 mice were treated on days 1-5 with equivalent estrogenic doses of DES (0.001 mg/kg/day) or genistein (50 mg/kg/day). At 18 months, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation. Thus, the use of soy-based infant formulas in the absence of medical necessity and the marketing of soy products designed to appeal to children should be closely examined.

[Potential health risks from consumption of water with arsenic in Colima, Mexico].

PubMed

Mendoza-Cano, Oliver; Sánchez-Piña, Ramón Alberto; Barrón-Quintana, Julián; Cuevas-Arellano, Herguin Benjamin; Escalante-Minakata, Pilar; Solano-Barajas, Ramón

2017-01-01

To estimate potential health risks due to chronic ingestion of arsenic from groundwater in Colima, Mexico. Samples were randomly taken in 36 wells from 10 local aquifers. Analysis was performed by ICP-OES following international standards. Geostatistical interpolation was performed with ArcGIS, implementing a model weighting inverse distance to estimate arsenic routes of exposure and consumption on each locality. The Hazard Quotient Ratio (HQ) and carcinogenic risk (R) for As were estimated. The weighted average HQ for arsenic in Colima is 2.41. There are HQ> 1 values indicating adverse non-cancer health effects by continuous and prolonged intake of water with arsenic, which could affect 183 832 individuals in the state. The risk of developing any type of cancer among the population in this study due to high arsenic concentrations in groundwater (R) is 1.089E-3, which could statistically cause 446 cases of cancer. Current levels of arsenic in groundwater increase carcinogenic and non-carcinogenic human health risks in Colima.

Development of health-based screening levels for use in state- or local-scale water-quality assessments

USGS Publications Warehouse

Toccalino, Patricia L.; Nowell, Lisa; Wilber, William; Zogorski, John S.; Donohue, Joyce; Eiden, Catherine; Krietzman, Sandra; Post, Gloria

2003-01-01

The U.S. Geological Survey (USGS) has a need to communicate the significance of the water-quality findings of its National Water-Quality Assessment (NAWQA) Program in a human-health context. Historically, the USGS has assessed water-quality conditions by comparing water concentration data against established drinking-water standards and guidelines. However, because drinking- water standards and guidelines do not exist for many of the contaminants analyzed by the NAWQA Program and other USGS studies, this approach has proven to be insufficient for placing USGS data in a human-health context. To help meet this need, health-based screening level (HBSL) concentrations or ranges are being determined for unregulated compounds (that is, those for which Federal or State drinking-water standards have not been established), using a consensus approach that was developed collaboratively by the USGS, U.S. Environmental Protection Agency(USEPA), New Jersey Department of Environmental Protection, and Oregon Health & Science University. USEPA Office of Water methodologies for calculating Lifetime Health Advisory and Risk-Specific Dose values for drinking water are being used to develop HBSL concentrations (for unregulated noncarcinogens) and HBSL concentration ranges (for most unregulated carcinogens). This report describes the methodologies used to develop HBSL concentrations and ranges for unregulated compounds in State- and local-scale analyses, and discusses how HBSL values can be used as tools in water-quality assessments. Comparisons of measured water concentrations with Maximum Contaminant Level values and HBSL values require that water-quality data be placed in the proper context, with regard to both hydrology and human health. The use of these HBSL concentrations and ranges by USGS will increase by 27 percent the number of NAWQA contaminants for which health-based benchmarks are available for comparison with USGS water-quality data. USGS can use HBSL values to assist the USEPA and State and local agencies by providing them with comparisons of measured water concentrations to scientifically defensible human health-based benchmarks, and by alerting them when measured concentrations approach or exceed these benchmarks.

Detection of rare and possibly carcinogenic human papillomavirus genotypes as single infections in invasive cervical cancer.

PubMed

Geraets, Daan; Alemany, Laia; Guimera, Nuria; de Sanjose, Silvia; de Koning, Maurits; Molijn, Anco; Jenkins, David; Bosch, Xavier; Quint, Wim

2012-12-01

The contribution of carcinogenic human papillomavirus (HPV) types to the burden of cervical cancer has been well established. However, the role and contribution of phylogenetically related HPV genotypes and rare variants remains uncertain. In a recent global study of 8977 HPV-positive invasive cervical carcinomas (ICCs), the genotype remained unidentified in 3.7% by the HPV SPF10 PCR-DEIA-LiPA25 (version 1) algorithm. The 331 ICC specimens with unknown genotype were analysed by a novel sequence methodology, using multiple selected short regions in L1. This demonstrated HPV genotypes that have infrequently or never been detected in ICC, ie HPV26, 30, 61, 67, 68, 69, 73 and 82, and rare variants of HPV16, 18, 26, 30, 34, 39, 56, 67, 68, 69, 82 and 91. These are not identified individually by LiPA25 and only to some extent by other HPV genotyping assays. Most identified genotypes have a close phylogenetic relationship with established carcinogenic HPVs and have been classified as possibly carcinogenic by IARC. Except for HPV85, all genotypes in α-species 5, 6, 7, 9 and 11 were encountered as single infections in ICCs. These species of established and possibly carcinogenic HPV types form an evolutionary clade. We have shown that the possibly carcinogenic types were detected only in squamous cell carcinomas, which were often keratinizing and diagnosed at a relatively higher mean age (55.3 years) than those associated with established carcinogenic types (50.9 years). The individual frequency of the possibly carcinogenic types in ICCs is low, but together they are associated with 2.25% of the 8338 included ICCs with a single HPV type. This fraction is greater than seven of the established carcinogenic types individually. This study provides evidence that possibly carcinogenic HPV types occur as single infections in invasive cervical cancer, strengthening the circumstantial evidence of a carcinogenic role. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Low-Dose Carcinogenicity Studies

EPA Science Inventory

One of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only 4 low-dose carcinogenicity studies and 5 low-dose biomarker/pre-n...

Theoretical and experimental approaches to possible thresholds of response in carcinogenicity

EPA Science Inventory

The determination and utilization of the actual low dose-response relationship for chemical carcinogens has long interested toxicologists, experimental pathologists, modelers and risk assessors. To date, no unequivocal examples of carcinogenic thresholds in humans are known. Ho...

Occupational cancer in Britain

PubMed Central

Chen, Yiqun; Osman, John

2012-01-01

Although only a relatively small proportion of cancer is attributable to occupational exposure to carcinogenic agents, the estimated number of deaths due to occupational cancer is high when compared to other deaths due to work-related ill health and injury. However, risk from occupational exposure to carcinogens can be minimised through proportionate but effective risk management. The Health and Safety Executive (HSE) is the regulator of workplace health and safety in Great Britain. As part of its aim to reduce ill health arising from failures to control properly exposure to hazards at work, HSE commissioned the research presented elsewhere in this supplement to enable it to identify priorities for preventing occupational cancer. The research has shown that occupational cancer remains a key health issue and that low-level exposure of a large number of workers to carcinogens is important. The finding that a small number of carcinogens have been responsible for the majority of the burden of occupational cancer provides key evidence in the development of priorities for significant reduction of occupational cancer. Although the research presented in this supplement reflects the consequences of past exposures to carcinogens, occupational cancer remains a problem. The potential for exposure to the agents considered in this research is still present in the workplace and the findings are relevant to prevention of future disease. In this article, the principle approaches for risk reduction are described. It provides supporting information on some of the initiatives already being undertaken, or those being put in place, to reduce occupational cancer in Great Britain. The need also for systematic collection of exposure information and the importance of raising awareness and changing behaviours are discussed. PMID:22710673

Occupational cancer in Britain. Preventing occupational cancer.

PubMed

Chen, Yiqun; Osman, John

2012-06-19

Although only a relatively small proportion of cancer is attributable to occupational exposure to carcinogenic agents, the estimated number of deaths due to occupational cancer is high when compared to other deaths due to work-related ill health and injury. However, risk from occupational exposure to carcinogens can be minimised through proportionate but effective risk management. The Health and Safety Executive (HSE) is the regulator of workplace health and safety in Great Britain. As part of its aim to reduce ill health arising from failures to control properly exposure to hazards at work, HSE commissioned the research presented elsewhere in this supplement to enable it to identify priorities for preventing occupational cancer. The research has shown that occupational cancer remains a key health issue and that low-level exposure of a large number of workers to carcinogens is important. The finding that a small number of carcinogens have been responsible for the majority of the burden of occupational cancer provides key evidence in the development of priorities for significant reduction of occupational cancer. Although the research presented in this supplement reflects the consequences of past exposures to carcinogens, occupational cancer remains a problem. The potential for exposure to the agents considered in this research is still present in the workplace and the findings are relevant to prevention of future disease. In this article, the principle approaches for risk reduction are described. It provides supporting information on some of the initiatives already being undertaken, or those being put in place, to reduce occupational cancer in Great Britain. The need also for systematic collection of exposure information and the importance of raising awareness and changing behaviours are discussed.

Comparative tumor promotion assessment of e-cigarette and cigarettes using the in vitro Bhas 42 cell transformation assay.

PubMed

Breheny, Damien; Oke, Oluwatobiloba; Pant, Kamala; Gaça, Marianna

2017-05-01

In vitro cell transformation assays (CTA) are used to assess the carcinogenic potential of chemicals and complex mixtures and can detect nongenotoxic as well as genotoxic carcinogens. The Bhas 42 CTA has been developed with both initiation and promotion protocols to distinguish between these two carcinogen classes. Cigarette smoke is known to be carcinogenic and is positive in in vitro genotoxicity assays. Cigarette smoke also contains nongenotoxic carcinogens and is a tumour promoter and cocarcinogen in vivo. We have combined a suite of in vitro assays to compare the relative biological effects of new categories of tobacco and nicotine products with traditional cigarettes. The Bhas promotion assay has been included in this test battery to provide an in vitro surrogate for detecting tumor promoters. The activity of an electronic cigarette (e-cigarette; Vype ePen) was compared to that of a reference cigarette (3R4F) in the promotion assay, using total particulate matter (TPM)/aerosol collected matter (ACM) and aqueous extracts (AqE) of product aerosol emissions. 3R4F TPM was positive in this assay at concentrations ≥6 µg/mL, while e-cigarette ACM did not have any promoter activity. AqE was found to be a lesssuitable test matrix in this assay due to high cytotoxicity. This is the first study to use the Bhas assay to compare tobacco and nicotine products and demonstrates the potential for its future application as part of a product assessment framework. These data add to growing evidence suggesting that e-cigarettes may provide a safer alternative to traditional cigarettes. Environ. Mol. Mutagen. 58:190-198, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

PubMed

Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

2017-03-01

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

Mechanism-based classification of PAH mixtures to predict carcinogenic potential

DOE PAGES

Tilton, Susan C.; Siddens, Lisbeth K.; Krueger, Sharon K.; ...

2015-04-22

We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[ a]pyrene (BaP). Therefore, we developed a pathway based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[ def,p]chrysene (DBC), BaP or environmental PAH mixtures (Mix 1-3) following a two-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC>>BaP=Mix2=Mix3>Mix1=Control, based on statistical significance. Gene expression profilesmore » measured in skin of mice collected 12 h post-initiation were compared to tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (p<0.05) for DNA damage, apoptosis, response to chemical stimulus and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of-concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. As a result, these data further provide a ‘source-to outcome’ model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action based risk assessment could be employed for environmental PAH mixtures.« less

Analysis of 23 polycyclic aromatic hydrocarbons in smokeless tobacco by gas chromatography-mass spectrometry

PubMed Central

Stepanov, Irina; Villalta, Peter W.; Knezevich, Aleksandar; Jensen, Joni; Hatsukami, Dorothy; Hecht, Stephen S.

2009-01-01

Smokeless tobacco contains 28 known carcinogens and causes precancerous oral lesions and oral and pancreatic cancer. A recent study conducted by our research team identified 8 different polycyclic aromatic hydrocarbons (PAH) in U.S. moist snuff, encouraging further investigations of this group of toxicants and carcinogens in smokeless tobacco products. In this study, we developed a gas chromatography-mass spectrometry method that allows simultaneous analysis of 23 various PAH in smokeless tobacco after a simple two-step extraction and purification procedure. The method produced coefficients of variation under 10% for most PAH. The limits of quantitation for different PAH varied between 0.3 ng/g tobacco and 11 ng/g tobacco, starting with a 300-mg sample. The recovery of the stable isotope-labeled internal standards averaged 87%. The method was applied to analysis of 23 moist snuff samples that include various flavors of the most popular U.S. moist snuff brands, as well as 17 samples representing the currently marketed brands of spit-free tobacco pouches, a relatively new type of smokeless tobacco. The sum of all detected PAH in conventional moist snuff averaged 11.6 (± 3.7) µg/g dry weight, 20% of this amount being comprised by carcinogenic PAH. The levels of PAH in new spit-free tobacco products were much lower than those in moist snuff, the sum of all detected PAH averaging 1.3 (±0.28) µg/g dry weight. Our findings render PAH one of the most prevalent groups of carcinogens in smokeless tobacco, along with tobacco-specific nitrosamines. Urgent measures are required from the U.S. tobacco industry to modify manufacturing processes so that the levels of these toxicants and carcinogens in the U.S. moist snuff are greatly reduced. PMID:19860436

Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential.

PubMed

Tilton, Susan C; Siddens, Lisbeth K; Krueger, Sharon K; Larkin, Andrew J; Löhr, Christiane V; Williams, David E; Baird, William M; Waters, Katrina M

2015-07-01

We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[a]pyrene (BaP). Therefore, we developed a pathway-based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[def,p]chrysene (DBC), BaP, or environmental PAH mixtures (Mix 1-3) following a 2-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC > BaP = Mix2 = Mix3 > Mix1 = Control, based on statistical significance. Gene expression profiles measured in skin of mice collected 12 h post-initiation were compared with tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (P < .05) for DNA damage, apoptosis, response to chemical stimulus, and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of-concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. These data further provide a 'source-to-outcome' model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action-based risk assessment could be employed for environmental PAH mixtures. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Low-dose carcinogenicity of 2-amino-3-methylimidazo[4,5-f ]quinoline in rats: Evidence for the existence of no-effect levels and a mechanism involving p21(Cip / WAF1).

PubMed

Wei, Min; Wanibuchi, Hideki; Nakae, Dai; Tsuda, Hiroyuki; Takahashi, Satoru; Hirose, Masao; Totsuka, Yukari; Tatematsu, Masae; Fukushima, Shoji

2011-01-01

The carcinogenicity of the low amounts of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and to investigate mechanisms by which IQ exerts its carcinogenic effects. A total of 1595 male F344 rats were divided into seven groups and administered with IQ at doses of 0, 0.001, 0.01, 0.1, 1, 10 and 100 p.p.m. in the diet for 16 weeks. We found that IQ doses of 1 p.p.m. and below did not induce preneoplastic lesions in either the liver or the colon, while IQ doses of 10 and 100 p.p.m. induced preneoplastic lesions in both of these organs. These results demonstrate the presence of no-effect levels of IQ for both liver and colon carcinogenicity in rats. The finding that p21(Cip/WAF1) was significantly induced in the liver at doses well below those required for IQ mediated carcinogenic effects suggests that induction of p21(Cip/WAF1) is one of the mechanisms responsible for the observed no-effect of low doses of IQ. Furthermore, IQ administration caused significant induction of CYP1A2 at doses of 0.01-10 p.p.m., but administration of 100 p.p.m. IQ induced CYP1A1 rather than CYP1A2. This result indicates the importance of dosage when interpreting data on the carcinogenicity and metabolic activation of IQ. Overall, our results suggest the existence of no-effect levels for the carcinogenicity of this genotoxic compound. © 2010 Japanese Cancer Association.

Effect of DNA type on response of DNA biosensor for carcinogens

NASA Astrophysics Data System (ADS)

Sani, Nor Diyana bt. Md.; Heng, Lee Yook; Surif, Salmijah; Lazim, Azwani Mat

2013-11-01

Carcinogens are cancer causing chemicals that can bind to DNA and cause damage to the DNA. These chemicals are available everywhere including in water, air, soil and food. Therefore, a sensor that can detect the presence of these chemicals will be a very useful tool. Since carcinogens bind to DNA, DNA can be used as the biological element in a biosensor. This study has utilized different types of DNA in a biosensor for carcinogen detection. The DNAs include double stranded calf thymus DNA, single stranded calf thymus DNA and guanine rich single stranded DNA. The modified SPE was exposed to a carcinogen followed by interaction with methylene blue which acts as the electroactive indicator. The SPE was then analysed using differential pulse voltammetry (DPV). Optimization studies were conducted for MB concentration and accumulation time, DNA concentration, as well as effect of buffer concentration, buffer pH and ionic strength. The performance of the biosensor was tested on a group 1 carcinogen, formaldehyde. The results indicated that the usage of guanine rich single stranded DNA also gives higher response as carcinogens prefer to bind with guanine compared to other bases.

Production of thymine glycols in DNA by radiation and chemical carcinogens as detected by a monoclonal antibody.

PubMed Central

Leadon, S. A.

1987-01-01

In order to understand the role in carcinogenesis of damage indirectly induced by chemical carcinogens, it is important to identify the primary DNA lesions. We have measured the formation and repair of one type of DNA modification, 5,6-dihydroxydihydrothymine (thymine glycol), following exposure of cultured human cells to the carcinogens N-hydroxy-2-naphthylamine or benzo(a)pyrene. The efficiency of production of thymine glycols in DNA by these carcinogens was compared to that by ionizing radiation and ultraviolet light. Thymine glycols were detected using a monoclonal antibody against this product in a sensitive immunoassay. We found that thymine glycols were produced in DNA in a dose dependent manner after exposure to the carcinogens and that their production was reduced if either catalase or superoxide dismutase or both were present at the time of treatment. The efficiency of thymine glycol production following exposure to the chemical carcinogens was greater than that following equi-toxic doses of radiation. Thymine glycols were efficiently removed from the DNA of human cells following treatment with either the chemical carcinogens, ionizing radiation or ultraviolet light. PMID:3477281

Cases series of malignant lymphohematopoietic disorder in korean semiconductor industry.

PubMed

Kim, Eun-A; Lee, Hye-Eun; Ryu, Hyung-Woo; Park, Seung-Hyun; Kang, Seong-Kyu

2011-06-01

Seven cases of malignant lymphohematopoietic (LHP) disorder were claimed to have developed from occupational exposure at two plants of a semiconductor company from 2007 to 2010. This study evaluated the possibility of exposure to carcinogenic agents for the cases. Clinical courses were reviewed with assessing possible exposure to carcinogenic agents related to LHP cancers. Chemicals used at six major semiconductor companies in Korea were reviewed. Airborne monitoring for chemicals, including benzene, was conducted and the ionizing radiation dose was measured from 2008 to 2010. The latency of seven cases (five leukemiae, a Non-Hodgkin's lymphoma, and an aplastic anemia) ranged from 16 months to 15 years and 5 months. Most chemical measurements were at levels of less than 10% of the Korean Occupational Exposure Limit value. No carcinogens related to LHP cancers were used or detected. Complete-shielded radiation-generating devices were used, but the ionizing radiation doses were 0.20-0.22 uSv/hr (background level: 0.21 µSv/hr). Airborne benzene was detected at 0.31 ppb when the detection limit was lowered as low as possible. Ethylene oxide and formaldehyde were not found in the cases' processes, while these two were determined to be among the 263 chemicals in the list that was used at the six semiconductor companies at levels lower than 0.1%. Exposures occurring before 2002 could not be assessed because of the lack of information. Considering the possibility of exposure to carcinogenic agents, we could not find any convincing evidence for occupational exposure in all investigated cases. However, further study is needed because the semiconductor industry is a newly developing one.

Cases Series of Malignant Lymphohematopoietic Disorder in Korean Semiconductor Industry

PubMed Central

Lee, Hye-Eun; Ryu, Hyung-Woo; Park, Seung-Hyun; Kang, Seong-Kyu

2011-01-01

Objectives Seven cases of malignant lymphohematopoietic (LHP) disorder were claimed to have developed from occupational exposure at two plants of a semiconductor company from 2007 to 2010. This study evaluated the possibility of exposure to carcinogenic agents for the cases. Methods Clinical courses were reviewed with assessing possible exposure to carcinogenic agents related to LHP cancers. Chemicals used at six major semiconductor companies in Korea were reviewed. Airborne monitoring for chemicals, including benzene, was conducted and the ionizing radiation dose was measured from 2008 to 2010. Results The latency of seven cases (five leukemiae, a Non-Hodgkin's lymphoma, and an aplastic anemia) ranged from 16 months to 15 years and 5 months. Most chemical measurements were at levels of less than 10% of the Korean Occupational Exposure Limit value. No carcinogens related to LHP cancers were used or detected. Complete-shielded radiation-generating devices were used, but the ionizing radiation doses were 0.20-0.22 uSv/hr (background level: 0.21 µSv/hr). Airborne benzene was detected at 0.31 ppb when the detection limit was lowered as low as possible. Ethylene oxide and formaldehyde were not found in the cases' processes, while these two were determined to be among the 263 chemicals in the list that was used at the six semiconductor companies at levels lower than 0.1%. Exposures occurring before 2002 could not be assessed because of the lack of information. Conclusion Considering the possibility of exposure to carcinogenic agents, we could not find any convincing evidence for occupational exposure in all investigated cases. However, further study is needed because the semiconductor industry is a newly developing one. PMID:22953195

Decreased survival of glioma patients with astrocytoma grade IV (glioblastoma multiforme) associated with long-term use of mobile and cordless phones.

PubMed

Carlberg, Michael; Hardell, Lennart

2014-10-16

On 31 May 2011 the WHO International Agency for Research on Cancer (IARC) categorised radiofrequency electromagnetic fields (RF-EMFs) from mobile phones, and from other devices that emit similar non-ionising electromagnetic fields, as a Group 2B, i.e., a "possible", human carcinogen. A causal association would be strengthened if it could be shown that the use of wireless phones has an impact on the survival of glioma patients. We analysed survival of 1678 glioma patients in our 1997-2003 and 2007-2009 case-control studies. Use of wireless phones in the >20 years latency group (time since first use) yielded an increased hazard ratio (HR) = 1.7, 95% confidence interval (CI) = 1.2-2.3 for glioma. For astrocytoma grade IV (glioblastoma multiforme; n = 926) mobile phone use yielded HR = 2.0, 95% CI = 1.4-2.9 and cordless phone use HR = 3.4, 95% CI = 1.04-11 in the same latency category. The hazard ratio for astrocytoma grade IV increased statistically significant per year of latency for wireless phones, HR = 1.020, 95% CI = 1.007-1.033, but not per 100 h cumulative use, HR = 1.002, 95% CI = 0.999-1.005. HR was not statistically significant increased for other types of glioma. Due to the relationship with survival the classification of IARC is strengthened and RF-EMF should be regarded as human carcinogen requiring urgent revision of current exposure guidelines.

Change of water sources reduces health risks from heavy metals via ingestion of water, soil, and rice in a riverine area, South China.

PubMed

Zhang, Li'e; Mo, Zhaoyu; Qin, Jian; Li, Qin; Wei, Yanhong; Ma, Shuyan; Xiong, Yuxia; Liang, Guiqiang; Qing, Li; Chen, Zhiming; Yang, Xiaobo; Zhang, Zhiyong; Zou, Yunfeng

2015-10-15

This study evaluates the effect of water source change on heavy metal concentrations in water, paddy soil, and rice, as well as the health risks to residents of three riverine communities in South China. The results show that after substituting the sources of drinking water, heavy metal levels (except for Pb at Tangjun) in drinking water were below WHO guideline values and the potential risk from drinking water may be negligible. The As (46.2-66.8%), Pb (65.7-82.6%), Cd (50.8-55.0%), and Hg (28.3-32.6%) concentrations in paddy soils in Sanhe and Lasha significantly (p<0.05) decreased with a change of irrigation water sources compared to Tangjun, without change of irrigation water source. Similarly, the Cd (39.1-81.3%) and Hg (60.0-75.0%) concentrations in rice grown at Sanhe and Lasha significantly (p<0.05) decreased compared to those at Tangjun. Consequently, replacing irrigation water source significantly (p<0.05) reduced the hazard quotient (HQ) and cancer risk for the corresponding single metal via soil ingestion and rice consumption. Despite that total non-carcinogenic and carcinogenic risks at Sanhe and Lasha were significantly decreased, they still exceeded the maximum acceptable limits recommended by US EPA, indicating that residents of these two communities remain at high risks of both non-cancer and cancer effects. Copyright © 2015. Published by Elsevier B.V.

USING PROTEOMICS TO MONITOR PROTEIN EXPRESSION IN HUMAN CELLS EXPOSED TO CARCINOGENS

EPA Science Inventory

People are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic properties in experimental systems. It has been estimated that exposure to environmental chemical carcinogens in the environment may contribute significantly to t...

[Risk assessment of carcinogenic and non-carcinogenic effects in the use of food].

PubMed

Frolova, O A; Karpova, M V

2012-01-01

Application of methodology for assessing the risk of diseases associated with consumption of contaminated foods, is aimed at predicting possible changes in the future and helps to create a framework for the prevention of negative effects on public health. The purpose of the study is assessment of health risks formed under the influence of chemical contaminants that pollute the food. Exponential average daily dose of receipt of chemicals in the body, non-carcinogenic and carcinogenic risks were calculated.

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review.

PubMed

Chappell, Grace; Pogribny, Igor P; Guyton, Kathryn Z; Rusyn, Ivan

2016-01-01

Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. Copyright © 2016 Elsevier B.V. All rights reserved.

Consumption of organic meat does not diminish the carcinogenic potential associated with the intake of persistent organic pollutants (POPs).

PubMed

Hernández, Ángel Rodríguez; Boada, Luis D; Mendoza, Zenaida; Ruiz-Suárez, Norberto; Valerón, Pilar F; Camacho, María; Zumbado, Manuel; Almeida-González, Maira; Henríquez-Hernández, Luis A; Luzardo, Octavio P

2017-02-01

Numerous studies have shown an epidemiological link between meat consumption and the incidence of cancer, and it has been suggested that this relationship may be motivated by the presence of carcinogenic contaminants on it. Among the most frequently detected contaminants in meat are several types of persistent organic pollutants (POPs), and it is well known that many of them are carcinogenic. On the other hand, an increasing number of consumers choose to feed on what are perceived as healthier foods. Thus, the number of consumers of organic food is growing. However, environmental contamination by POPs is ubiquitous, and it is therefore unlikely that the practices of organic food production are able to prevent this contamination. To test this hypothesis, we acquired 76 samples of meat (beef, chicken, and lamb) of two modes of production (organic and conventional) and quantified their levels of 33 carcinogenic POPs. On this basis, we determined the human meat-related daily dietary exposure to these carcinogens using as a model a population with a high consumption of meat, such as the Spanish population. The maximum allowable meat consumption for this population and the carcinogenic risk quotients associated with the current pattern of consumption were calculated. As expected, no sample was completely free of carcinogenic contaminants, and the differences between organically and conventionally produced meats were minimal. According to these results, the current pattern of meat consumption exceeded the maximum limits, which are set according to the levels of contaminations, and this is associated with a relevant carcinogenic risk. Strikingly, the consumption of organically produced meat does not diminish this carcinogenic risk, but on the contrary, it seems to be even higher, especially that associated with lamb consumption.

A review of biosensing techniques for detection of trace carcinogen contamination in food products.

PubMed

Li, Zhanming; Yu, Yue; Li, Zhiliang; Wu, Tao

2015-04-01

Carcinogen contaminations in the food chain, for example heavy metal ions, pesticides, acrylamide, and mycotoxins, have caused serious health problems. A major objective of food-safety research is the identification and prevention of exposure to these carcinogens, because of their impossible-to-reverse tumorigenic effects. However, carcinogen detection is difficult because of their trace-level presence in food. Thus, reliable and accurate separation and determination methods are essential to protect food safety and human health. This paper summarizes the state of the art in separation and determination methods for analyzing carcinogen contamination, especially the advances in biosensing methods. Furthermore, the application of promising technology including nanomaterials, imprinted polymers, and microdevices is detailed. Challenges and perspectives are also discussed.

Decrease of 5-hydroxymethylcytosine in rat liver with subchronic exposure to genotoxic carcinogens riddelliine and aristolochic acid.

PubMed

Lian, Christine Guo; Xu, Shuyun; Guo, Weimin; Yan, Jian; Frank, Maximilian Y M; Liu, Robert; Liu, Cynthia; Chen, Ying; Murphy, George F; Chen, Tao

2015-11-01

The level of 5-hydroxymethylcytosine (5-hmC) converted by ten-eleven translocation (TET) family is decreased in cancers. However, whether 5-hmC level is perturbed in early stages of carcinogenesis caused by genotoxic carcinogens is not defined. 5-hmC levels and TET2 expression were measured in liver of rats treated with genotoxic carcinogens, riddelliine, or aristolochic acid. Levels of 5-hmC and TET2 expression decreased in the liver of the carcinogens-treated rats. Loss of 5-hmC correlates well with documented induction of genetic mutations by the carcinogens, suggesting that TET2-mediated 5-hydroxymethylation plays an epigenetic role in early state of carcinogenesis. © 2014 Wiley Periodicals, Inc.

Decrease of 5-Hydroxymethylcytosine in Rat Liver with Subchronic Exposure to Genotoxic Carcinogens Riddelliine and Aristolochic Acid

PubMed Central

Lian, Christine Guo; Xu, Shuyun; Guo, Weimin; Yan, Jian; Frank, Maximilian Y M; Liu, Robert; Liu, Cynthia; Chen, Ying; Murphy, George F.; Chen, Tao

2018-01-01

The level of 5-hydroxymethylcytosine (5-hmC) converted by ten-eleven translocation (TET) family is decreased in cancers. However, whether 5-hmC level is perturbed in early stages of carcinogenesis caused by genotoxic carcinogens is not defined. 5-hmC levels and TET2 expression were measured in liver of rats treated with genotoxic carcinogens, riddelliine, or aristolochic acid. Levels of 5-hmC and TET2 expression decreased in the liver of the carcinogens-treated rats. Loss of 5-hmC correlates well with documented induction of genetic mutations by the carcinogens, suggesting that TET2-mediated 5-hydroxymethylation plays an epigenetic role in early state of carcinogenesis. PMID:25154389

INTEGRATION OF PATHOLOGY AND TOXICOLOGY IN RISK ASSESSMENT

EPA Science Inventory

In order to develop a scientifically defensible assessment of the risk for the development of cancer after long-term exposure to xenobiotics, regulatory agencies have adopted a uniform approach which includes the characterization of a carcinogenic mode of action and its biologica...

Estimation of Carcinogenicity using Hierarchical Clustering and Nearest Neighbor Methodologies

EPA Science Inventory

Previously a hierarchical clustering (HC) approach and a nearest neighbor (NN) approach were developed to model acute aquatic toxicity end points. These approaches were developed to correlate the toxicity for large, noncongeneric data sets. In this study these approaches applie...

FACTORS INFLUENCING AGE AND STRAIN-RELATED SUSCEPTIBILITY TO 3-METHYLCHOLANTHRENE CARCINOGENICITY

EPA Science Inventory

Fetal mice are more sensitive to chemical carcinogens than are adults. Further, some strains of mice are more susceptible to chemical carcinogens than others. We have been conducting studies to understand the interactions between age and genetic background underlying these suscep...

TOPICAL REVIEW: MUTAGENICITY AND CARCINOGENICITY OF AIR

EPA Science Inventory

Although both outdoor and indoor airs provide exposure to mutagens and carcinogens, this review shows that the level of hazard is highly variable. Outdoor air was first shown to be carcinogenic in 1942 and mutagenic in 1975; and studies examining the genotoxicity of indoor air so...

29 CFR 1990.131 - Priority lists for regulating potential occupational carcinogens.

Code of Federal Regulations, 2010 CFR

2010-07-01

... POTENTIAL OCCUPATIONAL CARCINOGENS Priority Setting § 1990.131 Priority lists for regulating potential occupational carcinogens. The Secretary shall establish two priority lists for regulating potential... 29 Labor 9 2010-07-01 2010-07-01 false Priority lists for regulating potential occupational...

Selection of an in vitro carcinogenicity test for derivatives of the carcinogen hexamethylphosphoramide.

PubMed Central

Ashby, J.; Styles, J. A.; Anderson, D.

1977-01-01

The demonstration that hexamethylphosphoramide (HMPA) possesses potent carcinogenic properties has raised doubts about the safety of exposure to other phosphoric amides. In order to define a suitable short-term test with which to evaluate such analogues, the response of the Salmonella typhimurium mutation assay of Ames and cell transformation assay of Styles to HMPA and 3 selected analogues has been studied. These analogues were the related leukaemogen phosphoramide, the putative non-carcinogen, phosphoric trianilide and N.N'N''-trimethylphosphorothioic triamide, a compound of unknown and hitherto unpredictable properties. While both tests found the trianilide negative, the Ames test failed to detect phosphoramide as positive and gave an erratic and predominantly negative response to HMPA. In contrast, the transformation assay found both phosphoramide and HMPA positive. This test response profile indicates that the transformation assay is the preferred test with which to evaluate analogues of HMPA for potential carcinogenicity. Some structural requirements for potential carcinogenicity within this class of compounds are tentatively deduced. PMID:337998

The Syrian hamster embryo cells transformation assay identifies efficiently nongenotoxic carcinogens, and can contribute to alternative, integrated testing strategies.

PubMed

Benigni, Romualdo; Bossa, Cecilia; Tcheremenskaia, Olga; Battistelli, Chiara Laura; Giuliani, Alessandro

2015-02-01

The long-term carcinogenesis bioassays have played a central role in protecting human health, but for ethical and practical reasons their use is dramatically diminishing and the genotoxicity short-term tests have taken the pivotal role in the pre-screening of chemical carcinogenicity. However, this strategy cannot detect nongenotoxic carcinogens. Since up to 25% of IARC human carcinogens are recognized to have nongenotoxic mechanisms of action, the risk they pose to human health cannot be disregarded, and it is urgent to fill the gap in the tools for alternative testing. In this paper, we analyze from different perspectives the ability of Cell Transformation Assays to identify nongenotoxic carcinogens, and we conclude that the Syrian hamster embryo cells test is able to identify nongenotoxic carcinogens with 80-90% efficiency, and thus, can play an important role in integrated, alternative testing strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

Sister chromatid exchanges induced by inhaled anesthetics

DOE Office of Scientific and Technical Information (OSTI.GOV)

White,A.E.; Takehisa, S.; Eger II, E.I.

1970-05-01

There is sufficient evidence that anesthetics may cause cancer to justify a test of their carcinogenic potential. Baden et al., using the Ames test, a rapid and inexpensive genetic indicator of carcinogenicity, have shown that among currently used anesthetics fluorxene alone caused bacterial mutations. The authors used the sister chromatid exchange (SCE) technique, another rapid assay of mutagenic-carcinogenic potential. The frequency of sister chromatid exchanges in Chinese hamster ovary cells increases when the cell cultures are exposed to mutagen-carcinogens, particulary in the presence of a metabolic activating system. With this test system a one-hour exposure to 1 MAC nitrous oxide,more » diethyl ether, trichloroethylene, halothane, enflurane, isoflurane, methoxyflurane, or chloroform did not increase SCE values. Divinyl ether, fluroxene and ethyl vinyl ether increased SCE values in the same circumstances. Results of this study of mammalian cells suggest that no currently used anesthetic is a mutagen-carcinogen. The results also suggest that anesthetics containing a vinyl moiety may be mutagen-carcinogens.« less

Cancer in the Garden of Eden

DOE Office of Scientific and Technical Information (OSTI.GOV)

Efron, E.

Despite abundant scientific evidence of natural carcinogens, governmental agencies fail to report on most of them, and warn only about industrial carcinogens. The apocalptic view that cancer is a modern moral and political disease caused by human greed and arrogance toward the environment is in contrast to a large body of literature indicating that nature is teeming with carcinogens as well as with substances, known as mutagens, that damage genetic material. Lab tests indicate that not only food items, but classic food preparation methods are carcinogenic or mutagenic. Man himself is made up of naturally carcinogenic components. If one acceptsmore » the no-threshold theory when assessing cancer risk, these findings would seem to be catastrophic. While industrial carcinogens are susceptible to political action, we cannot escape those in nature. A review of the literature, the debate over natural mutagens, and public fears and reactions concludes that literate Americans will reject the big cancer lie in cancer risk assessment.« less

Preventable Exposures Associated With Human Cancers

PubMed Central

Baan, Robert; Straif, Kurt; Grosse, Yann; Lauby-Secretan, Béatrice; El Ghissassi, Fatiha; Bouvard, Véronique; Benbrahim-Tallaa, Lamia; Guha, Neela; Freeman, Crystal; Galichet, Laurent; Wild, Christopher P.

2011-01-01

Information on the causes of cancer at specific sites is important to cancer control planners, cancer researchers, cancer patients, and the general public. The International Agency for Research on Cancer (IARC) Monograph series, which has classified human carcinogens for more than 40 years, recently completed a review to provide up-to-date information on the cancer sites associated with more than 100 carcinogenic agents. Based on IARC’s review, we listed the cancer sites associated with each agent and then rearranged this information to list the known and suspected causes of cancer at each site. We also summarized the rationale for classifications that were based on mechanistic data. This information, based on the forthcoming IARC Monographs Volume 100, offers insights into the current state-of-the-science of carcinogen identification. Use of mechanistic data to identify carcinogens is increasing, and epidemiological research is identifying additional carcinogens and cancer sites or confirming carcinogenic potential under conditions of lower exposure. Nevertheless, some common human cancers still have few (or no) identified causal agents. PMID:22158127

To the application of the emission Mössbauer and positron annihilation spectroscopies for detection of carcinogens

NASA Astrophysics Data System (ADS)

Bokov, A. V.; Byakov, V. M.; Kulikov, L. A.; Perfiliev, Yu. D.; Stepanov, S. V.

2017-11-01

Being the main cause of cancer, almost all chemical carcinogens are strong electrophiles, that is, they have a high affinity for the electron. We have shown that positron annihilation lifetime spectroscopy (PALS) is able to detect chemical carcinogens by their inhibition of positronium (Ps) formation in liquid media. Electrophilic carcinogens intercept thermalized track electrons, which are precursors of Ps, and as a result, when they are present Ps atom does not practically form. Available biophysical data seemingly indicate that frozen solutions model better an intracellular medium than the liquid ones. So it is reasonable to use emission Mössbauer spectroscopy (EMS) to detect chemical carcinogens, measuring the yield of 57Fe2+ions formed in reactions of Auger electrons and other secondary electrons they produced with 57Fe3+. These reactions are similar to the Ps formation process in the terminal part the positron track: e++ e- =>Ps. So EMS and PALS are complementary methods for detection of carcinogenic compounds.

Hazard assessment of nitrosamine and nitramine by-products of amine-based CCS: alternative approaches.

PubMed

Buist, H E; Devito, S; Goldbohm, R A; Stierum, R H; Venhorst, J; Kroese, E D

2015-04-01

Carbon capture and storage (CCS) technologies are considered vital and economic elements for achieving global CO2 reduction targets, and is currently introduced worldwide (for more information on CCS, consult for example the websites of the International Energy Agency (http://www.iea.org/topics/ccs/) and the Global CCS Institute (http://www.globalccsinstitute.com/)). One prominent CCS technology, the amine-based post-combustion process, may generate nitrosamines and their related nitramines as by-products, the former well known for their potential mutagenic and carcinogenic properties. In order to efficiently assess the carcinogenic potency of any of these by-products this paper reviews and discusses novel prediction approaches consuming less time, money and animals than the traditionally applied 2-year rodent assay. For this, available animal carcinogenicity studies with N-nitroso compounds and nitramines have been used to derive carcinogenic potency values, that were subsequently used to assess the predictive performance of alternative prediction approaches for these chemicals. Promising cancer prediction models are the QSARs developed by the Helguera group, in vitro transformation assays, and the in vivo initiation-promotion, and transgenic animal assays. All these models, however, have not been adequately explored for this purpose, as the number of N-nitroso compounds investigated is yet too limited, and therefore further testing with relevant N-nitroso compounds is needed. Copyright © 2015. Published by Elsevier Inc.

Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.

PubMed

Bradley, Ann E; Shoenfelt, Joanna L; Durda, Judi L

2016-04-01

Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines.

PubMed

Melnikova, Vladislava O; Bolshakov, Svetlana V; Walker, Christopher; Ananthaswamy, Honnavara N

2004-03-25

We have conducted an analysis of genetic alterations in spontaneous murine melanoma cell line B16F0 and its two metastatic clones, B16F1 and B16F10 and the carcinogen-induced murine melanoma cell lines CM519, CM3205, and K1735. We found that unlike human melanomas, the murine melanoma cell lines did not have activating mutations in the Braf oncogene at exon 11 or 15. However, there were distinct patterns of alterations in the ras, Ink4a/Arf, and p53 genes in the two melanoma groups. In the spontaneous B16 melanoma cell lines, expression of p16Ink4a and p19Arf tumor suppressor proteins was lost as a consequence of a large deletion spanning Ink4a/Arf exons 1alpha, 1beta, and 2. In contrast, the carcinogen-induced melanoma cell lines expressed p16Ink4a but had inactivating mutations in either p19Arf (K1735) or p53 (CM519 and CM3205). Inactivation of p19Arf or p53 in carcinogen-induced melanomas was accompanied by constitutive activation of mitogen-activated protein kinases (MAPKs) and/or mutation-associated activation of N-ras. These results indicate that genetic alterations in p16Ink4a/p19Arf, p53 and ras-MAPK pathways can cooperate in the development of murine melanoma.

Investigating the epigenetic effects of a prototype smoke-derived carcinogen in human cells.

PubMed

Tommasi, Stella; Kim, Sang-in; Zhong, Xueyan; Wu, Xiwei; Pfeifer, Gerd P; Besaratinia, Ahmad

2010-05-12

Global loss of DNA methylation and locus/gene-specific gain of DNA methylation are two distinct hallmarks of carcinogenesis. Aberrant DNA methylation is implicated in smoking-related lung cancer. In this study, we have comprehensively investigated the modulation of DNA methylation consequent to chronic exposure to a prototype smoke-derived carcinogen, benzo[a]pyrene diol epoxide (B[a]PDE), in genomic regions of significance in lung cancer, in normal human cells. We have used a pulldown assay for enrichment of the CpG methylated fraction of cellular DNA combined with microarray platforms, followed by extensive validation through conventional bisulfite-based analysis. Here, we demonstrate strikingly similar patterns of DNA methylation in non-transformed B[a]PDE-treated cells vs control using high-throughput microarray-based DNA methylation profiling confirmed by conventional bisulfite-based DNA methylation analysis. The absence of aberrant DNA methylation in our model system within a timeframe that precedes cellular transformation suggests that following carcinogen exposure, other as yet unknown factors (secondary to carcinogen treatment) may help initiate global loss of DNA methylation and region-specific gain of DNA methylation, which can, in turn, contribute to lung cancer development. Unveiling the initiating events that cause aberrant DNA methylation in lung cancer has tremendous public health relevance, as it can help define future strategies for early detection and prevention of this highly lethal disease.

Investigating the Epigenetic Effects of a Prototype Smoke-Derived Carcinogen in Human Cells

PubMed Central

Tommasi, Stella; Kim, Sang-in; Zhong, Xueyan; Wu, Xiwei; Pfeifer, Gerd P.; Besaratinia, Ahmad

2010-01-01

Global loss of DNA methylation and locus/gene-specific gain of DNA methylation are two distinct hallmarks of carcinogenesis. Aberrant DNA methylation is implicated in smoking-related lung cancer. In this study, we have comprehensively investigated the modulation of DNA methylation consequent to chronic exposure to a prototype smoke-derived carcinogen, benzo[a]pyrene diol epoxide (B[a]PDE), in genomic regions of significance in lung cancer, in normal human cells. We have used a pulldown assay for enrichment of the CpG methylated fraction of cellular DNA combined with microarray platforms, followed by extensive validation through conventional bisulfite-based analysis. Here, we demonstrate strikingly similar patterns of DNA methylation in non-transformed B[a]PDE-treated cells vs control using high-throughput microarray-based DNA methylation profiling confirmed by conventional bisulfite-based DNA methylation analysis. The absence of aberrant DNA methylation in our model system within a timeframe that precedes cellular transformation suggests that following carcinogen exposure, other as yet unknown factors (secondary to carcinogen treatment) may help initiate global loss of DNA methylation and region-specific gain of DNA methylation, which can, in turn, contribute to lung cancer development. Unveiling the initiating events that cause aberrant DNA methylation in lung cancer has tremendous public health relevance, as it can help define future strategies for early detection and prevention of this highly lethal disease. PMID:20485678

Potential late health effects of depleted uranium and tungsten used in armor-piercing munitions: comparison of neoplastic transformation and genotoxicity with the known carcinogen nickel.

PubMed

Miller, Alexandra C; Xu, Jiaquan; Stewart, Michael; Prasanna, Pataje G S; Page, Natalie

2002-02-01

Limited data exist to permit an accurate assessment of risks for carcinogenesis and mutagenesis from embedded fragments or inhaled particulates of depleted uranium (DU). Ongoing studies have been designed to provide information about the carcinogenic potential of DU using in vitro and in vivo assessments of morphological transformation as well as cytogenetic, mutagenic, and oncogenic effects. For comparison, we also examined tungsten alloys used in military projectiles and the known carcinogen nickel. Quantitative and qualitative in vitro transformation studies were done to assess the carcinogenic potential of radiation and chemical hazards. Using a human osteosarcoma cell model, we demonstrated that soluble and insoluble DU compounds can transform cells to the tumorigenic phenotype, as characterized by morphological, biochemical, and oncogenic changes consistent with tumor cell behavior. Tungsten alloys and nickel were also shown to be neoplastic transforming agents, although at a frequency less than that of DU. Sister chromatid exchange, micronuclei, and alkaline filter elution assays showed DU and tungsten alloys were genotoxic. Exposure to a nontoxic, nontransforming dose of DU induced a small but statistically significant increase in the number of dicentrics formed in cells. These results suggest that long-term exposure to DU or tungsten alloys could be critical to the development of neoplastic disease in humans and that additional studies are needed.

The effect of environmental chemicals on the tumor microenvironment

PubMed Central

Casey, Stephanie C.; Vaccari, Monica; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Barcellos-Hoff, Mary Helen; Brown, Dustin G.; Chapellier, Marion; Christopher, Joseph; Curran, Colleen S.; Forte, Stefano; Hamid, Roslida A.; Heneberg, Petr; Koch, Daniel C.; Krishnakumar, P.K.; Laconi, Ezio; Maguer-Satta, Veronique; Marongiu, Fabio; Memeo, Lorenzo; Mondello, Chiara; Raju, Jayadev; Roman, Jesse; Roy, Rabindra; Ryan, Elizabeth P.; Ryeom, Sandra; Salem, Hosni K.; Scovassi, A.Ivana; Singh, Neetu; Soucek, Laura; Vermeulen, Louis; Whitfield, Jonathan R.; Woodrick, Jordan; Colacci, Anna Maria; Bisson, William H.; Felsher, Dean W.

2015-01-01

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis. PMID:26106136

Role of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium in carcinogenesis.

PubMed Central

Kazantzis, G

1981-01-01

The possible carcinogenicity of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium is reviewed, taking into account epidemiological data, the results of animal experimental studies, data on mutagenic effects and on other in vitro test systems. Of the great variety of occupations where exposure to one of these metals may occur, only haematite mining has been clearly shown to involve an increased human cancer risk. While the possibility that haematite might in some way act as a carcinogen has to be taken into consideration it is more likely that other carcinogens are responsible. Certain platinum coordination complexes are used in cancer chemotherapy, are mutagenic, and likely to be carcinogenic. Cobalt, its oxide and sulfide, certain lead salts, one organomanganese, and one organotitanium compound have been shown to have a limited carcinogenic effect in experimental animal studies, and except for titanium appear to be mutagenic. Certain mercury compounds are mutagenic but none have been shown to be carcinogenic. The presently available data are inadequate to assess the possible carcinogenicity of selenium compounds, but a few observations suggest that selenium may suppress the effect of other carcinogens administered to experimental animals and may even be associated with lower cancer mortality rates in man. Epidemiological observations are essential for the assessment of a human cancer risk, but the difficulty in collecting past exposure data in occupational groups and the complexity of multiple occupational exposures with changes over time, limits the usefulness of retrospective epidemiological studies. PMID:7023929

Comparisons of false negative rates from a trend test alone and from a trend test jointly with a control-high groups pairwise test in the determination of the carcinogenicity of new drugs.

PubMed

Lin, Karl K; Rahman, Mohammad A

2018-05-21

Interest has been expressed in using a joint test procedure that requires that the results of both a trend test and a pairwise comparison test between the control and the high groups be statistically significant simultaneously at the levels of significance recommended in the FDA 2001 draft guidance for industry document for the separate tests in order for the drug effect on the development of an individual tumor type to be considered as statistically significant. Results of our simulation studies show that there is a serious consequence of large inflations of the false negative rate through large decreases of false positive rate in the use of the above joint test procedure in the final interpretation of the carcinogenicity potential of a new drug if the levels of significance recommended for separate tests are used. The inflation can be as high as 204.5% of the false negative rate when the trend test alone is required to test if the effect is statistically significant. To correct the problem, new sets of levels of significance have also been developed for those who want to use the joint test in reviews of carcinogenicity studies.

BENZENE OXIDE PROTEIN ADDUCTS AS BIOMARKERS OF BENZENE EXPOSURE

EPA Science Inventory

Benzene is known to be hematotoxic and carcinogenic in animals and humans. While metabolism is required for toxicity, the identity of the ultimate carcinogen(s) remains unknown. Benzene oxide (BO) is the first and most abundant of the metabolites, but very little is known about...

29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 7 2010-07-01 2010-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1915.1003 Section 1915.1003 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Hazardous Substances § 1915.1003 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable...

29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 7 2014-07-01 2014-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1915.1003 Section 1915.1003 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Hazardous Substances § 1915.1003 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable...

29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 8 2012-07-01 2012-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1926.1103 Section 1926.1103 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... § 1926.1103 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable to construction...

29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 8 2011-07-01 2011-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1926.1103 Section 1926.1103 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... § 1926.1103 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable to construction...

29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 8 2013-07-01 2013-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1926.1103 Section 1926.1103 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... § 1926.1103 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable to construction...

29 CFR 1926.1103 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 8 2014-07-01 2014-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1926.1103 Section 1926.1103 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... § 1926.1103 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable to construction...

29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 7 2013-07-01 2013-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1915.1003 Section 1915.1003 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Hazardous Substances § 1915.1003 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable...

29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 7 2011-07-01 2011-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1915.1003 Section 1915.1003 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Hazardous Substances § 1915.1003 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable...

29 CFR 1915.1003 - 13 carcinogens (4-Nitrobiphenyl, etc.).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 7 2012-07-01 2012-07-01 false 13 carcinogens (4-Nitrobiphenyl, etc.). 1915.1003 Section 1915.1003 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Hazardous Substances § 1915.1003 13 carcinogens (4-Nitrobiphenyl, etc.). Note: The requirements applicable...

Method for converting asbestos to non-carcinogenic compounds

DOEpatents

Selby, Thomas W.

1996-01-01

Hazardous and carcinogenic asbestos waste characterized by a crystalline fibrous structure is transformed into non-carcinogenic, relatively nonhazardous, and non-crystalline solid compounds and gaseous compounds which have commercial utilization. The asbestos waste is so transformed by the complete fluorination of the crystalline fibrous silicate mineral defining the asbestos.

Method for converting asbestos to non-carcinogenic compounds

DOEpatents

Selby, T.W.

1996-08-06

Hazardous and carcinogenic asbestos waste characterized by a crystalline fibrous structure is transformed into non-carcinogenic, relatively nonhazardous, and non-crystalline solid compounds and gaseous compounds which have commercial utilization. The asbestos waste is so transformed by the complete fluorination of the crystalline fibrous silicate mineral defining the asbestos. 7 figs.

USE OF GENE PROFILING TO DIFFERENTIATE A CARCINOGENIC FROM A NONCARCINOGENIC ALDEHYDE IN THE RAT NOSE

EPA Science Inventory

Abstract
Formaldehyde (FA) is cytotoxic and is carcinogenic to the rat nasal respiratory epithelium producing tumors after twelve months of exposure. In contrast, glutaraldehyde (GA) is also cytotoxic but not carcinogenic to nasal epithelium after 2 yrs of exposure. Other...

Genotoxicity of Swimming Pool Water and Carcinogenicity of Drinking Water

EPA Science Inventory

Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroaceticacid and chlorite) are not carcinogenic-in either of2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxicity...

Genotoxicity of Swimming Pool Water and Carcinogenicity of Drinking Water**

EPA Science Inventory

Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroaceticacid and chlorite) are not carcinogenic-in either of2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxicity...

Chemical carcinogens and inhibitors of carcinogenesis in the human diet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carr, B.I.

1985-01-01

The induction of cancer by chemicals as presently understood involves a series of steps, some of which require the passage of time. Many substances that are potent carcinogens in experimental animals are known to exist in nature and occur as part of the human diet. In addition, many of the substances that are known to inhibit experimental carcinogenesis also exist in the human diet. Thus, in addition to industrially produced carcinogens, humans can be presumed to have evolved in an environment that contains both carcinogens and anti-carcinogens. There is also a great deal of experimental and human epidemiologic data onmore » the influence of lipids, proteins and carbohydrates on cancer incidence rates; however, much of those data are confusing and conflicting.« less

Mutagens and carcinogens - Occurrence and role during chemical and biological evolution

NASA Technical Reports Server (NTRS)

Giner-Sorolla, A.; Oro, J.

1981-01-01

The roles of mutagenic and carcinogenic substances in early biologic evolution is examined, along with terrestrial and extraterrestrial sources of mutagens and carcinogens. UV solar radiation is noted to have served to stimulate prebiotic life while also causing harmful effects in plants and animals. Aromatic compounds have been found in meteorites, and comprise leukemogens, polycyclic hydrocarbons, and nitrasamine precursors. Other mutagenic sources are volcanoes, and the beginning of evolution with mutagenic substances is complicated by the appearance of malignancies due to the presence of carcinogens. The atmosphere of the Precambrian period contained both mutagens and early carcinogens and, combined with volcanic activity discharges, formed an atmospheric chemical background analogous to the background ionizing radiation. Carcinogenesis is concluded to be intrinsic to nature, having initiated evolution and, eventually, cancer cells.

Application of in vitro cell transformation assays in regulatory toxicology for pharmaceuticals, chemicals, food products and cosmetics.

PubMed

Vanparys, Philippe; Corvi, Raffaella; Aardema, Marilyn J; Gribaldo, Laura; Hayashi, Makoto; Hoffmann, Sebastian; Schechtman, Leonard

2012-04-11

Two year rodent bioassays play a key role in the assessment of carcinogenic potential of chemicals to humans. The seventh amendment to the European Cosmetics Directive will ban in 2013 the marketing of cosmetic and personal care products that contain ingredients that have been tested in animal models. Thus 2-year rodent bioassays will not be available for cosmetics/personal care products. Furthermore, for large testing programs like REACH, in vivo carcinogenicity testing is impractical. Alternative ways to carcinogenicity assessment are urgently required. In terms of standardization and validation, the most advanced in vitro tests for carcinogenicity are the cell transformation assays (CTAs). Although CTAs do not mimic the whole carcinogenesis process in vivo, they represent a valuable support in identifying transforming potential of chemicals. CTAs have been shown to detect genotoxic as well as non-genotoxic carcinogens and are helpful in the determination of thresholds for genotoxic and non-genotoxic carcinogens. The extensive review on CTAs by the OECD (OECD (2007) Environmental Health and Safety Publications, Series on Testing and Assessment, No. 31) and the proven within- and between-laboratories reproducibility of the SHE CTAs justifies broader use of these methods to assess carcinogenic potential of chemicals. Copyright © 2012 Elsevier B.V. All rights reserved.

Repression by sustained-release. beta. -glucuronidase inhibitors of chemical carcinogen-mediated induction of a marker oncofetal protein in rodents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walaszek, Z.; Hanausek-Walaszek, M.; Webb, T.E.

1988-01-01

The degree of induction of an oncofetal protein marker in rodents by selected chemical carcinogens has been correlated with changes in carcinogenicity induced by dietary D-glucaro-1,4-lactone (GL) based anticarcinogens. These potent anticarcinogens may act to increase the clearance of carcinogens as glucuronides through the inhibition of ..beta..-glucuronidase. The sustained-release forms are particularly effective, 1.5 mmol/kg of GL maintaining serum ..beta..-glucuronidase activity at or below 50% for only 1 h, while an equivalent amount of calcium glucarate (CGT) maintained this level of inhibition for over 5 h. CGT or other sustained-release inhibitors, when fed to rodents during administration of carcinogens thatmore » undergo glucuronidation, caused a marked reduction in the induction of the marker protein. For those systems where other markers of carcinogenesis were also assessed, it was determined the inhibition of marker-protein induction was quantitatively similar to both the inhibition of binding of the carcinogen to DNA and the subsequent induction of tumors in target organs. The following carcinogens were administered intraperitoneally: benzo(a)pryene; 7,12-demethylbenz(a)anthracene; 3-methylcholanthrene; 2-acetylaminofluorene; 2-naphthylamine; N-nitroso-N,N-dibutylamine; aflatoxin B1; 1-nitropyrene.« less

Is ionizing radiation regulated more stringently than chemical carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Travis, C.C.; Pack, S.R.; Hattemer-Frey, H.A.

1989-04-01

It is widely believed that United States government agencies regulate exposure to ionizing radiation more stringently than exposure to chemical carcinogens. It is difficult to verify this perception, however, because chemical carcinogens and ionizing radiation are regulated using vastly different strategies. Chemical carcinogens are generally regulated individually. Regulators consider the risk of exposure to one chemical rather than the cumulative radiation exposure from all sources. Moreover, standards for chemical carcinogens are generally set in terms of quantities released or resultant environmental concentrations, while standards for ionizing radiation are set in terms of dose to the human body. Since chemicals andmore » ionizing radiation cannot be compared on the basis of equal dose to the exposed individual, standards regulating chemicals and ionizing radiation cannot be compared directly. It is feasible, however, to compare the two sets of standards on the basis of equal risk to the exposed individual, assuming that standards for chemicals and ionizing radiation are equivalent if estimated risk levels are equitable. This paper compares risk levels associated with current standards for ionizing radiation and chemical carcinogens. The authors do not attempt to determine whether either type of risk is regulated too stringently or not stringently enough but endeavor only to ascertain if ionizing radiation is actually regulated more strictly than chemical carcinogens.« less

Concentrations of environmental organic contaminants in meat and meat products and human dietary exposure: A review.

PubMed

Domingo, José L

2017-09-01

Meat and meat products is one of the most relevant food groups in an important number of human diets. Recently, the IARC, based on results of a number of epidemiological studies, classified the consumptions of red meat and processed meat as "probably carcinogenic to humans" and as "carcinogenic to humans", respectively. It was suggested that the substances responsible of the potential carcinogenicity would be mainly generated during meat processing, such as curing and smoking, or when meat is heated at high temperatures. However, the exposure to environmental pollutants through meat consumption was not discussed. The purpose of the present paper was to review recent studies reporting the concentrations of PCDD/Fs, DL-PCBs and PAHs in meat and meat products, as well as the human exposure to these pollutants through the diet. It is concluded that the health risks derived from exposure to carcinogenic environmental contaminants must be considered in the context of each specific diet, which besides meat and meat products, includes other foodstuffs containing also chemical pollutants, some of them with carcinogenic potential. Anyhow, meat and meat products are not the main food group responsible of the dietary exposure to carcinogenic (or probably carcinogenic) environmental organic pollutants. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nonmutagenic carcinogens induce intrachromosomal recombination in dividing yeast cells.

PubMed

Schiestl, R H

1993-12-01

A large number of animal and human carcinogens without apparent genotoxic activity exist (nonmutagenic carcinogens) that are difficult or impossible to detect with the currently used short-term tests. Because of the association of carcinogenesis with genome rearrangement, a system selecting for intrachromosomal recombination (DEL recombination) that results in genome rearrangement has been constructed in the yeast Saccharomyces cerevisiae. Because DEL recombination is under different genetic control than interchromosomal recombination and meiotic recombination, it is probably due to a different mechanism. It has been found that DEL recombination is readily inducible by 10 mutagenic carcinogens and 17 nonmutagenic carcinogens that are not detectable (false negatives) with the Ames assay. In addition, three out of four mutagens that do not cause cancer (false positives in the Ames assay) do not induce DEL recombination. DEL recombination is inducible by UV only in dividing cells but not in cells synchronized in the G1 or G2 phase of the cell cycle. Interchromosomal recombination, on the other hand, is inducible in G1 but not in G2. The nonmutagenic carcinogens induce DEL recombination only in actively growing cells, which may give some indication as to their mechanism. Further characterization of the mechanism involved in induction of DEL recombination may contribute to the understanding of the biological activity of nonmutagenic carcinogens.

Chemical sensing of Benzo[a]pyrene using Corchorus depressus fluorescent flavonoids.

PubMed

Ahmad, Wajiha; Rana, Nosheen Fatima; Riaz, Sundus; Ahmad, Nasir Mehmood; Hameed, Maryam; Naeem, Ayesha; Tahir, Rabbiya

2018-04-01

Plant phytochemicals, such as flavonoids are in use for the development of optical biosensor. Benzo[a]pyrene (B[a]P), is a pervasive environmental and dietary carcinogen. A fluorescent assay is developed using plant isolated flavonoid for the detection of B[a]P. High content saponins are excluded from the flavonoid-containing methanolic extract of Corchorus depressus by implying reduction of silver ions by saponins resulting in formation of silver nanoparticles. Isolated plant flavonoids are used to develop a spectrofluorometric assay for the detection of B[a]P. Decrease in the flavonoid fluorescence intensity by B[a]P is found to be based on both static and dynamic quenching. Specificity of the assay for B[a]P was tested for other carcinogens belonging to different classes of compounds. Flavonoids-mediated sensing can be implied for the development of new generation of nanoparticle-based biosensors that can be more sensitive and less susceptible to external factors, such as temperature and humidity.

Risk Factors for Cancer | Did You Know?

Cancer.gov

Age, weight, exposure to carcinogens, and genetics can increase the risk of developing cancer. Learn more from this Did You Know? video produced by NCI's Surveillance, Epidemiology, and End Results (SEER) program.

PAH air pollution at a Portuguese urban area: carcinogenic risks and sources identification.

PubMed

Slezakova, K; Pires, J C M; Castro, D; Alvim-Ferraz, M C M; Delerue-Matos, C; Morais, S; Pereira, M C

2013-06-01

This study aimed to characterize air pollution and the associated carcinogenic risks of polycyclic aromatic hydrocarbon (PAHs) at an urban site, to identify possible emission sources of PAHs using several statistical methodologies, and to analyze the influence of other air pollutants and meteorological variables on PAH concentrations.The air quality and meteorological data were collected in Oporto, the second largest city of Portugal. Eighteen PAHs (the 16 PAHs considered by United States Environment Protection Agency (USEPA) as priority pollutants, dibenzo[a,l]pyrene, and benzo[j]fluoranthene) were collected daily for 24 h in air (gas phase and in particles) during 40 consecutive days in November and December 2008 by constant low-flow samplers and using polytetrafluoroethylene (PTFE) membrane filters for particulate (PM10 and PM2.5 bound) PAHs and pre-cleaned polyurethane foam plugs for gaseous compounds. The other monitored air pollutants were SO2, PM10, NO2, CO, and O3; the meteorological variables were temperature, relative humidity, wind speed, total precipitation, and solar radiation. Benzo[a]pyrene reached a mean concentration of 2.02 ng m(-3), surpassing the EU annual limit value. The target carcinogenic risks were equal than the health-based guideline level set by USEPA (10(-6)) at the studied site, with the cancer risks of eight PAHs reaching senior levels of 9.98 × 10(-7) in PM10 and 1.06 × 10(-6) in air. The applied statistical methods, correlation matrix, cluster analysis, and principal component analysis, were in agreement in the grouping of the PAHs. The groups were formed according to their chemical structure (number of rings), phase distribution, and emission sources. PAH diagnostic ratios were also calculated to evaluate the main emission sources. Diesel vehicular emissions were the major source of PAHs at the studied site. Besides that source, emissions from residential heating and oil refinery were identified to contribute to PAH levels at the respective area. Additionally, principal component regression indicated that SO2, NO2, PM10, CO, and solar radiation had positive correlation with PAHs concentrations, while O3, temperature, relative humidity, and wind speed were negatively correlated.

PAHs (Polycyclic Aromatic Hydrocarbons), Nitro-PAHs, Hopanes and Steranes Biomarkers in Sediments of Southern Lake Michigan, USA

PubMed Central

Huang, Lei; Chernyak, Sergei M.; Batterman, Stuart A.

2014-01-01

PAHs in the Great Lakes basin are of concern due to their toxicity and persistence in bottom sediments. Their nitro derivatives, nitro-PAHs (NPAHs), which can have stronger carcinogenic and mutagenic activity than parent PAHs, may follow similar transport routes and also are accumulated in sediments. Limited information exists regarding the current distribution, trends and loadings of these compounds, especially NPAHs, in Lake Michigan sediments. This study characterizes PAHs, NPAHs, and biomarkers steranes and hopanes in surface sediments collected at 24 offshore sites in southern Lake Michigan. The ΣPAH14 (sum of 14 compounds) ranged from 213 to 1291 ng/g dry weight (dw) across the sites, levels that are 2 to 10 times lower than those reported 20 to 30 years earlier. Compared to consensus-based sediment quality guidelines, PAH concentrations suggest very low risk to benthic organisms. The ΣNPAH5 concentration ranged from 2.9 to 18.6 ng/g dw, and included carcinogenic compounds 1-nitropyrene and 6-nitrochrysene. ΣSterane6 and ΣHopane5 concentrations ranged from 6.2 to 36 and 98 to 355 ng/g dw, respectively. Based on these concentrations, Lake Michigan is approximately receiving 11, 0.16, 0.25 and 3.6 metric tons per year (t/yr) of ΣPAH14, ΣNPAH5, ΣSterane6 and ΣHopane5, respectively. Maps of OC-adjusted concentrations display that concentrations decline with increasing off-shore distance. The major sources of PAHs and NPAHs are pyrogenic in nature, based on diagnostic ratios. Using chemical mass balance models, sources were apportioned to emissions from diesel engines (56±18%), coal power plants (27±14%), coal-tar pavement sealants (16±11%), and coke ovens (7±12%). The biomarkers identify a combination of petrogenic and biogenic sources, with the southern end of the lake more impacted by petroleum. This first report of NPAHs levels in sediments of Lake Michigan reveals several carcinogenic compounds at modest concentrations, and a need for further work to assess potential risks to aquatic organisms. PMID:24784742

Development of an exposure measurement database on five lung carcinogens (ExpoSYN) for quantitative retrospective occupational exposure assessment.

PubMed

Peters, Susan; Vermeulen, Roel; Olsson, Ann; Van Gelder, Rainer; Kendzia, Benjamin; Vincent, Raymond; Savary, Barbara; Williams, Nick; Woldbæk, Torill; Lavoué, Jérôme; Cavallo, Domenico; Cattaneo, Andrea; Mirabelli, Dario; Plato, Nils; Dahmann, Dirk; Fevotte, Joelle; Pesch, Beate; Brüning, Thomas; Straif, Kurt; Kromhout, Hans

2012-01-01

SYNERGY is a large pooled analysis of case-control studies on the joint effects of occupational carcinogens and smoking in the development of lung cancer. A quantitative job-exposure matrix (JEM) will be developed to assign exposures to five major lung carcinogens [asbestos, chromium, nickel, polycyclic aromatic hydrocarbons (PAH), and respirable crystalline silica (RCS)]. We assembled an exposure database, called ExpoSYN, to enable such a quantitative exposure assessment. Existing exposure databases were identified and European and Canadian research institutes were approached to identify pertinent exposure measurement data. Results of individual air measurements were entered anonymized according to a standardized protocol. The ExpoSYN database currently includes 356 551 measurements from 19 countries. In total, 140 666 personal and 215 885 stationary data points were available. Measurements were distributed over the five agents as follows: RCS (42%), asbestos (20%), chromium (16%), nickel (15%), and PAH (7%). The measurement data cover the time period from 1951 to present. However, only a small portion of measurements (1.4%) were performed prior to 1975. The major contributing countries for personal measurements were Germany (32%), UK (22%), France (14%), and Norway and Canada (both 11%). ExpoSYN is a unique occupational exposure database with measurements from 18 European countries and Canada covering a time period of >50 years. This database will be used to develop a country-, job-, and time period-specific quantitative JEM. This JEM will enable data-driven quantitative exposure assessment in a multinational pooled analysis of community-based lung cancer case-control studies.

Fetal alcohol exposure and mammary tumorigenesis in offspring: role of the estrogen and insulin-like growth factor systems.

PubMed

Cohick, Wendie S; Crismale-Gann, Catina; Stires, Hillary; Katz, Tiffany A

2015-01-01

Fetal alcohol spectrum disorders affect a significant number of live births each year, indicating that alcohol consumption during pregnancy is an important public health issue. Environmental exposures and lifestyle choices during pregnancy may affect the offspring's risk of disease in adulthood, leading to the idea that a woman's risk of breast cancer may be pre-programmed prior to birth. Exposure of pregnant rats to alcohol increases tumorigenesis in the adult offspring in response to mammary carcinogens. The estrogen and insulin-like growth factor (IGF-I) axes occupy central roles in normal mammary gland development and breast cancer. 17-β estradiol (E2) and IGF-I synergize to regulate formation of terminal end buds and ductal elongation during pubertal development. The intracellular signaling pathways mediated by the estrogen and IGF-I receptors cross-talk at multiple levels through both genomic and non-genomic mechanisms. Several components of the E2 and IGF-I systems are altered in early development in rat offspring exposed to alcohol in utero, therefore, these changes may play a role in the enhanced susceptibility to mammary carcinogens observed in adulthood. Alcohol exposure in utero induces a number of epigenetic alterations in non-mammary tissues in the offspring and other adverse in utero exposures induce epigenetic modifications in the mammary gland. Future studies will determine if fetal alcohol exposure can induce epigenetic modifications in genes that regulate E2/IGF action at key phases of mammary development, ultimately leading to changes in susceptibility to carcinogens.

Detection of genotoxic and non-genotoxic carcinogens in Xpc{sup −/−}p53{sup +/−} mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melis, Joost P.M.; Leiden University Medical Center, Department of Toxicogenetics, Leiden; Speksnijder, Ewoud N.

2013-01-15

An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances. However, over time it has become clear that this assay yields false positive results and also has several economic and ethical drawbacks including the use of large numbers of animals, the long duration, and the high cost. The need for a suitable alternative assay is therefore high. Previously, we have proposed themore » Xpa*p53 mouse model as a very suitable alternative to the two-year bioassay. We now show that the Xpc*p53 mouse model preserves all the beneficial traits of the Xpa*p53 model for sub-chronic carcinogen identification and can identify both genotoxic and non-genotoxic carcinogens. Moreover, Xpc*p53 mice appear to be more responsive than Xpa*p53 mice towards several genotoxic and non-genotoxic carcinogens. Furthermore, Xpc*p53 mice are far less sensitive than Xpa*p53 mice for the toxic activity of DNA damaging agents and as such clearly respond in a similar way as wild type mice do. These advantageous traits of the Xpc*p53 model make it a better alternative for in vivo carcinogen testing than Xpa*p53. This pilot study suggests that Xpc*p53 mice are suited for routine sub-chronic testing of both genotoxic and non-genotoxic carcinogens and as such represent a suitable alternative to possibly replace the murine life time cancer bioassay. Highlights: ► The Xpc*p53 mouse model is able to identify genotoxic and non-genotoxic carcinogens. ► Time, animals and cost can be significantly reduced compared to the 2-year bioassay. ► Xpc*p53 mice are more advantageous for carcinogen identification than Xpa*p53 mice. ► Xpc*p53 mice exhibit a wild type response upon exposure to genotoxicants.« less

Animal models of neoplastic development.

PubMed

Pitot, H C

2001-01-01

The basic animal model for neoplastic development used by regulatory agencies is the two-year chronic bioassay developed more than 30 years ago and based on the presumed mechanism of action of a few potential chemical carcinogens. Since that time, a variety of other model carcinogenic systems have been developed, usually involving shorter duration, single organ endpoints, multistage models, and those in genetically-engineered mice. The chronic bioassay is still the "gold standard" of regulatory agencies despite a number of deficiencies, while in this country the use of shorter term assays based on single organ endpoints has not been popular. The multistage model of carcinogenesis in mouse epidermis actually preceded the development of the chronic two-year bioassay, but it was not until multistage models in other organ systems were developed that the usefulness of such systems became apparent. Recently, several genetically-engineered mouse lines involving mutations in proto-oncogenes and tumour suppressor genes have been proposed as additional model systems for use in regulatory decisions. It is likely that a combination of several of these model systems may be most useful in both practical and basic applications of cancer prevention and therapy.

The carcinogenic effects of aspartame: The urgent need for regulatory re-evaluation.

PubMed

Soffritti, Morando; Padovani, Michela; Tibaldi, Eva; Falcioni, Laura; Manservisi, Fabiana; Belpoggi, Fiorella

2014-04-01

Aspartame (APM) is an artificial sweetener used since the 1980s, now present in >6,000 products, including over 500 pharmaceuticals. Since its discovery in 1965, and its first approval by the US Food and Drugs Administration (FDA) in 1981, the safety of APM, and in particular its carcinogenicity potential, has been controversial. The present commentary reviews the adequacy of the design and conduct of carcinogenicity bioassays on rodents submitted by G.D. Searle, in the 1970s, to the FDA for market approval. We also review how experimental and epidemiological data on the carcinogenic risks of APM, that became available in 2005 motivated the European Commission (EC) to call the European Food and Safety Authority (EFSA) for urgent re-examination of the available scientific documentation (including the Searle studies). The EC has further requested that, if the results of the evaluation should suggest carcinogenicity, major changes must be made to the current APM specific regulations. Taken together, the studies performed by G.D. Searle in the 1970s and other chronic bioassays do not provide adequate scientific support for APM safety. In contrast, recent results of life-span carcinogenicity bioassays on rats and mice published in peer-reviewed journals, and a prospective epidemiological study, provide consistent evidence of APM's carcinogenic potential. On the basis of the evidence of the potential carcinogenic effects of APM herein reported, a re-evaluation of the current position of international regulatory agencies must be considered an urgent matter of public health. © 2014 Wiley Periodicals, Inc.

Contrasting effects of non-starch polysaccharide and resistant starch-based diets on the disposition and excretion of the food carcinogen, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), in a rat model.

PubMed

Ferguson, Lynnette R; Zhu, Shuotun; Kestell, Philip

2003-06-01

It has commonly been believed that increasing fibre in the diet should reduce the incidence of cancers, especially those of the colon and rectum. The earliest definitions of dietary fibre restricted the term to plant cell walls in which non-starch polysaccharides are key chemical components. However, new definitions encompass a wider range of materials, including starches resistant to digestion in the colon (resistant starches). Nevertheless, most definitions require that "dietary fibres" show physiological effects considered beneficial against cancer, including enhanced laxation and faecal bulking. On theoretical grounds, such properties might be expected to dilute the concentration of any carcinogen present and move it more rapidly through the colon, thereby reducing bioavailability. We have compared the properties of two dietary fibre preparations that are primarily non-starch polysaccharides with two resistant starch preparations for effects on carcinogen disposition in a rodent model. Although both preparations enhanced laxation and faecal bulking, only the non-starch polysaccharide preparation reduced carcinogen biovailability. Indeed, carcinogen biovailability was significantly enhanced by resistant starch. We suggest that there may be fundamental differences in the manner by which non-starch polysaccharides or resistant starches affect carcinogen disposition, and express concern that the events seen with the resistant starches [RS] are unlikely to be beneficial with respect to protection against cancer by exogenous carcinogens. Furthermore, the data reveal that the observation of enhanced laxation and faecal bulking does not necessarily imply a reduction in carcinogen bioavailability.

Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish.

PubMed

Lin, Chun-Hung; Chou, Pei-Hsin; Chen, Pei-Jen

2014-07-30

Conazoles are a class of imidazole- or triazole-containing drugs commonly used as fungicides in agriculture and medicine. The broad application of azole drugs has led to the contamination of surface aquifers receiving the effluent of municipal or hospital wastewater or agricultural runoff. Several triazoles are rodent carcinogens; azole pollution is a concern to environmental safety and human health. However, the carcinogenic mechanisms associated with cytochrome P450 enzymes (CYPs) of conazoles remain unclear. We exposed adult medaka fish (Oryzias latipes) to continuous aqueous solutions of carcinogenic triadimefon and non-carcinogenic myclobutanil for 7 to 20 days at sub-lethal or environmentally relevant concentrations and assessed hepatic CYP activity and gene expression associated with CYP-mediated toxicity. Both triadimefon and myclobutanil induced hepatic CYP3A activity, but only triadimefon enhanced CYP1A activity. The gene expression of cyp3a38, cyp3a40, pregnane x receptor (pxr), cyp26b, retinoid acid receptor γ1 (rarγ1) and p53 was higher with triadimefon than myclobutanil. As well, yeast-based reporter gene assay revealed that 4 tested conazoles were weak agonists of aryl hydrocarbon receptor (AhR). We reveal differential CYP gene expression with carcinogenic and non-carcinogenic conazoles in a lower vertebrate, medaka fish. Liver CYP-enzyme induction may be a key event in conazole-induced tumorigenesis. This information is essential to evaluate the potential threat of conazoles to human health and fish populations in the aquatic environment. Copyright © 2014 Elsevier B.V. All rights reserved.

Chemistry of mutagens and carcinogens in broiled food.

PubMed Central

Nishimura, S

1986-01-01

From a chemical point of view, the following subjects are important areas in studies on mutagens and carcinogens in broiled foods. In addition to heterocyclic amines which need microsomal activation, the structural elucidation of more labile direct-acting mutagens is necessary. It is known that there are still various unknown minor mutagens in broiled foods. Although the structural characterization of such compounds is more difficult, it is important since they might be hazardous in spite of their low mutagenicity. A more feasible and easier method for quantitative analysis of mutagens, in addition to HPLC and GC/MS methods presently employed, must be developed. The mechanism of formation of mutagens by broiling of food should be studied. An effective chemical method to prevent formation of mutagens or to destroy them, once formed, should be developed. PMID:3757944

Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid

PubMed Central

Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

2016-01-01

Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. PMID:27399778

Synergism between Sodium Chloride and Sodium Taurocholate and Development of Pepsinogen‐altered Pyloric Glands: Relevance to a Medium‐term Bioassay System for Gastric Carcinogens and Promoters in Rats

PubMed Central

Tatematsu, Masae; Mutai, Mamoru; Inoue, Kaoru; Ozaki, Keisuke; Furihata, Chie; Ito, Nobuyuki

1989-01-01

In an approach to early detection of gastric carcinogens and promoters in an in vivo test system, promotion by sodium chloride (NaCl) and the synergistic effects of NaCl and sodium taurocholate (Na‐TC) on development of pepsinogen‐altered pyloric glands (PAPG) in rat glandular stomach after initiation with N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) were investigated. A total of 205 male WKY/NCrj rats were divided into 8 groups. Group 1 was given a single dose of MNNG of 160 mg/ kg body weight by gastric intubation, and starting 2 weeks later basal diet containing Na‐TC for 18 weeks. In addition, 1 ml doses of saturated NaCl solution were given by gastric intubation at weeks 4, 6, 8 and 10. Similarly, group 2 was treated with MNNG and Na‐TC, while group 3 animals received MNNG and NaCl. Group 4 was given MNNG alone. Groups 5–8 served as equivalent controls without MNNG initiation. The results revealed significantly enhanced induction of immunohisto‐chemically defined PAPG in the Na‐TC + NaCl (P< 0.001), Na‐TC (P<0.01) and NaCl (P<0.01) treated animals initiated with MNNG. Sodium chloride demonstrated a clear synergistic effect with Na‐TC in promoting the development of PAPG, suggesting possible advantage for its use in medium‐term in vivo assays for detection of gastric carcinogens and promoters. PMID:2514164

Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid.

PubMed

Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Orta, Manuel Luis; Guillén-Mancina, Emilio; Mateos, Santiago; López-Lázaro, Miguel

2016-07-08

Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee.

Quantitation of DNA adducts by stable isotope dilution mass spectrometry

PubMed Central

Tretyakova, Natalia; Goggin, Melissa; Janis, Gregory

2012-01-01

Exposure to endogenous and exogenous chemicals can lead to the formation of structurally modified DNA bases (DNA adducts). If not repaired, these nucleobase lesions can cause polymerase errors during DNA replication, leading to heritable mutations potentially contributing to the development of cancer. Due to their critical role in cancer initiation, DNA adducts represent mechanism-based biomarkers of carcinogen exposure, and their quantitation is particularly useful for cancer risk assessment. DNA adducts are also valuable in mechanistic studies linking tumorigenic effects of environmental and industrial carcinogens to specific electrophilic species generated from their metabolism. While multiple experimental methodologies have been developed for DNA adduct analysis in biological samples – including immunoassay, HPLC, and 32P-postlabeling – isotope dilution high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) generally has superior selectivity, sensitivity, accuracy, and reproducibility. As typical DNA adducts concentrations in biological samples are between 0.01 – 10 adducts per 108 normal nucleotides, ultrasensitive HPLC-ESI-MS/MS methodologies are required for their analysis. Recent developments in analytical separations and biological mass spectrometry – especially nanoflow HPLC, nanospray ionization MS, chip-MS, and high resolution MS – have pushed the limits of analytical HPLC-ESI-MS/MS methodologies for DNA adducts, allowing researchers to accurately measure their concentrations in biological samples from patients treated with DNA alkylating drugs and in populations exposed to carcinogens from urban air, drinking water, cooked food, alcohol, and cigarette smoke. PMID:22827593

Curbing the burden of lung cancer.

PubMed

Urman, Alexandra; Hosgood, H Dean

2016-06-01

Lung cancer contributes substantially to the global burden of disease and healthcare costs. New screening modalities using low-dose computerized tomography are promising tools for early detection leading to curative surgery. However, the screening and follow-up diagnostic procedures of these techniques may be costly. Focusing on prevention is an important factor to reduce the burden of screening, treatment, and lung cancer deaths. The International Agency for Research on Cancer has identified several lung carcinogens, which we believe can be considered actionable when developing prevention strategies. To curb the societal burden of lung cancer, healthcare resources need to be focused on early detection and screening and on mitigating exposure(s) of a person to known lung carcinogens, such as active tobacco smoking, household air pollution (HAP), and outdoor air pollution. Evidence has also suggested that these known lung carcinogens may be associated with genetic predispositions, supporting the hypothesis that lung cancers attributed to differing exposures may have developed from unique underlying genetic mechanisms attributed to the exposure of interest. For instance, smokingattributed lung cancer involves novel genetic markers of risk compared with HAP-attributed lung cancer. Therefore, genetic risk markers may be used in risk stratification to identify subpopulations that are at a higher risk for developing lung cancer attributed to a given exposure. Such targeted prevention strategies suggest that precision prevention strategies may be possible in the future; however, much work is needed to determine whether these strategies will be viable.

Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer

PubMed Central

Danforth, David N.

2016-01-01

Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women. PMID:27559297

THE CARCINOGENIC RESPONSE TO A MIXTURE OF DRINKING WATER DISINFECTION BY-PRODUCTS (DBP) WAS LESS THAN ADDITIVE

EPA Science Inventory

THE CARCINOGENIC RESPONSE TO A MIXTURE OF DRINKING WATER DISINFECTION BY -PRODUCTS (DBP) W AS LESS THAN ADDITIVE.

Current default risk assessments for chemical mixtures assume additivity of carcinogenic effects but this may under or over represent the actual biological res...

OVERVIEW OF DRINKING WATER MUTAGENICITY AND CARCINOGENICITY AND RISK FOR BLADDER CANCER

EPA Science Inventory

Among the 11 disinfection by-products (DBPs) in drinking water that are regulated by the U.S. EPA, (a) 2 DBPs (chloroacetic acid and chlorite) are not carcinogenic-in either of 2 species; (b) chlorite is not carcinogenic in 3 rodent assays and has never been tested for genotoxici...

DIRECT-ACTING, DNA-DAMAGING AS (III)-METHYLATED SPECIES: IMPLICATIONS FOR A CARCINOGENIC MECHANISM OF ACTION OF ARSENICALS

EPA Science Inventory

Direct-acting, DNA-damaging As (III)-methylated species: implications for a carcinogenic . mechanism of action of arsenicals

Inorganic arsenic (iAs, arsenite and arsenate) has been thought to act as a carcinogen without reacting directly with DNA; neither iAs nor the As(...

Arsenic and lead in foods: a potential threat to human health in Bangladesh.

PubMed

Islam, Md Saiful; Ahmed, Md Kawser; Habibullah-Al-Mamun, Md; Islam, Kazi Nazrul; Ibrahim, Md; Masunaga, Shigeki

2014-01-01

The non-carcinogenic and carcinogenic risk of arsenic and lead to adults and children via daily dietary intake of food composites in Bangladesh was estimated. The target hazard quotients (THQs), hazard index (HI) and target carcinogenic risk (TR) were calculated to evaluate the non-carcinogenic and carcinogenic health risk from arsenic and lead. Most of the individual food composites contain a considerable amount of arsenic and lead. The highest mean concentrations of arsenic were found in cereals (0.254 mg kg⁻¹ fw) and vegetables (0.250 mg kg⁻¹ fw), and lead in vegetables (0.714 mg kg⁻¹ fw) and fish (0.326 mg kg⁻¹ fw). The results showed the highest THQs of arsenic in cereals and lead in vegetables for both adults and children which exceeded the safe limit (> 1) indicating that cereals and vegetables are the main food items contributing to the potential health risk. The estimated TR from ingesting dietary arsenic and lead from most of the foods exceeded 10⁻⁶, indicating carcinogenic risks for all adult people of the study area.

Rodent carcinogens: Setting priorities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gold, L.S.; Slone, T.H.; Stern, B.R.

1992-10-09

The human diet contains an enormous background of natural chemicals, such as plant pesticides and the products of cooking, that have not been a focus of carcinogenicity testing. A broadened perspective that includes these natural chemicals is necessary. A comparison of possible hazards for 80 daily exposures to rodent carcinogens from a variety of sources is presented, using an index (HERP) that relates human exposure to carcinogenic potency in rodents. A similar ordering would be expected with the use of standard risk assessment methodology for the same human exposure values. Results indicate that, when viewed against the large background ofmore » naturally occurring carcinogens in typical portions of common foods, the residues of synthetic pesticides or environmental pollutants rank low. A similar result is obtained in a separate comparison of 32 average daily exposures to natural pesticides and synthetic pesticides residues in the diet. Although the findings do not indicate that these natural dietary carcinogens are important in human cancer, they cast doubt on the relative importance for human cancer of low-dose exposures to synthetic chemicals.« less

Estimating occupational exposure to carcinogens in Quebec.

PubMed

Labrèche, France; Duguay, Patrice; Ostiguy, Claude; Boucher, Alexandre; Roberge, Brigitte; Peters, Cheryl E; Demers, Paul A

2013-09-01

We estimated the extent of exposure to occupational carcinogens in Quebec, Canada, to help raise awareness of occupational cancers. Proportions of workers exposed to 21 recognized and 17 probable carcinogens (according to Quebec occupational health regulation and the International Agency for Research on Cancer [IARC] classification) were extracted from various sources: workplace monitoring data, research projects, a population survey, radiation protection data, exposure estimates from the Carcinogen Exposure Canada (CAREX Canada) Project database, and published exposure data. These proportions were applied to Quebec labor force data. Among the 38 studied, carcinogens with the largest proportions of exposed workers were solar radiation (6.6% of workers), night shift work/rotating shift work including nights (6.0%), diesel exhaust fumes (4.4%), wood dust (2.9%) and polycyclic aromatic hydrocarbons (2.0%). More than 15 carcinogens were identified in several industrial sectors, and up to 100,000 young workers are employed in these sectors. Although crude, estimates obtained with different data sources allow identification of research and intervention priorities for cancer in Quebec. Copyright © 2013 Wiley Periodicals, Inc.

Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?

PubMed Central

Doktorova, T. Y.; Yildirimman, Reha; Ceelen, Liesbeth; Vilardell, Mireia; Vanhaecke, Tamara; Vinken, Mathieu; Ates, Gamze; Heymans, Anja; Gmuender, Hans; Bort, Roque; Corvi, Raffaella; Phrakonkham, Pascal; Li, Ruoya; Mouchet, Nicolas; Chesne, Christophe; van Delft, Joost; Kleinjans, Jos; Castell, Jose; Herwig, Ralf; Rogiers, Vera

2014-01-01

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances. PMID:26417288

Application of the two-stage clonal expansion model in characterizing the joint effect of exposure to two carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zielinski, J.M.; Krewski, D.

1992-12-31

In this paper, we describe application of the two-stage clonal expansion model to characterize the joint effect of exposure to two carcinogens. This biologically based model of carcinogenesis provides a useful framework for the quantitative description of carcinogenic risks and for defining agents that act as initiators, promoters, and completers. Depending on the mechanism of action, the agent-specific relative risk following exposure to two carcinogens can be additive, multiplicative, or supramultiplicative, with supra-additive relative risk indicating a synergistic effect between the two agents. Maximum-likelihood methods for fitting the two-stage clonal expansion model with intermittent exposure to two carcinogens are describedmore » and illustrated, using data on lung-cancer mortality among Colorado uranium miners exposed to both radon and tobacco smoke.« less

[Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline enterprise].

PubMed

Morgano, Gian Paolo; Davoli, Marina; Moja, Lorenzo; Amato, Laura; Ferroni, Eliana; Tirani, Marcello

2015-06-01

Guideline developers worldwide are struggling with the lack of guidance for the practical steps in the guideline enterprise. Our objective was to systematically compile a comprehensive checklist of items linked to relevant resources and tools that guideline developers would consider for development and support of implementation. Data sources included manuals of international guideline developers, literature on guidelines for guidelines with a focus on international and national guideline agencies, professional societies, and recent systematic guidance articles. We reviewed these sources in duplicate, extracted items using a sensitive approach and developed overarching topics that are relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions. We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers (http://cebgrade.mcmaster.ca/guidecheck.html). The topics and items included cover all stages of the guideline enterprise, from planning to formulating recommendations, to dissemination and evaluation. The final itemized guideline development checklist (GDC) includes links to training material and resources for methodology. The GDC will serve as a resource for those involved in guideline development and we will use crowdsourcing to keep the checklist up to date and enhance it.

Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Xin; Mandal, Ardhendu K.; Saito, Hiroshi

2012-07-01

Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealedmore » that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway. -- Highlights: ► Carcinogenic metals in drinking water promote colorectal tumor formation in vivo. ► Carcinogenic metals induce β-catenin activation in vivo and in vitro. ► ROS generation induced by carcinogenic metals mediated β-catenin activation.« less

Developing clinical practice guidelines: reviewing, reporting, and publishing guidelines; updating guidelines; and the emerging issues of enhancing guideline implementability and accounting for comorbid conditions in guideline development

PubMed Central

2012-01-01

Clinical practice guidelines are one of the foundations of efforts to improve health care. In 1999, we authored a paper about methods to develop guidelines. Since it was published, the methods of guideline development have progressed both in terms of methods and necessary procedures and the context for guideline development has changed with the emergence of guideline clearing houses and large scale guideline production organisations (such as the UK National Institute for Health and Clinical Excellence). It therefore seems timely to, in a series of three articles, update and extend our earlier paper. In this third paper we discuss the issues of: reviewing, reporting, and publishing guidelines; updating guidelines; and the two emerging issues of enhancing guideline implementability and how guideline developers should approach dealing with the issue of patients who will be the subject of guidelines having co-morbid conditions. PMID:22762242

Occupational exposure limits for carcinogens--variant approaches by different countries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cook, W.A.

1989-09-01

The differences in treatment of occupational exposure limits for carcinogens by 24 countries is described along with a discussion of the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values (TLV) treatment, the similar treatment of the new Occupational Safety and Health Administration (OSHA) standard, and the treatment by provinces of Canada. The unique listing by the Federal Republic of Germany of so-called technical guiding concentrations of a group of carcinogens is discussed with the note that Austria used this same system. Publications on justification for establishing occupational exposure limits for certain carcinogens are discussed also.

A NEW MEDIUM‐TERM BIOASSAY SYSTEM FOR DETECTION OF ENVIRONMENTAL CARCINOGENS USING DIETHYLNITROSAMINE‐INITIATED RAT LIVER FOLLOWED BY D‐GALACTOSAMINE TREATMENT AND PARTIAL HEPATECTOMY

PubMed Central

Ito, Nobuyuki; Imaida, Katsumi; de Camargo, Joao Lauro V.; Takahashi, Satoru; Asamoto, Makoto; Tsuda, Hiroyuki

1988-01-01

The effects of D‐galactosamine on induction of preneoplastic glutathione S‐transferase placental form positive liver foci were investigated in F344 rats pretreated with diethylnitrosamine (DEN) in an attempt to improve the predictive value of the medium‐term bioassay system developed in our laboratory. Two weeks after the initial single ip dose (200 mg/kg) of DEN, administration of test compounds was commenced simultaneously with an ip injection of D‐galactosamine at a dose of 300 mg/kg body wt. All rats were then subjected to two‐thirds partial hepatectomy (PH) at week 5 and sacrificed for assessment of lesion yield at week 8. Measurement and comparison of the numbers and areas of glutathione S‐transferase placental form positive (GST‐P+) foci per cm2 revealed a positive response to more carcinogens, including non‐hepatocarcinogens, than did the same bioassay system without injection of D‐galactosamine. Thus the results suggest that inclusion of this extra proliferative stimulus may improve the medium‐term detection of carcinogens and modifiers. PMID:3136108

Activation of the germ-cell potential of human bone marrow-derived cells by a chemical carcinogen

PubMed Central

Liu, Chunfang; Ma, Zhan; Xu, Songtao; Hou, Jun; Hu, Yao; Yu, Yinglu; Liu, Ruilai; Chen, Zhihong; Lu, Yuan

2014-01-01

Embryonic/germ cell traits are common in malignant tumors and are thought to be involved in malignant tumor behaviors. The reasons why tumors show strong embryonic/germline traits (displaced germ cells or gametogenic programming reactivation) are controversial. Here, we show that a chemical carcinogen, 3-methyl-cholanthrene (3-MCA), can trigger the germ-cell potential of human bone marrow-derived cells (hBMDCs). 3-MCA promoted the generation of germ cell-like cells from induced hBMDCs that had undergone malignant transformation, whereas similar results were not observed in the parallel hBMDC culture at the same time point. The malignant transformed hBMDCs spontaneously and more efficiently generated into germ cell-like cells even at the single-cell level. The germ cell-like cells from induced hBMDCs were similar to natural germ cells in many aspects, including morphology, gene expression, proliferation, migration, further development, and teratocarcinoma formation. Therefore, our results demonstrate that a chemical carcinogen can reactivate the germline phenotypes of human somatic tissue-derived cells, which might provide a novel idea to tumor biology and therapy. PMID:24998261

Non-covalent interactions of the carcinogen (+)-anti-BPDE with exon 1 of the human K-ras proto-oncogene

NASA Astrophysics Data System (ADS)

Rodriguez, Jorge H.; Deligkaris, Christos

2013-03-01

Investigating the complementary, but different, effects of physical (non-covalent) and chemical (covalent) mutagen-DNA and carcinogen-DNA interactions is important for understanding possible mechanisms of development and prevention of mutagenesis and carcinogenesis. A highly mutagenic and carcinogenic metabolite of the polycyclic aromatic hydrocarbon benzo[ α]pyrene, namely (+)-anti-BPDE, is known to undergo both physical and chemical complexation with DNA. The major covalent adduct, a promutagenic, is known to be an external (+)-trans-anti-BPDE-N2-dGuanosine configuration whose origins are not fully understood. Thus, it is desirable to study the mechanisms of external non-covalent BPDE-DNA binding and their possible relationships to external covalent trans adduct formation. We present a detailed codon-by-codon computational study of the non-covalent interactions of (+)-anti-BPDE with DNA which explains and correctly predicts preferential (+)-anti-BPDE binding at minor groove guanosines. Due to its relevance to carcinogenesis, the interaction of (+)-anti-BPDE with exon 1 of the human K-ras gene has been studied in detail. Present address: Department of Physics, Drury University