Application of Model Animals in the Study of Drug Toxicology

NASA Astrophysics Data System (ADS)

Song, Yagang; Miao, Mingsan

2018-01-01

Drug safety is a key factor in drug research and development, Drug toxicology test is the main method to evaluate the safety of drugs, The body condition of an animal has important implications for the results of the study, Previous toxicological studies of drugs were carried out in normal animals in the past, There is a great deviation from the clinical practice.The purpose of this study is to investigate the necessity of model animals as a substitute for normal animals for toxicological studies, It is expected to provide exact guidance for future drug safety evaluation.

77 FR 40358 - Meeting of the Scientific Advisory Committee on Alternative Toxicological Methods (SACATM)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-09

... Alternative Toxicological Methods (SACATM) AGENCY: Division of the National Toxicology Program (DNTP.../live ). SACATM advises the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM...

QUANTITATIVE TOXICOLOGIC PATHOLOGY-METHODS AND INTERPRETATION' SESSION AT THE JOINT MEETING OF SOCIETY OF TOXICOLOGIC PATHOLOGISTS AND THE INTERNATIONAL FEDERATION OF SOCIETIES OF TOXICOLOGIC PATHOLOGISTS

EPA Science Inventory

Report of the 'Quantitative Toxicologic Pathology - Methods and Interpretation' session at the Joint meeting of Society of Toxicologic Pathologists and the International Federation of Societies of Toxicologic Pathologists, Orlando, Florida, USA, June 24-28, 2001. Douglas C. Wolf,...

Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology".

PubMed

Insel, Paul A; Amara, Susan G; Blaschke, Terrence F; Meyer, Urs A

2017-01-06

Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme for a number of articles in this volume. These include ones that review the development and use of new experimental tools and approaches (e.g., nanobodies and techniques to explore protein-protein interactions), new types of therapeutics (e.g., aptamers and antisense oligonucleotides), and systems pharmacology, which assembles (big) data derived from omics studies together with information regarding drugs and patients. The application of these new methods and therapeutic approaches has the potential to have a major impact on basic and clinical research in pharmacology and toxicology as well as on patient care.

76 FR 23323 - Meeting of the Scientific Advisory Committee on Alternative Toxicological Methods (SACATM)

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-26

... Alternative Toxicological Methods (SACATM) AGENCY: National Toxicology Program (NTP), National Institute of... the Validation of Alternative Methods (ICCVAM), the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), and the Director of the NIEHS and NTP regarding statutorily...

Aerospace Toxicology and Microbiology

NASA Technical Reports Server (NTRS)

James, John T.; Parmet, A. J.; Pierson, Duane L.

2007-01-01

Toxicology dates to the very earliest history of humanity with various poisons and venom being recognized as a method of hunting or waging war with the earliest documentation in the Evers papyrus (circa 1500 BCE). The Greeks identified specific poisons such as hemlock, a method of state execution, and the Greek word toxos (arrow) became the root of our modern science. The first scientific approach to the understanding of poisons and toxicology was the work during the late middle ages of Paracelsus. He formulated what were then revolutionary views that a specific toxic agent or "toxicon" caused specific dose-related effects. His principles have established the basis of modern pharmacology and toxicology. In 1700, Bernardo Ramazzini published the book De Morbis Artificum Diatriba (The Diseases of Workers) describing specific illnesses associated with certain labor, particularly metal workers exposed to mercury, lead, arsenic, and rock dust. Modern toxicology dates from development of the modern industrial chemical processes, the earliest involving an analytical method for arsenic by Marsh in 1836. Industrial organic chemicals were synthesized in the late 1800 s along with anesthetics and disinfectants. In 1908, Hamilton began the long study of occupational toxicology issues, and by WW I the scientific use of toxicants saw Haber creating war gases and defining time-dosage relationships that are used even today.

Fire toxicology program. JSC methodology

NASA Technical Reports Server (NTRS)

Schneider, H.; Bafus, D.

1978-01-01

Toxicological testing of spacecraft materials was initiated in 1965. Toxicological evaluations of the pyrolysis/combustion products of candidate spacecraft materials were performed using a modified 142 liter Bethlehem Chamber equipped with a Linberg Model 55031 furnace external to the chamber. In all of the assessments, lethality was chosen as the endpoint. A new pyrolysis/combustion chamber was developed for toxicological testing and ranking of both spacecraft and aircraft materials. The pyrolysis/combustion chamber permits the use of both behavior and physiological measurements as indicators of incapacitation. Methods were developed which employ high resolution gas chromatography/mass spectrometry to generate chamber atmospheric profiles which indicate the reproductibility of pyrolysate concentrations. The atmospheric volatile profiles in combination with CO, CO2, and O2 analysis indicates that small chamber equipped with an internal furnace will give reproducible results.

Crowd-Sourced Verification of Computational Methods and Data in Systems Toxicology: A Case Study with a Heat-Not-Burn Candidate Modified Risk Tobacco Product.

PubMed

Poussin, Carine; Belcastro, Vincenzo; Martin, Florian; Boué, Stéphanie; Peitsch, Manuel C; Hoeng, Julia

2017-04-17

Systems toxicology intends to quantify the effect of toxic molecules in biological systems and unravel their mechanisms of toxicity. The development of advanced computational methods is required for analyzing and integrating high throughput data generated for this purpose as well as for extrapolating predictive toxicological outcomes and risk estimates. To ensure the performance and reliability of the methods and verify conclusions from systems toxicology data analysis, it is important to conduct unbiased evaluations by independent third parties. As a case study, we report here the results of an independent verification of methods and data in systems toxicology by crowdsourcing. The sbv IMPROVER systems toxicology computational challenge aimed to evaluate computational methods for the development of blood-based gene expression signature classification models with the ability to predict smoking exposure status. Participants created/trained models on blood gene expression data sets including smokers/mice exposed to 3R4F (a reference cigarette) or noncurrent smokers/Sham (mice exposed to air). Participants applied their models on unseen data to predict whether subjects classify closer to smoke-exposed or nonsmoke exposed groups. The data sets also included data from subjects that had been exposed to potential modified risk tobacco products (MRTPs) or that had switched to a MRTP after exposure to conventional cigarette smoke. The scoring of anonymized participants' predictions was done using predefined metrics. The top 3 performers' methods predicted class labels with area under the precision recall scores above 0.9. Furthermore, although various computational approaches were used, the crowd's results confirmed our own data analysis outcomes with regards to the classification of MRTP-related samples. Mice exposed directly to a MRTP were classified closer to the Sham group. After switching to a MRTP, the confidence that subjects belonged to the smoke-exposed group decreased significantly. Smoking exposure gene signatures that contributed to the group separation included a core set of genes highly consistent across teams such as AHRR, LRRN3, SASH1, and P2RY6. In conclusion, crowdsourcing constitutes a pertinent approach, in complement to the classical peer review process, to independently and unbiasedly verify computational methods and data for risk assessment using systems toxicology.

Implementation of the 3Rs (refinement, reduction, and replacement): validation and regulatory acceptance considerations for alternative toxicological test methods.

PubMed

Schechtman, Leonard M

2002-01-01

Toxicological testing in the current regulatory environment is steeped in a history of using animals to answer questions about the safety of products to which humans are exposed. That history forms the basis for the testing strategies that have evolved to satisfy the needs of the regulatory bodies that render decisions that affect, for the most part, virtually all phases of premarket product development and evaluation and, to a lesser extent, postmarketing surveillance. Only relatively recently have the levels of awareness of, and responsiveness to, animal welfare issues reached current proportions. That paradigm shift, although sluggish, has nevertheless been progressive. New and alternative toxicological methods for hazard evaluation and risk assessment have now been adopted and are being viewed as a means to address those issues in a manner that considers humane treatment of animals yet maintains scientific credibility and preserves the goal of ensuring human safety. To facilitate this transition, regulatory agencies and regulated industry must work together toward improved approaches. They will need assurance that the methods will be reliable and the results comparable with, or better than, those derived from the current classical methods. That confidence will be a function of the scientific validation and resultant acceptance of any given method. In the United States, to fulfill this need, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and its operational center, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), have been constituted as prescribed in federal law. Under this mandate, ICCVAM has developed a process and established criteria for the scientific validation and regulatory acceptance of new and alternative methods. The role of ICCVAM in the validation and acceptance process and the criteria instituted toward that end are described. Also discussed are the participation of the US Food and Drug Administration (FDA) in the ICCVAM process and that agency's approach to the application and implementation of ICCVAM-recommended methods.

77 FR 72858 - Toxicological Review of Inorganic Arsenic (Cancer and Noncancer Effects): In Support of Summary...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-06

... public stakeholder workshop to inform the development of a state of the science toxicological review of... database. Workshop participants will be asked to highlight significant new and emerging research, discuss methods for evaluating literature, identify critical research issues (including mode of action) that may...

Integration of QSAR and in vitro toxicology.

PubMed Central

Barratt, M D

1998-01-01

The principles of quantitative structure-activity relationships (QSAR) are based on the premise that the properties of a chemical are implicit in its molecular structure. Therefore, if a mechanistic hypothesis can be proposed linking a group of related chemicals with a particular toxic end point, the hypothesis can be used to define relevant parameters to establish a QSAR. Ways in which QSAR and in vitro toxicology can complement each other in development of alternatives to live animal experiments are described and illustrated by examples from acute toxicological end points. Integration of QSAR and in vitro methods is examined in the context of assessing mechanistic competence and improving the design of in vitro assays and the development of prediction models. The nature of biological variability is explored together with its implications for the selection of sets of chemicals for test development, optimization, and validation. Methods are described to support the use of data from in vivo tests that do not meet today's stringent requirements of acceptability. Integration of QSAR and in vitro methods into strategic approaches for the replacement, reduction, and refinement of the use of animals is described with examples. PMID:9599692

Mind the Gap! A Journey towards Computational Toxicology.

PubMed

Mangiatordi, Giuseppe Felice; Alberga, Domenico; Altomare, Cosimo Damiano; Carotti, Angelo; Catto, Marco; Cellamare, Saverio; Gadaleta, Domenico; Lattanzi, Gianluca; Leonetti, Francesco; Pisani, Leonardo; Stefanachi, Angela; Trisciuzzi, Daniela; Nicolotti, Orazio

2016-09-01

Computational methods have advanced toxicology towards the development of target-specific models based on a clear cause-effect rationale. However, the predictive potential of these models presents strengths and weaknesses. On the good side, in silico models are valuable cheap alternatives to in vitro and in vivo experiments. On the other, the unconscious use of in silico methods can mislead end-users with elusive results. The focus of this review is on the basic scientific and regulatory recommendations in the derivation and application of computational models. Attention is paid to examine the interplay between computational toxicology and drug discovery and development. Avoiding the easy temptation of an overoptimistic future, we report our view on what can, or cannot, realistically be done. Indeed, studies of safety/toxicity represent a key element of chemical prioritization programs carried out by chemical industries, and primarily by pharmaceutical companies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Considerations regarding the validation of chromatographic mass spectrometric methods for the quantification of endogenous substances in forensics.

PubMed

Hess, Cornelius; Sydow, Konrad; Kueting, Theresa; Kraemer, Michael; Maas, Alexandra

2018-02-01

The requirement for correct evaluation of forensic toxicological results in daily routine work and scientific studies is reliable analytical data based on validated methods. Validation of a method gives the analyst tools to estimate the efficacy and reliability of the analytical method. Without validation, data might be contested in court and lead to unjustified legal consequences for a defendant. Therefore, new analytical methods to be used in forensic toxicology require careful method development and validation of the final method. Until now, there are no publications on the validation of chromatographic mass spectrometric methods for the detection of endogenous substances although endogenous analytes can be important in Forensic Toxicology (alcohol consumption marker, congener alcohols, gamma hydroxy butyric acid, human insulin and C-peptide, creatinine, postmortal clinical parameters). For these analytes, conventional validation instructions cannot be followed completely. In this paper, important practical considerations in analytical method validation for endogenous substances will be discussed which may be used as guidance for scientists wishing to develop and validate analytical methods for analytes produced naturally in the human body. Especially the validation parameters calibration model, analytical limits, accuracy (bias and precision) and matrix effects and recovery have to be approached differently. Highest attention should be paid to selectivity experiments. Copyright © 2017 Elsevier B.V. All rights reserved.

The Emergence of Systematic Review in Toxicology.

PubMed

Stephens, Martin L; Betts, Kellyn; Beck, Nancy B; Cogliano, Vincent; Dickersin, Kay; Fitzpatrick, Suzanne; Freeman, James; Gray, George; Hartung, Thomas; McPartland, Jennifer; Rooney, Andrew A; Scherer, Roberta W; Verloo, Didier; Hoffmann, Sebastian

2016-07-01

The Evidence-based Toxicology Collaboration hosted a workshop on "The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology," on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

The Emergence of Systematic Review in Toxicology

PubMed Central

Stephens, Martin L.; Betts, Kellyn; Beck, Nancy B.; Cogliano, Vincent; Dickersin, Kay; Fitzpatrick, Suzanne; Freeman, James; Gray, George; Hartung, Thomas; McPartland, Jennifer; Rooney, Andrew A.; Scherer, Roberta W.; Verloo, Didier; Hoffmann, Sebastian

2016-01-01

The Evidence-based Toxicology Collaboration hosted a workshop on “The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology,” on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology. PMID:27208075

Green Toxicology-Know Early About and Avoid Toxic Product Liabilities.

PubMed

Maertens, Alexandra; Hartung, Thomas

2018-02-01

Toxicology uniquely among the life sciences relies largely on methods which are more than 40-years old. Over the last 3 decades with more or less success some additions to and few replacements in this toolbox took place, mainly as alternatives to animal testing. The acceptance of such new approaches faces the needs of formal validation and the conservative attitude toward change in safety assessments. Only recently, there is growing awareness that the same alternative methods, especially in silico and in vitro tools can also much earlier and before validation inform decision-taking in the product life cycle. As similar thoughts developed in the context of Green Chemistry, the term of Green Toxicology was coined to describe this change in approach. Here, the current developments in the alternative field, especially computational and more organo-typic cell cultures are reviewed, as they lend themselves to front-loaded chemical safety assessments. The initiatives of the Center for Alternatives to Animal Testing Green Toxicology Collaboration are presented. They aim first of all for forming a community to promote this concept and then for a cultural change in companies with the necessary training of chemists, product stewards and later regulators. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Bibliometrics for Social Validation.

PubMed

Hicks, Daniel J

2016-01-01

This paper introduces a bibliometric, citation network-based method for assessing the social validation of novel research, and applies this method to the development of high-throughput toxicology research at the US Environmental Protection Agency. Social validation refers to the acceptance of novel research methods by a relevant scientific community; it is formally independent of the technical validation of methods, and is frequently studied in history, philosophy, and social studies of science using qualitative methods. The quantitative methods introduced here find that high-throughput toxicology methods are spread throughout a large and well-connected research community, which suggests high social validation. Further assessment of social validation involving mixed qualitative and quantitative methods are discussed in the conclusion.

Bibliometrics for Social Validation

PubMed Central

2016-01-01

This paper introduces a bibliometric, citation network-based method for assessing the social validation of novel research, and applies this method to the development of high-throughput toxicology research at the US Environmental Protection Agency. Social validation refers to the acceptance of novel research methods by a relevant scientific community; it is formally independent of the technical validation of methods, and is frequently studied in history, philosophy, and social studies of science using qualitative methods. The quantitative methods introduced here find that high-throughput toxicology methods are spread throughout a large and well-connected research community, which suggests high social validation. Further assessment of social validation involving mixed qualitative and quantitative methods are discussed in the conclusion. PMID:28005974

Toxicological evaluation in silico and in vivo of secondary metabolites of Cissampelos sympodialis in Mus musculus mice following inhalation.

PubMed

Alves, Mateus Feitosa; Ferreira, Larissa Adilis Maria Paiva; Gadelha, Francisco Allysson Assis Ferreira; Ferreira, Laércia Karla Diega Paiva; Felix, Mayara Barbalho; Scotti, Marcus Tullius; Scotti, Luciana; de Oliveira, Kardilândia Mendes; Dos Santos, Sócrates Golzio; Diniz, Margareth de Fátima Formiga Melo

2017-12-04

The ethanolic extract of the leaves of Cissampelos sympodialis showed great pharmacological potential, with inflammatory and immunomodulatory activities, however, it showed some toxicological effects. Therefore, this study aims to verify the toxicological potential of alkaloids of the genus Cissampelos through in silico methodologies, to develop a method in LC-MS/MS verifying the presence of alkaloids in the infusion and to evaluate the toxicity of the infusion of the leaves of C. sympodialis when inhaled by Swiss mice. Results in silico showed that alkaloid 93 presented high toxicological potential along with the products of its metabolism. LC-MS/MS results showed that the infusion of the leaves of this plant contained the alkaloids warifteine and methylwarifteine. Finally, the in vivo toxicological analysis of the C. sympodialis infusion showed results, both in biochemistry, organ weights and histological analysis, that the infusion of C. sympodialis leaves presents a low toxicity.

ACToR A Aggregated Computational Toxicology Resource ...

EPA Pesticide Factsheets

We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology. We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology.

ACToR A Aggregated Computational Toxicology Resource (S) ...

EPA Pesticide Factsheets

We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology. We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology.

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

Using default methodologies to derive an acceptable daily exposure (ADE).

PubMed

Faria, Ellen C; Bercu, Joel P; Dolan, David G; Morinello, Eric J; Pecquet, Alison M; Seaman, Christopher; Sehner, Claudia; Weideman, Patricia A

2016-08-01

This manuscript discusses the different historical and more recent default approaches that have been used to derive an acceptable daily exposure (ADE). While it is preferable to derive a health-based ADE based on a complete nonclinical and clinical data package, this is not always possible. For instance, for drug candidates in early development there may be no or limited nonclinical or clinical trial data. Alternative approaches that can support decision making with less complete data packages represent a variety of methods that rely on default assumptions or data inputs where chemical-specific data on health effects are lacking. A variety of default approaches are used including those based on certain toxicity estimates, a fraction of the therapeutic dose, cleaning-based limits, the threshold of toxicological concern (TTC), and application of hazard banding tools such as occupational exposure banding (OEB). Each of these default approaches is discussed in this manuscript, including their derivation, application, strengths, and limitations. In order to ensure patient safety when faced with toxicological and clinical data-gaps, default ADE methods should be purposefully as or more protective than ADEs derived from full data packages. Reliance on the subset of default approaches (e.g., TTC or OEB) that are based on toxicological data is preferred over other methods for establishing ADEs in early development while toxicology and clinical data are still being collected. Copyright © 2016. Published by Elsevier Inc.

Analysis of Statistical Methods Currently used in Toxicology Journals

PubMed Central

Na, Jihye; Yang, Hyeri

2014-01-01

Statistical methods are frequently used in toxicology, yet it is not clear whether the methods employed by the studies are used consistently and conducted based on sound statistical grounds. The purpose of this paper is to describe statistical methods used in top toxicology journals. More specifically, we sampled 30 papers published in 2014 from Toxicology and Applied Pharmacology, Archives of Toxicology, and Toxicological Science and described methodologies used to provide descriptive and inferential statistics. One hundred thirteen endpoints were observed in those 30 papers, and most studies had sample size less than 10, with the median and the mode being 6 and 3 & 6, respectively. Mean (105/113, 93%) was dominantly used to measure central tendency, and standard error of the mean (64/113, 57%) and standard deviation (39/113, 34%) were used to measure dispersion, while few studies provide justifications regarding why the methods being selected. Inferential statistics were frequently conducted (93/113, 82%), with one-way ANOVA being most popular (52/93, 56%), yet few studies conducted either normality or equal variance test. These results suggest that more consistent and appropriate use of statistical method is necessary which may enhance the role of toxicology in public health. PMID:25343012

Analysis of Statistical Methods Currently used in Toxicology Journals.

PubMed

Na, Jihye; Yang, Hyeri; Bae, SeungJin; Lim, Kyung-Min

2014-09-01

Statistical methods are frequently used in toxicology, yet it is not clear whether the methods employed by the studies are used consistently and conducted based on sound statistical grounds. The purpose of this paper is to describe statistical methods used in top toxicology journals. More specifically, we sampled 30 papers published in 2014 from Toxicology and Applied Pharmacology, Archives of Toxicology, and Toxicological Science and described methodologies used to provide descriptive and inferential statistics. One hundred thirteen endpoints were observed in those 30 papers, and most studies had sample size less than 10, with the median and the mode being 6 and 3 & 6, respectively. Mean (105/113, 93%) was dominantly used to measure central tendency, and standard error of the mean (64/113, 57%) and standard deviation (39/113, 34%) were used to measure dispersion, while few studies provide justifications regarding why the methods being selected. Inferential statistics were frequently conducted (93/113, 82%), with one-way ANOVA being most popular (52/93, 56%), yet few studies conducted either normality or equal variance test. These results suggest that more consistent and appropriate use of statistical method is necessary which may enhance the role of toxicology in public health.

Toxicology as a nanoscience? – Disciplinary identities reconsidered

PubMed Central

Kurath, Monika; Maasen, Sabine

2006-01-01

Toxicology is about to establish itself as a leading scientific discipline in addressing potential health effects of materials on the nanosize level. Entering into a cutting-edge field, has an impact on identity-building processes within the involved academic fields. In our study, we analyzed the ways in which the entry into the field of nanosciences impacts on the formation of disciplinary identities. Using the methods of qualitative interviews with particle toxicologists in Germany, Holland, Switzerland and the USA, we could demonstrate that currently, toxicology finds itself in a transitional phase. The development of its disciplinary identity is not yet clear. Nearly all of our interview partners stressed the necessity of repositioning toxicology. However, they each suggested different approaches. While one part is already propagandizing the establishment of a new discipline – 'nanotoxicology'- others are more reserved and are demanding a clear separation of traditional and new research areas. In phases of disciplinary new-orientation, research communities do not act consistently. Rather, they establish diverse options. By expanding its disciplinary boundaries, participating in new research fields, while continuing its previous research, and only vaguely defining its topics, toxicology is feeling its way into the new fields without giving up its present self-conception. However, the toxicological research community is also discussing a new disciplinary identity. Within this, toxicology could develop from an auxiliary into a constitutive position, and take over a basic role in the cognitive, institutional and social framing of the nanosciences. PMID:16646961

Toxicological perspectives of inhaled therapeutics and nanoparticles.

PubMed

Hayes, Amanda J; Bakand, Shahnaz

2014-07-01

The human respiratory system is an important route for the entry of inhaled therapeutics into the body to treat diseases. Inhaled materials may consist of gases, vapours, aerosols and particulates. In all cases, assessing the toxicological effect of inhaled therapeutics has many challenges. This article provides an overview of in vivo and in vitro models for testing the toxicity of inhaled therapeutics and nanoparticles implemented in drug delivery. Traditionally, inhalation toxicity has been performed on test animals to identify the median lethal concentration of airborne materials. Later maximum tolerable concentration denoted by LC0 has been introduced as a more ethically acceptable end point. More recently, in vitro methods have been developed, allowing the direct exposure of airborne material to cultured human target cells on permeable porous membranes at the air-liquid interface. Modifications of current inhalation therapies, new pulmonary medications for respiratory diseases and implementation of the respiratory tract for systemic drug delivery are providing new challenges when conducting well-designed inhalation toxicology studies. In particular, the area of nanoparticles and nanocarriers is of critical toxicological concern. There is a need to develop toxicological test models, which characterise the toxic response and cellular interaction between inhaled particles and the respiratory system.

From Classical Toxicology to Tox21: Some Critical Conceptual and Technological Advances in the Molecular Understanding of the Toxic Response Beginning From the Last Quarter of the 20th Century.

PubMed

Choudhuri, Supratim; Patton, Geoffrey W; Chanderbhan, Ronald F; Mattia, Antonia; Klaassen, Curtis D

2018-01-01

Toxicology has made steady advances over the last 60+ years in understanding the mechanisms of toxicity at an increasingly finer level of cellular organization. Traditionally, toxicological studies have used animal models. However, the general adoption of the principles of 3R (Replace, Reduce, Refine) provided the impetus for the development of in vitro models in toxicity testing. The present commentary is an attempt to briefly discuss the transformation in toxicology that began around 1980. Many genes important in cellular protection and metabolism of toxicants were cloned and characterized in the 80s, and gene expression studies became feasible, too. The development of transgenic and knockout mice provided valuable animal models to investigate the role of specific genes in producing toxic effects of chemicals or protecting the organism from the toxic effects of chemicals. Further developments in toxicology came from the incorporation of the tools of "omics" (genomics, proteomics, metabolomics, interactomics), epigenetics, systems biology, computational biology, and in vitro biology. Collectively, the advances in toxicology made during the last 30-40 years are expected to provide more innovative and efficient approaches to risk assessment. A goal of experimental toxicology going forward is to reduce animal use and yet be able to conduct appropriate risk assessments and make sound regulatory decisions using alternative methods of toxicity testing. In that respect, Tox21 has provided a big picture framework for the future. Currently, regulatory decisions involving drugs, biologics, food additives, and similar compounds still utilize data from animal testing and human clinical trials. In contrast, the prioritization of environmental chemicals for further study can be made using in vitro screening and computational tools. Published by Oxford University Press on behalf of the Society of Toxicology 2017. This work is written by US Government employees and is in the public domain in the US.

Intersection of toxicogenomics and high throughput screening in the Tox21 program: an NIEHS perspective.

PubMed

Merrick, B Alex; Paules, Richard S; Tice, Raymond R

Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the toxicological effects of chemicals. Tox21 is a collaboration among US government agencies initiated in 2008 that aims to shift chemical hazard assessment from traditional animal toxicology to target-specific, mechanism-based, biological observations using in vitro assays and lower organism models. HTS uses biocomputational methods for probing thousands of chemicals in in vitro assays for gene-pathway response patterns predictive of adverse human health outcomes. In 1999, NIEHS began exploring the application of toxicogenomics to toxicology and recent advances in NextGen sequencing should greatly enhance the biological content obtained from HTS platforms. We foresee an intersection of new technologies in toxicogenomics and HTS as an innovative development in Tox21. Tox21 goals, priorities, progress, and challenges will be reviewed.

ISOTOPIC STUDY OF THE INHALATION TOXICOLOGY OF OXIDANTS

EPA Science Inventory

The purpose of these studies was to develop novel methods to investigate the biological fate of inhaled ozone and other oxygen-containing pollutants in animal and human tissues using the heavy isotope of oxygen, oxygen-18 (18O). Methods were developed which facilitated the conver...

Overview of Forensic Toxicology, Yesterday, Today and in the Future.

PubMed

Chung, Heesun; Choe, Sanggil

2017-01-01

The scope of forensic toxicology has been tremendously expanded over the past 50 years. From two general sections forensic toxicology can be further classified into 8-9 sections. The most outstanding improvement in forensic toxicology is the changes brought by instrumental development. The field of forensic toxicology was revolutionized by the development of immunoassay and benchtop GC-MS in the 1980's and LC-MS-MS in 2000's. Detection of trace amounts of analytes has allowed the use of new specimens such as hair and oral fluids, along with blood and urine. Over a longer period of time, continuous efforts have been made to efficiently extract and separate drug and poison from biological fluids. International endeavors to develop high quality standards and guidelines for drugs and poisons in biological specimens and to promote them in order to increase reliability of laboratories are also part of the recent advancement of forensic toxicology. Interpretation of postmortem toxicology encompasses various factors including postmortem redistribution and stability. Considering the recent trend, the interpretation of toxicological results should account for autopsy findings, crime scene information, and related medical history. The fields of forensic toxicology will continuously develop to improve analysis of target analytes from various specimens, quality assurance program, and results interpretation. In addition, the development of analytical techniques will also contribute further advancement of forensic toxicology. The societies of forensic toxicologists, such as TIAFT, will play an important role for the advancement of forensic toxicology by collaborating and sharing ideas between toxicologists from both developed and developing countries. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Electronic cigarettes in the USA: a summary of available toxicology data and suggestions for the future

PubMed Central

Orr, Michael S

2014-01-01

Objective To review the available evidence evaluating the toxicological profiles of electronic cigarettes (e-cigarettes) in order to understand the potential impact of e-cigarettes on individual users and the public health. Methods Systematic literature searches were conducted between October 2012 and October 2013 using five electronic databases. Search terms such as ‘e-cigarettes’ and ‘electronic delivery devices’ were used to identify the toxicology information for e-cigarettes. Results As of October 2013, the scientific literature contains very limited information regarding the toxicity of e-cigarettes commercially available in the USA. While some preliminary toxicology data suggests that e-cigarette users are exposed to lower levels of toxicants relative to cigarette smokers, the data available is extremely limited at this time. At present, there is insufficient toxicological data available to perform thorough risk assessment analyses for e-cigarettes; few toxicology studies evaluating e-cigarettes have been conducted to date, and standard toxicological testing paradigms have not been developed for comparing disparate types of tobacco products such as e-cigarettes and traditional cigarettes. Conclusions Overall, the limited toxicology data on e-cigarettes in the public domain is insufficient to allow a thorough toxicological evaluation of this new type of tobacco product. In the future, the acquisition of scientific datasets that are derived from scientifically robust standard testing paradigms, include comprehensive chemical characterisation of the aerosol, provide information on users’ toxicant exposure levels, and from studies replicated by independent researchers will improve the scientific community's ability to perform robust toxicological evaluations of e-cigarettes. PMID:24732158

Forensic Toxicology: An Introduction.

PubMed

Smith, Michael P; Bluth, Martin H

2016-12-01

This article presents an overview of forensic toxicology. The authors describe the three components that make up forensic toxicology: workplace drug testing, postmortem toxicology, and human performance toxicology. Also discussed are the specimens that are tested, the methods used, and how the results are interpreted in this particular discipline. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessing the scientific research productivity of a leading toxicology journal: A case study of Human & Experimental Toxicology from 2003 to 2012

PubMed Central

Al-Jabi, Samah W; Sweileh, Waleed M; Awang, Rahmat

2014-01-01

Background: Bibliometric studies are increasingly being used for research assessments. Bibliometric indicators involve the application of statistical methods to scientific publications to obtain the bibliographics for each journal. The main objective of this study was to conduct a bibliometric evaluation of Human & Experimental Toxicology retrieved from the Scopus database. Methods: This study obtained data from Scopus published from 1 January 2003 till 31 December 2012. The keywords entered in Scopus to accomplish the objective of this study were ‘Human’, ‘Experimental’ and ‘Toxicology’ as ‘Source Title’. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analysing (a) total and trends in Human & Experimental Toxicology contributions in research between 2003 and 2012; (b) Human & Experimental Toxicology authorship patterns and productivity; (c) collaboration patterns; and (d) the citations received by the publications. Results: There were 1229 research articles published in Human & Experimental Toxicology. Of the articles included, 947 (77.1%) were original articles and 104 (8.5%) were review articles. The Hirsch-index of the retrieved documents was 35. The largest number of publications in Human & Experimental Toxicology was from the United States (19.6%), followed by India (12.8%) and Turkey (10.9%). The total number of citations was 9119, with a median (interquartile range) of 3 (1–9) in 6797 documents. The highest median (interquartile range) number of citations was 8 (2.7–12.7) for France, followed by 7.5 (2–22.5) for Iran and 6 (3–13.5) for the United Kingdom. The country most often citing articles that were published in Human & Experimental Toxicology was the United States, which made citations in 1508 documents, followed by India with citations in 792 documents. Conclusion: The documents in Human & Experimental Toxicology focus principally on original data, with very few review articles. Review articles tend to have higher citation rates than original articles, and hence, the editors and authors of Human & Experimental Toxicology might usefully promote the submission of reviews in the future to improve the impact of the journal. PMID:26770709

Accelerating the Development of 21st-Century Toxicology: Outcome of a Human Toxicology Project Consortium Workshop

PubMed Central

Stephens, Martin L.; Barrow, Craig; Andersen, Melvin E.; Boekelheide, Kim; Carmichael, Paul L.; Holsapple, Michael P.; Lafranconi, Mark

2012-01-01

The U.S. National Research Council (NRC) report on “Toxicity Testing in the 21st century” calls for a fundamental shift in the way that chemicals are tested for human health effects and evaluated in risk assessments. The new approach would move toward in vitro methods, typically using human cells in a high-throughput context. The in vitro methods would be designed to detect significant perturbations to “toxicity pathways,” i.e., key biological pathways that, when sufficiently perturbed, lead to adverse health outcomes. To explore progress on the report’s implementation, the Human Toxicology Project Consortium hosted a workshop on 9–10 November 2010 in Washington, DC. The Consortium is a coalition of several corporations, a research institute, and a non-governmental organization dedicated to accelerating the implementation of 21st-century Toxicology as aligned with the NRC vision. The goal of the workshop was to identify practical and scientific ways to accelerate implementation of the NRC vision. The workshop format consisted of plenary presentations, breakout group discussions, and concluding commentaries. The program faculty was drawn from industry, academia, government, and public interest organizations. Most presentations summarized ongoing efforts to modernize toxicology testing and approaches, each with some overlap with the NRC vision. In light of these efforts, the workshop identified recommendations for accelerating implementation of the NRC vision, including greater strategic coordination and planning across projects (facilitated by a steering group), the development of projects that test the proof of concept for implementation of the NRC vision, and greater outreach and communication across stakeholder communities. PMID:21948868

The Salmonella Mutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21 st Century

EPA Science Inventory

OBJECTIVES: According to the 2007 National Research Council report Toxicology for the Twenty-first Century, modem methods ("omics," in vitro assays, high-throughput testing, computational methods, etc.) will lead to the emergence of a new approach to toxicology. The Salmonella ma...

The Toxicology Education Summit: Building the Future of Toxicology Through Education

PubMed Central

Barchowsky, Aaron; Buckley, Lorrene A.; Carlson, Gary P.; Fitsanakis, Vanessa A.; Ford, Sue M.; Genter, Mary Beth; Germolec, Dori R.; Leavens, Teresa L.; Lehman-McKeeman, Lois D.; Safe, Stephen H.; Sulentic, Courtney E. W.; Eidemiller, Betty J.

2012-01-01

Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the “Total Toxicologist”; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives. PMID:22461448

The Toxicology Education Summit: building the future of toxicology through education.

PubMed

Barchowsky, Aaron; Buckley, Lorrene A; Carlson, Gary P; Fitsanakis, Vanessa A; Ford, Sue M; Genter, Mary Beth; Germolec, Dori R; Leavens, Teresa L; Lehman-McKeeman, Lois D; Safe, Stephen H; Sulentic, Courtney E W; Eidemiller, Betty J

2012-06-01

Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the "Total Toxicologist"; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives.

[Research advances in eco-toxicological diagnosis of soil pollution].

PubMed

Liu, Feng; Teng, Hong-Hui; Ren, Bai-Xiang; Shi, Shu-Yun

2014-09-01

Soil eco-toxicology provides a theoretical basis for ecological risk assessment of contaminated soils and soil pollution control. Research on eco-toxicological effects and molecular mechanisms of toxic substances in soil environment is the central content of the soil eco-toxicology. Eco-toxicological diagnosis not only gathers all the information of soil pollution, but also provides the overall toxic effects of soil. Therefore, research on the eco-toxicological diagnosis of soil pollution has important theoretical and practical significance. Based on the research of eco-toxicological diagnosis of soil pollution, this paper introduced some common toxicological methods and indicators, with the advantages and disadvantages of various methods discussed. However, conventional biomarkers can only indicate the class of stress, but fail to explain the molecular mechanism of damage or response happened. Biomarkers and molecular diagnostic techniques, which are used to evaluate toxicity of contaminated soil, can explore deeply detoxification mechanisms of organisms under exogenous stress. In this paper, these biomarkers and techniques were introduced systematically, and the future research trends were prospected.

Highlight report: Launch of a large integrated European in vitro toxicology project: EU-ToxRisk.

PubMed

Daneshian, Mardas; Kamp, Hennicke; Hengstler, Jan; Leist, Marcel; van de Water, Bob

2016-05-01

The integrated European project, EU-ToxRisk, proudly sees itself as "flagship" exploring new alternative-to-animal approaches to chemical safety evaluation. It promotes mechanism-based toxicity testing and risk assessment according to the principles laid down for toxicology for the twenty-first century. The project was officially launched in January 2016 with a kickoff meeting in Egmond aan Zee, the Netherlands. Over 100 scientists representing academia and industry as well as regulatory authorities attended the inaugural meeting. The project will integrate advances in in vitro and in silico toxicology, read-across methods, and adverse outcome pathways. EU-ToxRisk will continue to make use of the case study strategy deployed in SEURAT-1, a FP7 initiative ended in December 2015. Even though the development of new non-animal methods is one target of EU-ToxRisk, the project puts special emphasis on their acceptance and implementation in regulatory contexts. This €30 million Horizon 2020 project involves 38 European partners and one from the USA. EU-ToxRisk aims at the "development of a new way of risk assessment."

Toxicological Evaluation of Realistic Emission Source Aerosols (TERESA): Introduction and overview

PubMed Central

Godleski, John J.; Rohr, Annette C.; Kang, Choong M.; Diaz, Edgar A.; Ruiz, Pablo A.; Koutrakis, Petros

2013-01-01

Determining the health impacts of sources and components of fine particulate matter (PM2.5) is an important scientific goal. PM2.5 is a complex mixture of inorganic and organic constituents that are likely to differ in their potential to cause adverse health outcomes. The Toxicological Evaluation of Realistic Emissions of Source Aerosols (TERESA) study focused on two PM sources—coal-fired power plants and mobile sources—and sought to investigate the toxicological effects of exposure to emissions from these sources. The set of papers published here document the power plant experiments. TERESA attempted to delineate health effects of primary particles, secondary (aged) particles, and mixtures of these with common atmospheric constituents. TERESA involved withdrawal of emissions from the stacks of three coal-fired power plants in the United States. The emissions were aged and atmospherically transformed in a mobile laboratory simulating downwind power plant plume processing. Toxicological evaluations were carried out in laboratory rats exposed to different emission scenarios with extensive exposure characterization. The approach employed in TERESA was ambitious and innovative. Technical challenges included the development of stack sampling technology that prevented condensation of water vapor from the power plant exhaust during sampling and transfer, while minimizing losses of primary particles; development and optimization of a photochemical chamber to provide an aged aerosol for animal exposures; development and evaluation of a denuder system to remove excess gaseous components; and development of a mobile toxicology laboratory. This paper provides an overview of the conceptual framework, design, and methods employed in the study. PMID:21639692

Society of Toxicologic Pathologists (STP) Annual Symposium General Session II: Modem Pathology Methods for Neural Investigations

EPA Science Inventory

This half-day session at the 20I0 Joint Symposium of the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP) explored many deceptively simple questions related to toxicologic neuropathology. What is the best met...

Recent advances of liquid chromatography-(tandem) mass spectrometry in clinical and forensic toxicology.

PubMed

Peters, Frank T

2011-01-01

Liquid chromatography (LC) coupled to mass spectrometry (MS) or tandem mass spectrometry (MS/MS) has become increasingly important in clinical and forensic toxicology as well as doping control and is now a robust and reliable technique for routine analysis in these fields. In recent years, methods for LC-MS(/MS)-based systematic toxicological analysis using triple quadrupole or ion trap instruments have been considerably improved and a new screening approach based on high-resolution MS analysis using benchtop time-of-flight MS instruments has been developed. Moreover, many applications for so-called multi-target screening and/or quantification of drugs, poisons, and or their metabolites in various biomatrices have been published. The present paper will provide an overview and discuss these recent developments focusing on the literature published after 2006. Copyright © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Recent advances of liquid chromatography-(tandem) mass spectrometry in clinical and forensic toxicology - An update.

PubMed

Remane, Daniela; Wissenbach, Dirk K; Peters, Frank T

2016-09-01

Liquid chromatography (LC) coupled to mass spectrometry (MS) or tandem mass spectrometry (MS/MS) is a well-established and widely used technique in clinical and forensic toxicology as well as doping control especially for quantitative analysis. In recent years, many applications for so-called multi-target screening and/or quantification of drugs, poisons, and or their metabolites in biological matrices have been developed. Such methods have proven particularly useful for analysis of so-called new psychoactive substances that have appeared on recreational drug markets throughout the world. Moreover, the evolvement of high resolution MS techniques and the development of data-independent detection modes have opened new possibilities for applications of LC-(MS/MS) in systematic toxicological screening analysis in the so called general unknown setting. The present paper will provide an overview and discuss these recent developments focusing on the literature published after 2010. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Data governance in predictive toxicology: A review.

PubMed

Fu, Xin; Wojak, Anna; Neagu, Daniel; Ridley, Mick; Travis, Kim

2011-07-13

Due to recent advances in data storage and sharing for further data processing in predictive toxicology, there is an increasing need for flexible data representations, secure and consistent data curation and automated data quality checking. Toxicity prediction involves multidisciplinary data. There are hundreds of collections of chemical, biological and toxicological data that are widely dispersed, mostly in the open literature, professional research bodies and commercial companies. In order to better manage and make full use of such large amount of toxicity data, there is a trend to develop functionalities aiming towards data governance in predictive toxicology to formalise a set of processes to guarantee high data quality and better data management. In this paper, data quality mainly refers in a data storage sense (e.g. accuracy, completeness and integrity) and not in a toxicological sense (e.g. the quality of experimental results). This paper reviews seven widely used predictive toxicology data sources and applications, with a particular focus on their data governance aspects, including: data accuracy, data completeness, data integrity, metadata and its management, data availability and data authorisation. This review reveals the current problems (e.g. lack of systematic and standard measures of data quality) and desirable needs (e.g. better management and further use of captured metadata and the development of flexible multi-level user access authorisation schemas) of predictive toxicology data sources development. The analytical results will help to address a significant gap in toxicology data quality assessment and lead to the development of novel frameworks for predictive toxicology data and model governance. While the discussed public data sources are well developed, there nevertheless remain some gaps in the development of a data governance framework to support predictive toxicology. In this paper, data governance is identified as the new challenge in predictive toxicology, and a good use of it may provide a promising framework for developing high quality and easy accessible toxicity data repositories. This paper also identifies important research directions that require further investigation in this area.

Data governance in predictive toxicology: A review

PubMed Central

2011-01-01

Background Due to recent advances in data storage and sharing for further data processing in predictive toxicology, there is an increasing need for flexible data representations, secure and consistent data curation and automated data quality checking. Toxicity prediction involves multidisciplinary data. There are hundreds of collections of chemical, biological and toxicological data that are widely dispersed, mostly in the open literature, professional research bodies and commercial companies. In order to better manage and make full use of such large amount of toxicity data, there is a trend to develop functionalities aiming towards data governance in predictive toxicology to formalise a set of processes to guarantee high data quality and better data management. In this paper, data quality mainly refers in a data storage sense (e.g. accuracy, completeness and integrity) and not in a toxicological sense (e.g. the quality of experimental results). Results This paper reviews seven widely used predictive toxicology data sources and applications, with a particular focus on their data governance aspects, including: data accuracy, data completeness, data integrity, metadata and its management, data availability and data authorisation. This review reveals the current problems (e.g. lack of systematic and standard measures of data quality) and desirable needs (e.g. better management and further use of captured metadata and the development of flexible multi-level user access authorisation schemas) of predictive toxicology data sources development. The analytical results will help to address a significant gap in toxicology data quality assessment and lead to the development of novel frameworks for predictive toxicology data and model governance. Conclusions While the discussed public data sources are well developed, there nevertheless remain some gaps in the development of a data governance framework to support predictive toxicology. In this paper, data governance is identified as the new challenge in predictive toxicology, and a good use of it may provide a promising framework for developing high quality and easy accessible toxicity data repositories. This paper also identifies important research directions that require further investigation in this area. PMID:21752279

[The development of the methods for the determination of nickel and its urine levels by inversion voltamperometry].

PubMed

Antoshina, L I; Pavlovskaia, N A

1999-01-01

The authors created a method detecting nickel through inversion voltamperometry by Russian analyzer CVA = 1BM. The method is diagnostic in hygienic, clinical and toxicologic studies for measuring quantity of nickel that enters human body during occupational activities.

National Toxicology Program

MedlinePlus

... develops and applies tools of modern toxicology and molecular biology to identify substances in the environment that may ... application of new technologies for modern toxicology and molecular biology. A world leader in toxicology research, NTP has ...

Toxicology and methods of committing suicide other than overdose.

PubMed

Coklo, Miran; Stemberga, Valter; Cuculic, Drazen; Sosa, Ivan; Bosnar, Alan

2009-11-01

Suicide represents a serious public health problem throughout the world. Toxicology plays a crucial role in the investigation of suicide. Psychoactive substances are recognized in the literature as the main suicide-generating stimuli. Ethanol is known to produce disinhibition and increased self-confidence. Other psychoactive substances can predominantly be central nervous system (CNS) stimulants or depressors. In cases of overdose as a method of suicide, the link between toxicology and the method of suicide is a matter of common sense and requires no additional explanation. On the other hand, in cases of non-overdose suicides this link is much more complex, and has not yet been extensively elucidated. We hypothesize a close relationship between toxicology and the choice of the method of committing suicide other than overdose. Negative findings may reflect either poor prescribed drug compliance in psychiatric patients, or suggest the role of other (non-toxicological) suicide-generating stimuli. On the other hand, positive findings influence the choice of the suicide method in a way that it depends on the prevalence of either stimulation or depression of the CNS, and consequent degree of behavioral aggression. Simplified, if the prevailing effect is CNS stimulation (with an increase in aggression), the method would be more drastic and more immediately fatal one, while with the CNS depression the method would be less immediately fatal and less drastic. There are only a few studies on the prevalence of psychoactive substances amongst completed suicides and even fewer studies have attempted to examine the relationship between substances used and the circumstances surrounding suicide. In evaluation of our hypothesis, we suggest thorough studies of toxicology and the choice of methods of committing suicides other than overdose. The scientific knowledge gained this way will eventually make toxicology a useful target in suicide prevention, especially amongst younger population.

A Multi-Stakeholder Perspective on the Use of Alternative Test Strategies for Nanomaterial Safety Assessment

PubMed Central

Nel, Andre E.; Nasser, Elina; Godwin, Hilary; Avery, David; Bahadori, Tina; Bergeson, Lynn; Beryt, Elizabeth; Bonner, James C.; Boverhof, Darrell; Carter, Janet; Castranova, Vince; DeShazo, J. R.; Hussain, Saber M.; Kane, Agnes B.; Klaessig, Fred; Kuempel, Eileen; Lafranconi, Mark; Landsiedel, Robert; Malloy, Timothy; Miller, Mary Beth; Morris, Jeffery; Moss, Kenneth; Oberdorster, Gunter; Pinkerton, Kent; Pleus, Richard C.; Shatkin, Jo Anne; Thomas, Rusty; Tolaymat, Thabet; Wang, Amy; Wong, Jeffrey

2014-01-01

There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis. PMID:23924032

Toxicology in Asia--Past, present, and future.

PubMed

Satoh, T

2015-12-01

The Asian Society of Toxicology (ASIATOX), which consists of the seven national toxicology member societies of Japan, Korea, China, Taiwan, Thailand, Singapore, and Iran, now boasts of more than 3,000 members from a variety of industries, academia, and regulatory organizations. ASIATOX congresses are spaced three years apart and rotated among the member societies. In 1995, ASIATOX joined the International Union of Toxicology (IUTOX) as a regional society, and now serves as the scientific voice of toxicology in Asia under the IUTOX umbrella. Since its inauguration, the society has worked diligently to handle matters deemed essential to promoting the vision set fourth by its founders. Future perspectives of ASIATOX include the establishment of education and training programs, and the certification and accreditation of toxicologists. As the leading voice of toxicology in Asia, the society seeks to extend knowledge of toxicological issues to developing nations in Asia based on the following missions and goals: (1) to provide leadership as a worldwide scientific organization that objectively addresses global issues involving the toxicological sciences, (2) to broaden the geographical base of toxicology as a discipline and profession to all countries of the world, and (3) to pursue capacity building in toxicology, particularly in developing countries, while utilizing its global perspective and network to contribute to the enhancement of toxicology education and the career development of young toxicologists. © The Author(s) 2015.

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

Wassom, John S.; Malling, Heinrich V.; Sankaranarayanan, K.

This article traces the development of the field of mutagenesis and its metamorphosis into the research area we now call genetic toxicology. In 1969 this transitional event led to the founding of the Environmental Mutagen Society (EMS). The charter of this new Society was to encourage interest in and study of mutagens in the human environment, particularly as these may be of concern to public health. As the mutagenesis field unfolded and expanded, the lexicon changed and new wording appeared to better describe this evolving area of research. The term genetic toxicology was coined and became an important subspecialty ofmore » the broad area of toxicology. Genetic toxicology is now set for a thorough reappraisal of its methods, goals, and priorities to meet the challenges of the 21st Century. To better understand these challenges, we have revisited the primary goal that the EMS founders had in mind for the Society s main mission and objective, namely, the quantitative assessment of genetic (hereditary) risks to human populations exposed to environmental agents. We also have reflected upon some of the seminal events over the last 40 years that have influenced the advancement of the genetic toxicology discipline and the extent to which the Society s major goal and allied objectives have been achieved. Additionally, we have provided suggestions on how EMS can further advance the science of genetic toxicology in the postgenome era. Chronicling all events and publications that influenced the development of the mutagenesis and genetic toxicology research area for this article was not possible, but some key happenings that contributed to the field s development have been reviewed. Events that led to the origin of EMS are also presented in celebration of the Society s 40th anniversary. Any historical accounting will have perceived deficiencies. Key people, publications, or events that some readers may feel have had significant impact on development of the subject under review may have been overlooked and left out. We are sure that such will be the case with the appraisal given in this article. However, any oversight or failure to make proper acknowledgment of individuals, events, or the citation of relevant references is unintentional.« less

Methods for the Compilation of a Core List of Journals in Toxicology.

ERIC Educational Resources Information Center

Kuch, T. D. C.

Previously reported methods for the compilation of core lists of journals in multidisciplinary areas are first examined, with toxicology used as an example of such an area. Three approaches to the compilation of a core list of journals in toxicology were undertaken and the results analyzed with the aid of models. Analysis of the results of the…

Pollinator Risk Assessment: an International Workshop

EPA Pesticide Factsheets

This 2011 Society of Environmental Toxicology and Chemistry (SETAC) workshop brought together statisticians, bee biologists, modelers, beekeepers, risk assessors and risk managers to develop exposure measurement methods and identify pesticide effects.

Advancing Systematic Review Workshop (December 2015)

EPA Pesticide Factsheets

EPA hosted an event to examine the systematic review process for development and applications of methods for different types of evidence (epidemiology, animal toxicology, and mechanistic). The presentations are also available.

METHODS FOR MONITORING THE EFFECTS OF ENVIRONMENTAL TOXINS ON THE VISUAL SYSTEM.

EPA Science Inventory

A high percentage of neurotoxic compounds adversely effect the visual system. Our goal is to apply the tools of vision science to problems of toxicological import, exposure-related alterations in visual physiology, psychophysical function, and ocular development. Methods can ...

ACToR A Aggregated Computational Toxicology Resource

EPA Science Inventory

We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology.

ACToR A Aggregated Computational Toxicology Resource (S)

EPA Science Inventory

We are developing the ACToR system (Aggregated Computational Toxicology Resource) to serve as a repository for a variety of types of chemical, biological and toxicological data that can be used for predictive modeling of chemical toxicology.

Emerging approaches in predictive toxicology.

PubMed

Zhang, Luoping; McHale, Cliona M; Greene, Nigel; Snyder, Ronald D; Rich, Ivan N; Aardema, Marilyn J; Roy, Shambhu; Pfuhler, Stefan; Venkatactahalam, Sundaresan

2014-12-01

Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. © 2014 Wiley Periodicals, Inc.

Emerging Approaches in Predictive Toxicology

PubMed Central

Zhang, Luoping; McHale, Cliona M.; Greene, Nigel; Snyder, Ronald D.; Rich, Ivan N.; Aardema, Marilyn J.; Roy, Shambhu; Pfuhler, Stefan; Venkatactahalam, Sundaresan

2016-01-01

Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. PMID:25044351

[The analysis of the articles concerning toxicological (forensic) chemistry published in the journal "Sudebno-meditsinskaya ekspertiza (Forensic Medical Expertise)" during the period from 2004 to 2013. Part 2. The analysis and assessment of the publications, peculiarities of the development of investigations].

PubMed

Orlova, A M

2016-01-01

The author presents the results of the analysis of the publications concerning toxicological (forensic) chemistry issues published in the journal "Sudebno-meditsinskaya ekspertiza" during the period from 2004 to 2013 with their assessment making use of scientometrical methods. Special emphasis is laid on the publications devoted to the development and improvement of the approaches to the investigation into narcotic and psychotropic drugs as well as other toxic substances. Specific features of such investigations are described.

Tox21 Enricher: Web-based Chemical/Biological Functional Annotation Analysis Tool Based on Tox21 Toxicity Screening Platform.

PubMed

Hur, Junguk; Danes, Larson; Hsieh, Jui-Hua; McGregor, Brett; Krout, Dakota; Auerbach, Scott

2018-05-01

The US Toxicology Testing in the 21st Century (Tox21) program was established to develop more efficient and human-relevant toxicity assessment methods. The Tox21 program screens >10,000 chemicals using quantitative high-throughput screening (qHTS) of assays that measure effects on toxicity pathways. To date, more than 70 assays have yielded >12 million concentration-response curves. The patterns of activity across assays can be used to define similarity between chemicals. Assuming chemicals with similar activity profiles have similar toxicological properties, we may infer toxicological properties based on its neighbourhood. One approach to inference is chemical/biological annotation enrichment analysis. Here, we present Tox21 Enricher, a web-based chemical annotation enrichment tool for the Tox21 toxicity screening platform. Tox21 Enricher identifies over-represented chemical/biological annotations among lists of chemicals (neighbourhoods), facilitating the identification of the toxicological properties and mechanisms in the chemical set. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel Methods for Mosquito Control using RNAi.

USDA-ARS?s Scientific Manuscript database

The discovery and development of novel insecticides for vector control is a primary focus of toxicology research conducted at the Mosquito and Fly Research Unit, Gainesville, FL. Targeting critical genes/proteins in mosquitoes using RNA interference (RNAi) is being investigated as a method to devel...

Stem cell-derived systems in toxicology assessment.

PubMed

Suter-Dick, Laura; Alves, Paula M; Blaauboer, Bas J; Bremm, Klaus-Dieter; Brito, Catarina; Coecke, Sandra; Flick, Burkhard; Fowler, Paul; Hescheler, Jürgen; Ingelman-Sundberg, Magnus; Jennings, Paul; Kelm, Jens M; Manou, Irene; Mistry, Pratibha; Moretto, Angelo; Roth, Adrian; Stedman, Donald; van de Water, Bob; Beilmann, Mario

2015-06-01

Industrial sectors perform toxicological assessments of their potential products to ensure human safety and to fulfill regulatory requirements. These assessments often involve animal testing, but ethical, cost, and time concerns, together with a ban on it in specific sectors, make appropriate in vitro systems indispensable in toxicology. In this study, we summarize the outcome of an EPAA (European Partnership of Alternatives to Animal Testing)-organized workshop on the use of stem cell-derived (SCD) systems in toxicology, with a focus on industrial applications. SCD systems, in particular, induced pluripotent stem cell-derived, provide physiological cell culture systems of easy access and amenable to a variety of assays. They also present the opportunity to apply the vast repository of existing nonclinical data for the understanding of in vitro to in vivo translation. SCD systems from several toxicologically relevant tissues exist; they generally recapitulate many aspects of physiology and respond to toxicological and pharmacological interventions. However, focused research is necessary to accelerate implementation of SCD systems in an industrial setting and subsequent use of such systems by regulatory authorities. Research is required into the phenotypic characterization of the systems, since methods and protocols for generating terminally differentiated SCD cells are still lacking. Organotypical 3D culture systems in bioreactors and microscale tissue engineering technologies should be fostered, as they promote and maintain differentiation and support coculture systems. They need further development and validation for their successful implementation in toxicity testing in industry. Analytical measures also need to be implemented to enable compound exposure and metabolism measurements for in vitro to in vivo extrapolation. The future of SCD toxicological tests will combine advanced cell culture technologies and biokinetic measurements to support regulatory and research applications. However, scientific and technical hurdles must be overcome before SCD in vitro methods undergo appropriate validation and become accepted in the regulatory arena.

Translational toxicology: a developmental focus for integrated research strategies.

PubMed

Hughes, Claude; Waters, Michael; Allen, David; Obasanjo, Iyabo

2013-09-30

Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of "translational toxicology" be taken to mean? Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures.The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan; 2) Defining modes of action and relevance of data from animal models; 3) Use of mathematical models to develop plausible predictions as the basis for: 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics.

Postmortem aviation forensic toxicology: an overview.

PubMed

Chaturvedi, Arvind K

2010-05-01

An overview of the subtopic aviation combustion toxicology of the field of aerospace toxicology has been published. In a continuation of the overview, the findings associated with postmortem aviation forensic toxicology are being summarized in the present overview. A literature search for the period of 1960-2007 was performed. The important findings related to postmortem toxicology were evaluated. In addition to a brief introduction, this overview is divided into the sections of analytical methods; carboxyhemoglobin and blood cyanide ion; ethanol; drugs; result interpretation; glucose and hemoglobin A(1c); and references. Specific details of the subject matter were discussed. It is anticipated that this overview will be an outline source for aviation forensic toxicology within the field of aerospace toxicology.

Underestimating the toxicological challenges associated with the use of herbal medicinal products in developing countries.

PubMed

Neergheen-Bhujun, Vidushi S

2013-01-01

Various reports suggest a high contemporaneous prevalence of herb-drug use in both developed and developing countries. The World Health Organisation indicates that 80% of the Asian and African populations rely on traditional medicine as the primary method for their health care needs. Since time immemorial and despite the beneficial and traditional roles of herbs in different communities, the toxicity and herb-drug interactions that emanate from this practice have led to severe adverse effects and fatalities. As a result of the perception that herbal medicinal products have low risk, consumers usually disregard any association between their use and any adverse reactions hence leading to underreporting of adverse reactions. This is particularly common in developing countries and has led to a paucity of scientific data regarding the toxicity and interactions of locally used traditional herbal medicine. Other factors like general lack of compositional and toxicological information of herbs and poor quality of adverse reaction case reports present hurdles which are highly underestimated by the population in the developing world. This review paper addresses these toxicological challenges and calls for natural health product regulations as well as for protocols and guidance documents on safety and toxicity testing of herbal medicinal products.

75 FR 57027 - National Toxicology Program (NTP); NTP Interagency Center for the Evaluation of Alternative...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-17

... for the Evaluation of Alternative Toxicological Methods (NICEATM); Availability of Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Test Method Evaluation Reports: In Vitro Ocular Safety Testing Methods and Strategies, and Routine Use of Topical Anesthetics, Systemic...

Evolving the Principles and Practice of Validation for New Alternative Approaches to Toxicity Testing.

PubMed

Whelan, Maurice; Eskes, Chantra

Validation is essential for the translation of newly developed alternative approaches to animal testing into tools and solutions suitable for regulatory applications. Formal approaches to validation have emerged over the past 20 years or so and although they have helped greatly to progress the field, it is essential that the principles and practice underpinning validation continue to evolve to keep pace with scientific progress. The modular approach to validation should be exploited to encourage more innovation and flexibility in study design and to increase efficiency in filling data gaps. With the focus now on integrated approaches to testing and assessment that are based on toxicological knowledge captured as adverse outcome pathways, and which incorporate the latest in vitro and computational methods, validation needs to adapt to ensure it adds value rather than hinders progress. Validation needs to be pursued both at the method level, to characterise the performance of in vitro methods in relation their ability to detect any association of a chemical with a particular pathway or key toxicological event, and at the methodological level, to assess how integrated approaches can predict toxicological endpoints relevant for regulatory decision making. To facilitate this, more emphasis needs to be given to the development of performance standards that can be applied to classes of methods and integrated approaches that provide similar information. Moreover, the challenge of selecting the right reference chemicals to support validation needs to be addressed more systematically, consistently and in a manner that better reflects the state of the science. Above all however, validation requires true partnership between the development and user communities of alternative methods and the appropriate investment of resources.

Student Preferences Regarding Teaching Methods in a Drug-Induced Diseases and Clinical Toxicology Course

PubMed Central

Gim, Suzanna

2013-01-01

Objectives. To determine which teaching method in a drug-induced diseases and clinical toxicology course was preferred by students and whether their preference correlated with their learning of drug-induced diseases. Design. Three teaching methods incorporating active-learning exercises were implemented. A survey instrument was developed to analyze students’ perceptions of the active-learning methods used and how they compared to the traditional teaching method (lecture). Examination performance was then correlated to students’ perceptions of various teaching methods. Assessment. The majority of the 107 students who responded to the survey found traditional lecture significantly more helpful than active-learning methods (p=0.01 for all comparisons). None of the 3 active-learning methods were preferred over the others. No significant correlations were found between students’ survey responses and examination performance. Conclusions. Students preferred traditional lecture to other instructional methods. Learning was not influenced by the teaching method or by preference for a teaching method. PMID:23966726

Chemical and toxicological characterization of commercial smokeless tobacco products available on the Canadian market.

PubMed

Rickert, W S; Joza, P J; Trivedi, A H; Momin, R A; Wagstaff, W G; Lauterbach, J H

2009-03-01

Some health experts are recommending that smokers who refuse to quit or refuse to use nicotine replacement therapy (NRT) such as nicotine-containing chewing gum switch to certain types of smokeless tobacco products (STP) such as Swedish snus. Other health experts disagree citing the uncertainty in the composition of commercially available STP, the lack of governmental regulations to ensure that STP advertised to meet certain standards (i.e., GothiaTek) do actually meet such standards, and the uncertainty that any STP can provide as safe as alternative to smoking as NRT. One reason for uncertainty is the dearth of detailed chemical and toxicological information on contemporary STP. Unlike the situation with cigarettes, there are few standardized methods for analytical and toxicological studies of STP. Consequently, the objective for this work was to characterize several types of STP available on the Canadian market using the modifications of the Official Health Canada chemical and toxicological methods developed for cigarettes. Moist snuff samples tested had TSNA and B[a]P levels somewhat above the GothiaTek standard while samples of Swedish snus, low-moisture snuff, and US-style chewing tobacco did not. Use of in vitro assays to assess STP toxicity was of limited utility in distinguishing product types.

Nails in Forensic Toxicology: An Update.

PubMed

Solimini, Renata; Minutillo, Adele; Kyriakou, Chrystalla; Pichini, Simona; Pacifici, Roberta; Busardo, Francesco Paolo

2017-01-01

The analysis of nails as a keratinized matrix to detect drugs or illicit substances has been increasingly used in forensic and clinical toxicology as a complementary test, especially for the specific characteristics of stably accumulating substances for long periods of time. This allows a retrospective investigation of chronic drug abuse, monitoring continuous drug or pharmaceutical use, reveal in utero drug exposure or environmental exposures. We herein review the recent literature investigating drug incorporation mechanisms and drug detection in nails for forensic toxicological purposes. Mechanisms of drug incorporation have not yet been fully elucidated. However, some research has lately contributed to a better understanding of how substances are incorporated into nails, suggesting three potential mechanisms of drug incorporation: contamination from sweat, incorporation from nail bed and incorporation from germinal matrix. In addition, numerous methods dealing with the determination of drugs of abuse, medications and alcohol biomarkers in nails have been reported in studies over the years. The latter methods could find application in clinical and forensic toxicology. The studies herein reviewed point out how important it is to standardize and harmonize the methodologies (either pre-analytical or analytical) for nails analysis and the optimization of sampling as well as the development of proficiency testing programs and the determination of cut-off values. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Development of novel in silico model for developmental toxicity assessment by using naïve Bayes classifier method.

PubMed

Zhang, Hui; Ren, Ji-Xia; Kang, Yan-Li; Bo, Peng; Liang, Jun-Yu; Ding, Lan; Kong, Wei-Bao; Zhang, Ji

2017-08-01

Toxicological testing associated with developmental toxicity endpoints are very expensive, time consuming and labor intensive. Thus, developing alternative approaches for developmental toxicity testing is an important and urgent task in the drug development filed. In this investigation, the naïve Bayes classifier was applied to develop a novel prediction model for developmental toxicity. The established prediction model was evaluated by the internal 5-fold cross validation and external test set. The overall prediction results for the internal 5-fold cross validation of the training set and external test set were 96.6% and 82.8%, respectively. In addition, four simple descriptors and some representative substructures of developmental toxicants were identified. Thus, we hope the established in silico prediction model could be used as alternative method for toxicological assessment. And these obtained molecular information could afford a deeper understanding on the developmental toxicants, and provide guidance for medicinal chemists working in drug discovery and lead optimization. Copyright © 2017 Elsevier Inc. All rights reserved.

OpenTox predictive toxicology framework: toxicological ontology and semantic media wiki-based OpenToxipedia

PubMed Central

2012-01-01

Background The OpenTox Framework, developed by the partners in the OpenTox project (http://www.opentox.org), aims at providing a unified access to toxicity data, predictive models and validation procedures. Interoperability of resources is achieved using a common information model, based on the OpenTox ontologies, describing predictive algorithms, models and toxicity data. As toxicological data may come from different, heterogeneous sources, a deployed ontology, unifying the terminology and the resources, is critical for the rational and reliable organization of the data, and its automatic processing. Results The following related ontologies have been developed for OpenTox: a) Toxicological ontology – listing the toxicological endpoints; b) Organs system and Effects ontology – addressing organs, targets/examinations and effects observed in in vivo studies; c) ToxML ontology – representing semi-automatic conversion of the ToxML schema; d) OpenTox ontology– representation of OpenTox framework components: chemical compounds, datasets, types of algorithms, models and validation web services; e) ToxLink–ToxCast assays ontology and f) OpenToxipedia community knowledge resource on toxicology terminology. OpenTox components are made available through standardized REST web services, where every compound, data set, and predictive method has a unique resolvable address (URI), used to retrieve its Resource Description Framework (RDF) representation, or to initiate the associated calculations and generate new RDF-based resources. The services support the integration of toxicity and chemical data from various sources, the generation and validation of computer models for toxic effects, seamless integration of new algorithms and scientifically sound validation routines and provide a flexible framework, which allows building arbitrary number of applications, tailored to solving different problems by end users (e.g. toxicologists). Availability The OpenTox toxicological ontology projects may be accessed via the OpenTox ontology development page http://www.opentox.org/dev/ontology; the OpenTox ontology is available as OWL at http://opentox.org/api/1 1/opentox.owl, the ToxML - OWL conversion utility is an open source resource available at http://ambit.svn.sourceforge.net/viewvc/ambit/branches/toxml-utils/ PMID:22541598

OpenTox predictive toxicology framework: toxicological ontology and semantic media wiki-based OpenToxipedia.

PubMed

Tcheremenskaia, Olga; Benigni, Romualdo; Nikolova, Ivelina; Jeliazkova, Nina; Escher, Sylvia E; Batke, Monika; Baier, Thomas; Poroikov, Vladimir; Lagunin, Alexey; Rautenberg, Micha; Hardy, Barry

2012-04-24

The OpenTox Framework, developed by the partners in the OpenTox project (http://www.opentox.org), aims at providing a unified access to toxicity data, predictive models and validation procedures. Interoperability of resources is achieved using a common information model, based on the OpenTox ontologies, describing predictive algorithms, models and toxicity data. As toxicological data may come from different, heterogeneous sources, a deployed ontology, unifying the terminology and the resources, is critical for the rational and reliable organization of the data, and its automatic processing. The following related ontologies have been developed for OpenTox: a) Toxicological ontology - listing the toxicological endpoints; b) Organs system and Effects ontology - addressing organs, targets/examinations and effects observed in in vivo studies; c) ToxML ontology - representing semi-automatic conversion of the ToxML schema; d) OpenTox ontology- representation of OpenTox framework components: chemical compounds, datasets, types of algorithms, models and validation web services; e) ToxLink-ToxCast assays ontology and f) OpenToxipedia community knowledge resource on toxicology terminology.OpenTox components are made available through standardized REST web services, where every compound, data set, and predictive method has a unique resolvable address (URI), used to retrieve its Resource Description Framework (RDF) representation, or to initiate the associated calculations and generate new RDF-based resources.The services support the integration of toxicity and chemical data from various sources, the generation and validation of computer models for toxic effects, seamless integration of new algorithms and scientifically sound validation routines and provide a flexible framework, which allows building arbitrary number of applications, tailored to solving different problems by end users (e.g. toxicologists). The OpenTox toxicological ontology projects may be accessed via the OpenTox ontology development page http://www.opentox.org/dev/ontology; the OpenTox ontology is available as OWL at http://opentox.org/api/1 1/opentox.owl, the ToxML - OWL conversion utility is an open source resource available at http://ambit.svn.sourceforge.net/viewvc/ambit/branches/toxml-utils/

76 FR 29752 - Nomination of In Vitro Test Methods for Detection and Quantification of Botulinum Neurotoxins and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-23

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Nomination of In Vitro Test Methods for Detection and... Evaluated by These Test Methods AGENCY: Division of National Toxicology Program (NTP), National Institute of... Methods (ICCVAM), the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods...

Assessing the scientific research productivity of a leading toxicology journal: A case study of Human & Experimental Toxicology from 2003 to 2012.

PubMed

Zyoud, Sa'ed H; Al-Jabi, Samah W; Sweileh, Waleed M; Awang, Rahmat

2014-01-01

Bibliometric studies are increasingly being used for research assessments. Bibliometric indicators involve the application of statistical methods to scientific publications to obtain the bibliographics for each journal. The main objective of this study was to conduct a bibliometric evaluation of Human & Experimental Toxicology retrieved from the Scopus database. This study obtained data from Scopus published from 1 January 2003 till 31 December 2012. The keywords entered in Scopus to accomplish the objective of this study were 'Human', 'Experimental' and 'Toxicology' as 'Source Title'. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analysing (a) total and trends in Human & Experimental Toxicology contributions in research between 2003 and 2012; (b) Human & Experimental Toxicology authorship patterns and productivity; (c) collaboration patterns; and (d) the citations received by the publications. There were 1229 research articles published in Human & Experimental Toxicology. Of the articles included, 947 (77.1%) were original articles and 104 (8.5%) were review articles. The Hirsch-index of the retrieved documents was 35. The largest number of publications in Human & Experimental Toxicology was from the United States (19.6%), followed by India (12.8%) and Turkey (10.9%). The total number of citations was 9119, with a median (interquartile range) of 3 (1-9) in 6797 documents. The highest median (interquartile range) number of citations was 8 (2.7-12.7) for France, followed by 7.5 (2-22.5) for Iran and 6 (3-13.5) for the United Kingdom. The country most often citing articles that were published in Human & Experimental Toxicology was the United States, which made citations in 1508 documents, followed by India with citations in 792 documents. The documents in Human & Experimental Toxicology focus principally on original data, with very few review articles. Review articles tend to have higher citation rates than original articles, and hence, the editors and authors of Human & Experimental Toxicology might usefully promote the submission of reviews in the future to improve the impact of the journal.

Agent-Based Multicellular Modeling for Predictive Toxicology

EPA Science Inventory

Biological modeling is a rapidly growing field that has benefited significantly from recent technological advances, expanding traditional methods with greater computing power, parameter-determination algorithms, and the development of novel computational approaches to modeling bi...

A practice analysis of toxicology.

PubMed

Wood, Carol S; Weis, Christopher P; Caro, Carla M; Roe, Amy

2016-12-01

In 2015, the American Board of Toxicology (ABT), with collaboration from the Society of Toxicology (SOT), in consultation with Professional Examination Service, performed a practice analysis study of the knowledge required for general toxicology. The purpose of this study is to help assure that the examination and requirements for attainment of Diplomate status are relevant to modern toxicology and based upon an empirical foundation of knowledge. A profile of the domains and tasks used in toxicology practice was developed by subject-matter experts representing a broad range of experiences and perspectives. An on-line survey of toxicologists, including Diplomates of the ABT and SOT members, confirmed the delineation. Results of the study can be used to improve understanding of toxicology practice, to better serve all toxicologists, and to present the role of toxicologists to those outside the profession. Survey results may also be used by the ABT Board of Directors to develop test specifications for the certifying examination and will be useful for evaluating and updating the content of professional preparation, development, and continuing education programs. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Locally Weighted Learning Methods for Predicting Dose-Dependent Toxicity with Application to the Human Maximum Recommended Daily Dose

DTIC Science & Technology

2012-09-10

Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, United States ABSTRACT: Toxicological ...species. Thus, it is more advantageous to predict the toxicological effects of a compound on humans directly from the human toxicological data of related...compounds. However, many popular quantitative structure−activity relationship ( QSAR ) methods that build a single global model by fitting all training

The current status of alternatives to animal testing and predictive toxicology methods using liver microfluidic biochips.

PubMed

Prot, Jean Matthieu; Leclerc, Eric

2012-06-01

In this paper, we will consider new in vitro cell culture platforms and the progress made, based on the microfluidic liver biochips dedicated to pharmacological and toxicological studies. Particular emphasis will be given to recent developments in the microfluidic tools dedicated to cell culture (more particularly liver cell culture), in silico opportunities for Physiologically Based PharmacoKinetic (PBPK) modelling, the challenge of the mechanistic interpretations offered by the approaches resulting from "multi-omics" data (transcriptomics, proteomics, metabolomics, cytomics) and imaging microfluidic platforms. Finally, we will discuss the critical features regarding microfabrication, design and materials, and cell functionality as the key points for the future development of new microfluidic liver biochips.

The current role of on-line extraction approaches in clinical and forensic toxicology.

PubMed

Mueller, Daniel M

2014-08-01

In today's clinical and forensic toxicological laboratories, automation is of interest because of its ability to optimize processes, to reduce manual workload and handling errors and to minimize exposition to potentially infectious samples. Extraction is usually the most time-consuming step; therefore, automation of this step is reasonable. Currently, from the field of clinical and forensic toxicology, methods using the following on-line extraction techniques have been published: on-line solid-phase extraction, turbulent flow chromatography, solid-phase microextraction, microextraction by packed sorbent, single-drop microextraction and on-line desorption of dried blood spots. Most of these published methods are either single-analyte or multicomponent procedures; methods intended for systematic toxicological analysis are relatively scarce. However, the use of on-line extraction will certainly increase in the near future.

77 FR 35393 - Biennial Progress Report of the Interagency Coordinating Committee on the Validation of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-13

... Committee on the Validation of Alternative Methods (ICCVAM) AGENCY: Division of the National Toxicology... Alternative Toxicological Methods (NICEATM) announces the availability of the Biennial Progress Report 2010-2011: Interagency Coordinating Committee on the Validation of Alternative Methods. The report was...

Combining exposure and effect modeling into an integrated probabilistic environmental risk assessment for nanoparticles.

PubMed

Jacobs, Rianne; Meesters, Johannes A J; Ter Braak, Cajo J F; van de Meent, Dik; van der Voet, Hilko

2016-12-01

There is a growing need for good environmental risk assessment of engineered nanoparticles (ENPs). Environmental risk assessment of ENPs has been hampered by lack of data and knowledge about ENPs, their environmental fate, and their toxicity. This leads to uncertainty in the risk assessment. To deal with uncertainty in the risk assessment effectively, probabilistic methods are advantageous. In the present study, the authors developed a method to model both the variability and the uncertainty in environmental risk assessment of ENPs. This method is based on the concentration ratio and the ratio of the exposure concentration to the critical effect concentration, both considered to be random. In this method, variability and uncertainty are modeled separately so as to allow the user to see which part of the total variation in the concentration ratio is attributable to uncertainty and which part is attributable to variability. The authors illustrate the use of the method with a simplified aquatic risk assessment of nano-titanium dioxide. The authors' method allows a more transparent risk assessment and can also direct further environmental and toxicological research to the areas in which it is most needed. Environ Toxicol Chem 2016;35:2958-2967. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Toxicologic evaluation of analytes from Tank 241-C-103

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

Mahlum, D.D.; Young, J.Y.; Weller, R.E.

1994-11-01

Westinghouse Hanford Company requested PNL to assemble a toxicology review panel (TRP) to evaluate analytical data compiled by WHC, and provide advice concerning potential health effects associated with exposure to tank-vapor constituents. The team`s objectives would be to (1) review procedures used for sampling vapors from tanks, (2) identify constituents in tank-vapor samples that could be related to symptoms reported by workers, (3) evaluate the toxicological implications of those constituents by comparison to establish toxicological databases, (4) provide advice for additional analytical efforts, and (5) support other activities as requested by WHC. The TRP represents a wide range of expertise,more » including toxicology, industrial hygiene, and occupational medicine. The TRP prepared a list of target analytes that chemists at the Oregon Graduate Institute/Sandia (OGI), Oak Ridge National Laboratory (ORNL), and PNL used to establish validated methods for quantitative analysis of head-space vapors from Tank 241-C-103. this list was used by the analytical laboratories to develop appropriate analytical methods for samples from Tank 241-C-103. Target compounds on the list included acetone, acetonitrile, ammonia, benzene, 1, 3-butadiene, butanal, n-butanol, hexane, 2-hexanone, methylene chloride, nitric oxide, nitrogen dioxide, nitrous oxide, dodecane, tridecane, propane nitrile, sulfur oxide, tributyl phosphate, and vinylidene chloride. The TRP considered constituent concentrations, current exposure limits, reliability of data relative to toxicity, consistency of the analytical data, and whether the material was carcinogenic or teratogenic. A final consideration in the analyte selection process was to include representative chemicals for each class of compounds found.« less

Terminal Behavioral Objectives for Teaching Clinical Toxicology to Clinical Pharmacists

ERIC Educational Resources Information Center

Veltri, Joseph C.; And Others

1976-01-01

As a first step in the development of a competency-based clinical toxicology clerkship, a set of terminal behavioral objectives were developed that reflect the anticipated role that clinical pharmacists should play as part of the clinical toxicology team. The evaluation approaches used at the University of Utah are presented. (LBH)

Toxicology in the 21st Century (Tox21)

EPA Pesticide Factsheets

Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects.

Toxicology Testing in the 21st Century (Tox21)

EPA Pesticide Factsheets

Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects.

Automatic miniaturized fluorometric flow system for chemical and toxicological control of glibenclamide.

PubMed

Ribeiro, David S M; Prior, João A V; Taveira, Christian J M; Mendes, José M A F S; Santos, João L M

2011-06-15

In this work, and for the first time, it was developed an automatic and fast screening miniaturized flow system for the toxicological control of glibenclamide in beverages, with application in forensic laboratory investigations, and also, for the chemical control of commercially available pharmaceutical formulations. The automatic system exploited the multipumping flow (MPFS) concept and allowed the implementation of a new glibenclamide determination method based on the fluorometric monitoring of the drug in acidic medium (λ(ex)=301 nm; λ(em)=404 nm), in the presence of an anionic surfactant (SDS), promoting an organized micellar medium to enhance the fluorometric measurements. The developed approach assured good recoveries in the analysis of five spiked alcoholic beverages. Additionally, a good agreement was verified when comparing the results obtained in the determination of glibenclamide in five commercial pharmaceutical formulations by the proposed method and by the pharmacopoeia reference procedure. Copyright © 2011 Elsevier B.V. All rights reserved.

In silico toxicology protocols.

PubMed

Myatt, Glenn J; Ahlberg, Ernst; Akahori, Yumi; Allen, David; Amberg, Alexander; Anger, Lennart T; Aptula, Aynur; Auerbach, Scott; Beilke, Lisa; Bellion, Phillip; Benigni, Romualdo; Bercu, Joel; Booth, Ewan D; Bower, Dave; Brigo, Alessandro; Burden, Natalie; Cammerer, Zoryana; Cronin, Mark T D; Cross, Kevin P; Custer, Laura; Dettwiler, Magdalena; Dobo, Krista; Ford, Kevin A; Fortin, Marie C; Gad-McDonald, Samantha E; Gellatly, Nichola; Gervais, Véronique; Glover, Kyle P; Glowienke, Susanne; Van Gompel, Jacky; Gutsell, Steve; Hardy, Barry; Harvey, James S; Hillegass, Jedd; Honma, Masamitsu; Hsieh, Jui-Hua; Hsu, Chia-Wen; Hughes, Kathy; Johnson, Candice; Jolly, Robert; Jones, David; Kemper, Ray; Kenyon, Michelle O; Kim, Marlene T; Kruhlak, Naomi L; Kulkarni, Sunil A; Kümmerer, Klaus; Leavitt, Penny; Majer, Bernhard; Masten, Scott; Miller, Scott; Moser, Janet; Mumtaz, Moiz; Muster, Wolfgang; Neilson, Louise; Oprea, Tudor I; Patlewicz, Grace; Paulino, Alexandre; Lo Piparo, Elena; Powley, Mark; Quigley, Donald P; Reddy, M Vijayaraj; Richarz, Andrea-Nicole; Ruiz, Patricia; Schilter, Benoit; Serafimova, Rositsa; Simpson, Wendy; Stavitskaya, Lidiya; Stidl, Reinhard; Suarez-Rodriguez, Diana; Szabo, David T; Teasdale, Andrew; Trejo-Martin, Alejandra; Valentin, Jean-Pierre; Vuorinen, Anna; Wall, Brian A; Watts, Pete; White, Angela T; Wichard, Joerg; Witt, Kristine L; Woolley, Adam; Woolley, David; Zwickl, Craig; Hasselgren, Catrin

2018-07-01

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

76 FR 10906 - Proposed Substances To Be Evaluated for Set 25 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-28

...-269] Proposed Substances To Be Evaluated for Set 25 Toxicological Profiles AGENCY: Agency for Toxic... comments on the proposed substances to be evaluated for Set 25 toxicological profiles. SUMMARY: ATSDR is initiating the development of its 25th set of toxicological profiles (CERCLA Set 25). This notice announces...

78 FR 58548 - Request for Information: The National Toxicology Program Requests Information on Use, Human...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-24

... validate new and better testing methods. Other activities of the program focus on strengthening the science... National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS... FURTHER INFORMATION CONTACT: Dr. Inok Surh, Research Fellow, Toxicology Branch, Division of the NTP, NIH...

Aggregating Data for Computational Toxicology Applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System

EPA Science Inventory

Computational toxicology combines data from high-throughput test methods, chemical structure analyses and other biological domains (e.g., genes, proteins, cells, tissues) with the goals of predicting and understanding the underlying mechanistic causes of chemical toxicity and for...

Development of Practical Methods for Assessing the Chronic Toxicity of Effluents

EPA Science Inventory

This is a short introductory essay, invited as front matter to the journal "Environmental Toxicology and Chemistry". It was invited to provide an overview of the development of a previous article by the first author (when he was an EPA employee) which is being recognized as one ...

Developing Predictive Toxicity Signatures Using In Vitro Data from the EPA ToxCast Program

EPA Science Inventory

A major focus in toxicology research is the development of in vitro methods to predict in vivo chemical toxicity. Numerous studies have evaluated the use of targeted biochemical, cell-based and genomic assay approaches. Each of these techniques is potentially helpful, but provide...

Are we in the dark ages of environmental toxicology?

PubMed

McCarty, L S

2013-12-01

Environmental toxicity is judged to be in a "dark ages" period due to longstanding limitations in the implementation of the simple conceptual model that is the basis of current aquatic toxicity testing protocols. Fortunately, the environmental regulatory revolution of the last half-century is not substantially compromised as development of past regulatory guidance was designed to deal with limited amounts of relatively poor quality toxicity data. However, as regulatory objectives have substantially increased in breadth and depth, aquatic toxicity data derived with old testing methods are no longer adequate. In the near-term explicit model description and routine assumption validation should be mandatory. Updated testing methods could provide some improvements in toxicological data quality. A thorough reevaluation of toxicity testing objectives and methods resulting in substantially revised standard testing methods, plus a comprehensive scheme for classification of modes/mechanisms of toxic action, should be the long-term objective. Copyright © 2013 Elsevier Inc. All rights reserved.

High-resolution mass spectrometry in toxicology: current status and future perspectives.

PubMed

Maurer, H H; Meyer, Markus R

2016-09-01

This paper reviews high-resolution mass spectrometry (HRMS) approaches using time-of-flight or Orbitrap techniques for research and application in various toxicology fields, particularly in clinical toxicology and forensic toxicology published since 2013 and referenced in PubMed. In the introduction, an overview on applications of HRMS in various toxicology fields is given with reference to current review articles. Papers concerning HRMS in metabolism, screening, and quantification of pharmaceuticals, drugs of abuse, and toxins in human body samples are critically reviewed. Finally, a discussion on advantages as well as limitations and future perspectives of these methods is included.

Toxicology of chemical mixtures: Experimental approaches, underlying concepts, and some results

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

Yang, R.S.; Long, H.L.; Boorman, G.A.

1990-07-01

The toxicology of chemical mixtures will be the toxicology of the 1990s and beyond. While this branch of toxicology most closely reflects the actual human exposure situation, as yet there is no standard protocol or consensus methodology for investigating the toxicology of mixtures. Thus, in this emerging science, experimentation is required just to develop a broadly applicable evaluation system. Several examples are discussed to illustrate the different experimental designs and the concepts behind each. These include the health effects studies of Love Canal soil samples, the Lake Ontario Coho salmon, the water samples repurified from secondary sewage in the citymore » of Denver Potable Water Reuse Demonstration Plant, and the National Toxicology Program (NTP) effort on a mixture of 25 frequently detected groundwater contaminants derived from hazardous waste disposal sites. In the last instance, an extensive research program has been ongoing for the last two years at the NTP, encompassing general toxicology, immunotoxicology, developmental and reproductive toxicology, biochemical toxicology, myelotoxicology, genetic toxicology, neurobehavioral toxicology, and hepato- and renal toxicology.« less

Teaching Techniques in Clinical Chemistry.

ERIC Educational Resources Information Center

Wilson, Diane

This master's thesis presents several instructional methods and techniques developed for each of eleven topics or subject areas in clinical chemistry: carbohydrate metabolism, lipid metabolism, diagnostic enzymology, endocrinology, toxicology, quality control, electrolytes, acid base balance, hepatic function, nonprotein nitrogenous compounds, and…

A Hierarchical Clustering Methodology for the Estimation of Toxicity

EPA Science Inventory

A Quantitative Structure Activity Relationship (QSAR) methodology based on hierarchical clustering was developed to predict toxicological endpoints. This methodology utilizes Ward's method to divide a training set into a series of structurally similar clusters. The structural sim...

EPAS TOXCAST PROGRAM FOR PREDICTING HAZARD AND PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS(S).

EPA Science Inventory

EPAs National Center for Computational Toxicology is developing methods that apply computational chemistry, high-throughput screening (HTS) and genomic technologies to predict potential toxicity and prioritize the use of limited testing resources.

A bibliometric analysis of toxicology research productivity in Middle Eastern Arab countries during a 10-year period (2003–2012)

PubMed Central

2014-01-01

Background Bibliometric studies are increasingly being used for research assessment by involving the application of statistical methods to scientific publications to obtain the bibliographics for each country. The main objective of this study was to analyse the research productivity originating from 13 Middle Eastern Arab (MEA) countries with articles published in toxicology journals. Methods Data from January 1, 2003 till December 31, 2012 were searched for documents with specific words in the toxicology field as a “source title” in any one of the 13 MEA countries. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product (GDP) per capita. Results Documents (n = 1,240) were retrieved from 73 international peer-reviewed toxicology journals. The h-index of the retrieved documents was 39. Of the 73 journal titles, 52 (69.9%) have their IF listed in the ISI Journal Citation Reports 2012; 198 documents (16.0%) were published in journals that had no official IF. After adjusting for economy and population power, Egypt (193.6), Palestine (18.1), Kingdom of Saudi Arabia (KSA) (13.0), and Jordan (11.5) had the highest research productivity. Countries with large economies, such as the Kuwait, United Arab Emirates (UAE), and Oman, tended to rank relatively low after adjustment of GDP. The total number of citations at the time of data analysis (August 4, 2013) was 10,991, with a median (interquartile range) of 4 (1–11). MEA collaborated more with countries in the MEA regions (16.7%), especially KSA, Egypt, and UAE, followed by Europe (14.4%), especially with the United Kingdom and Germany. Conclusions The present data show a promising rise and a good start for toxicology research activity in toxicology journals in the Arab world. Research output is low in some countries, which can be improved by investing in more international and national collaborative research projects in the field of toxicology. PMID:24443999

Toxicology: a discipline in need of academic anchoring--the point of view of the German Society of Toxicology.

PubMed

Gundert-Remy, U; Barth, H; Bürkle, A; Degen, G H; Landsiedel, R

2015-10-01

The paper describes the importance of toxicology as a discipline, its past achievements, current scientific challenges, and future development. Toxicological expertise is instrumental in the reduction of human health risks arising from chemicals and drugs. Toxicological assessment is needed to evaluate evidence and arguments, whether or not there is a scientific base for concern. The immense success already achieved by toxicological work is exemplified by reduced pollution of air, soil, water, and safer working places. Predominantly predictive toxicological testing is derived from the findings to assess risks to humans and the environment. Assessment of the adversity of molecular effects (including epigenetic effects), the effects of mixtures, and integration of exposure and biokinetics into in vitro testing are emerging challenges for toxicology. Toxicology is a translational science with its base in fundamental science. Academic institutions play an essential part by providing scientific innovation and education of young scientists.

An Integrated Chemical Environment to Support 21st-Century Toxicology.

PubMed

Bell, Shannon M; Phillips, Jason; Sedykh, Alexander; Tandon, Arpit; Sprankle, Catherine; Morefield, Stephen Q; Shapiro, Andy; Allen, David; Shah, Ruchir; Maull, Elizabeth A; Casey, Warren M; Kleinstreuer, Nicole C

2017-05-25

SUMMARY : Access to high-quality reference data is essential for the development, validation, and implementation of in vitro and in silico approaches that reduce and replace the use of animals in toxicity testing. Currently, these data must often be pooled from a variety of disparate sources to efficiently link a set of assay responses and model predictions to an outcome or hazard classification. To provide a central access point for these purposes, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods developed the Integrated Chemical Environment (ICE) web resource. The ICE data integrator allows users to retrieve and combine data sets and to develop hypotheses through data exploration. Open-source computational workflows and models will be available for download and application to local data. ICE currently includes curated in vivo test data, reference chemical information, in vitro assay data (including Tox21 TM /ToxCast™ high-throughput screening data), and in silico model predictions. Users can query these data collections focusing on end points of interest such as acute systemic toxicity, endocrine disruption, skin sensitization, and many others. ICE is publicly accessible at https://ice.ntp.niehs.nih.gov. https://doi.org/10.1289/EHP1759.

An Integrated Chemical Environment to Support 21st-Century Toxicology

PubMed Central

Bell, Shannon M.; Phillips, Jason; Sedykh, Alexander; Tandon, Arpit; Sprankle, Catherine; Morefield, Stephen Q.; Shapiro, Andy; Allen, David; Shah, Ruchir; Maull, Elizabeth A.; Casey, Warren M.

2017-01-01

Summary: Access to high-quality reference data is essential for the development, validation, and implementation of in vitro and in silico approaches that reduce and replace the use of animals in toxicity testing. Currently, these data must often be pooled from a variety of disparate sources to efficiently link a set of assay responses and model predictions to an outcome or hazard classification. To provide a central access point for these purposes, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods developed the Integrated Chemical Environment (ICE) web resource. The ICE data integrator allows users to retrieve and combine data sets and to develop hypotheses through data exploration. Open-source computational workflows and models will be available for download and application to local data. ICE currently includes curated in vivo test data, reference chemical information, in vitro assay data (including Tox21TM/ToxCast™ high-throughput screening data), and in silico model predictions. Users can query these data collections focusing on end points of interest such as acute systemic toxicity, endocrine disruption, skin sensitization, and many others. ICE is publicly accessible at https://ice.ntp.niehs.nih.gov. https://doi.org/10.1289/EHP1759 PMID:28557712

Aquatic toxicology: fact or fiction?

PubMed Central

Macek, K J

1980-01-01

A brief history of the development of the field of aquatic toxicology is provided. In order to provide a perspective on the state-of-the-art in aquatic toxicology relative to classical toxicology, the two fields are compared from the standpoint of the type of scientist practicing each field, the respective objectives of each, the forces which drive the activity in each field, and the major advantages and disadvantages accruing to the practitioner of aquatic toxicology as a result of the differences in objectives and driving forces. PMID:6993200

Molecular dynamics simulations and applications in computational toxicology and nanotoxicology.

PubMed

Selvaraj, Chandrabose; Sakkiah, Sugunadevi; Tong, Weida; Hong, Huixiao

2018-02-01

Nanotoxicology studies toxicity of nanomaterials and has been widely applied in biomedical researches to explore toxicity of various biological systems. Investigating biological systems through in vivo and in vitro methods is expensive and time taking. Therefore, computational toxicology, a multi-discipline field that utilizes computational power and algorithms to examine toxicology of biological systems, has gained attractions to scientists. Molecular dynamics (MD) simulations of biomolecules such as proteins and DNA are popular for understanding of interactions between biological systems and chemicals in computational toxicology. In this paper, we review MD simulation methods, protocol for running MD simulations and their applications in studies of toxicity and nanotechnology. We also briefly summarize some popular software tools for execution of MD simulations. Published by Elsevier Ltd.

Advancing alternatives analysis: The role of predictive toxicology in selecting safer chemical products and processes.

PubMed

Malloy, Timothy; Zaunbrecher, Virginia; Beryt, Elizabeth; Judson, Richard; Tice, Raymond; Allard, Patrick; Blake, Ann; Cote, Ila; Godwin, Hilary; Heine, Lauren; Kerzic, Patrick; Kostal, Jakub; Marchant, Gary; McPartland, Jennifer; Moran, Kelly; Nel, Andre; Ogunseitan, Oladele; Rossi, Mark; Thayer, Kristina; Tickner, Joel; Whittaker, Margaret; Zarker, Ken

2017-09-01

Alternatives analysis (AA) is a method used in regulation and product design to identify, assess, and evaluate the safety and viability of potential substitutes for hazardous chemicals. It requires toxicological data for the existing chemical and potential alternatives. Predictive toxicology uses in silico and in vitro approaches, computational models, and other tools to expedite toxicological data generation in a more cost-effective manner than traditional approaches. The present article briefly reviews the challenges associated with using predictive toxicology in regulatory AA, then presents 4 recommendations for its advancement. It recommends using case studies to advance the integration of predictive toxicology into AA, adopting a stepwise process to employing predictive toxicology in AA beginning with prioritization of chemicals of concern, leveraging existing resources to advance the integration of predictive toxicology into the practice of AA, and supporting transdisciplinary efforts. The further incorporation of predictive toxicology into AA would advance the ability of companies and regulators to select alternatives to harmful ingredients, and potentially increase the use of predictive toxicology in regulation more broadly. Integr Environ Assess Manag 2017;13:915-925. © 2017 SETAC. © 2017 SETAC.

Results of a Wildlife Toxicology Workshop held by the Smithsonian Institution ? Identification and prioritization of problem statements

USGS Publications Warehouse

Grim, K.C.; Fairbrother, A.; Monfort, S.; Tan, S.; Rattner, B.A.; Gerould, S.; Beasley, V.; Aguirre, A.; Rowles, T.

2007-01-01

On March 13-15, 2007 nearly 50 scientists and administrators from the US and Canada participated in a Smithsonian-sponsored Wildlife Toxicology Workshop. Invitees were from academic, government, conservation and the private organizations and were selected to represent the diverse disciplines that encompass wildlife toxicology. The workshop addressed scientific and policy issues, strengths and weaknesses of current research strategies, interdisciplinary and science-based approaches in the study of complex contaminant issues, mechanisms for disseminating data to policy-makers, and the development of a partner network to meet the challenges facing wildlife toxicology over the next decade. Prior to the meeting, participants were asked to submit issues they deemed to be of highest concern which shaped four thematic groups for discussion: Wildlife Toxicology in Education, Risk Assessment, Multiple Stressors/Complex Mixtures, and Sub-Lethal to Population-Level Effects. From these discussion groups, 18 problem statements were developed and prioritized outlining what were deemed the most important issues to address now and into the future. Along with each problem statement participants developed potential solutions and action steps geared to move each issue forward. The workshop served as a stepping stone for action in the field of wildlife toxicology. These problem statements and the resulting action items are presented to the inter-disciplinary wildlife toxicology community for adoption, and future work and action items in these areas are encouraged. The workshop outcome looks to generate conversation and collaboration that will lead to the development of innovative research, future mechanisms for funding, workshops, working groups, and listserves within the wildlife toxicology community.

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...

Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology

PubMed Central

Amemiya, Takahiro; Honma, Masashi; Kariya, Yoshiaki; Ghosh, Samik; Kitano, Hiroaki; Kurachi, Yoshihisa; Fujita, Ken-ichi; Sasaki, Yasutsuna; Homma, Yukio; Abernethy, Darrel R; Kume, Haruki; Suzuki, Hiroshi

2015-01-01

Background/Objectives: Targeted kinase inhibitors are an important class of agents in anticancer therapeutics, but their limited tolerability hampers their clinical performance. Identification of the molecular mechanisms underlying the development of adverse reactions will be helpful in establishing a rational method for the management of clinically adverse reactions. Here, we selected sunitinib as a model and demonstrated that the molecular mechanisms underlying the adverse reactions associated with kinase inhibitors can efficiently be identified using a systems toxicological approach. Methods: First, toxicological target candidates were short-listed by comparing the human kinase occupancy profiles of sunitinib and sorafenib, and the molecular mechanisms underlying adverse reactions were predicted by sequential simulations using publicly available mathematical models. Next, to evaluate the probability of these predictions, a clinical observation study was conducted in six patients treated with sunitinib. Finally, mouse experiments were performed for detailed confirmation of the hypothesized molecular mechanisms and to evaluate the efficacy of a proposed countermeasure against adverse reactions to sunitinib. Results: In silico simulations indicated the possibility that sunitinib-mediated off-target inhibition of phosphorylase kinase leads to the generation of oxidative stress in various tissues. Clinical observations of patients and mouse experiments confirmed the validity of this prediction. The simulation further suggested that concomitant use of an antioxidant may prevent sunitinib-mediated adverse reactions, which was confirmed in mouse experiments. Conclusions: A systems toxicological approach successfully predicted the molecular mechanisms underlying clinically adverse reactions associated with sunitinib and was used to plan a rational method for the management of these adverse reactions. PMID:28725458

4th Annual Predictive Toxicology Summit 2012.

PubMed

Cui, Zhanfeng

2013-08-01

This meeting report presents a brief summary on the 4th Annual Predictive Toxicology Summit 2012, which was held on 15 - 16 February 2012 in London. The majority of presentations came from global pharmaceutical companies, although small and medium enterprise (SME) and academic researchers were represented too. Major regulatory bodies were also present. The article highlights the summit, which was considered a good learning opportunity to catch up on the recent advances in predictive toxicology. Predictive toxicology has become more and more important due to social and economic pressure and scientific reasons. Technological developments are rapid, but there is a gulf between the technology developers and the pharmaceutical end users; hence, early engagement is desirable. Stem cell-derived cell-based assays as well as three-dimensional in vitro tissue/organ model development are within the reach now, but a lot needs to be done to optimise and validate the developed protocols and products. The field of predictive toxicology needs fundamental research of interdisciplinary nature, which requires much needed trained personnel and funding.

Genetic toxicology at the crossroads-from qualitative hazard evaluation to quantitative risk assessment.

PubMed

White, Paul A; Johnson, George E

2016-05-01

Applied genetic toxicology is undergoing a transition from qualitative hazard identification to quantitative dose-response analysis and risk assessment. To facilitate this change, the Health and Environmental Sciences Institute (HESI) Genetic Toxicology Technical Committee (GTTC) sponsored a workshop held in Lancaster, UK on July 10-11, 2014. The event included invited speakers from several institutions and the contents was divided into three themes-1: Point-of-departure Metrics for Quantitative Dose-Response Analysis in Genetic Toxicology; 2: Measurement and Estimation of Exposures for Better Extrapolation to Humans and 3: The Use of Quantitative Approaches in Genetic Toxicology for human health risk assessment (HHRA). A host of pertinent issues were discussed relating to the use of in vitro and in vivo dose-response data, the development of methods for in vitro to in vivo extrapolation and approaches to use in vivo dose-response data to determine human exposure limits for regulatory evaluations and decision-making. This Special Issue, which was inspired by the workshop, contains a series of papers that collectively address topics related to the aforementioned themes. The Issue includes contributions that collectively evaluate, describe and discuss in silico, in vitro, in vivo and statistical approaches that are facilitating the shift from qualitative hazard evaluation to quantitative risk assessment. The use and application of the benchmark dose approach was a central theme in many of the workshop presentations and discussions, and the Special Issue includes several contributions that outline novel applications for the analysis and interpretation of genetic toxicity data. Although the contents of the Special Issue constitutes an important step towards the adoption of quantitative methods for regulatory assessment of genetic toxicity, formal acceptance of quantitative methods for HHRA and regulatory decision-making will require consensus regarding the relationships between genetic damage and disease, and the concomitant ability to use genetic toxicity results per se. © Her Majesty the Queen in Right of Canada 2016. Reproduced with the permission of the Minister of Health.

Applications of Proteomic Technologies to Toxicology

EPA Science Inventory

Proteomics is the large-scale study of gene expression at the protein level. This cutting edge technology has been extensively applied to toxicology research recently. The up-to-date development of proteomics has presented the toxicology community with an unprecedented opportunit...

Refinement, Reduction, and Replacement of Animal Toxicity Tests by Computational Methods.

PubMed

Ford, Kevin A

2016-12-01

Widespread public and scientific interest in promoting the care and well-being of animals used for toxicity testing has given rise to improvements in animal welfare practices and views over time, as well as laws and regulations that support means to reduce, refine, and replace animal use (known as the 3Rs) in certain toxicity studies. One way these regulations continue to achieve their aim is by promoting the research, development, and application of alternative testing approaches to characterize potential toxicities either without animals or with minimal use. An important example of an alternative approach is the use of computational toxicology models. Along with the potential capacity to reduce or replace the use of animals for the assessment of particular toxicological endpoints, computational models offer several advantages compared to in vitro and in vivo approaches, including cost-effectiveness, rapid availability of results, and the ability to fully standardize procedures. Pharmaceutical research incorporating the use of computational models has increased steadily over the past 15 years, likely driven by the motivation of companies to screen out toxic compounds in the early stages of development. Models are currently available to aid in the prediction of several important toxicological endpoints, including mutagenicity, carcinogenicity, eye irritation, hepatotoxicity, and skin sensitization, albeit with varying degrees of success. This review serves to introduce the concepts of computational toxicology and evaluate their role in the safety assessment of compounds, while also highlighting the application of in silico methods in the support of the goal and vision of the 3Rs. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research.All rights reserved. For permissions, please email: journals.permissions@oup.com.

77 FR 35395 - Draft Five-Year Plan (2013-2017) for the National Toxicology Program Interagency Center for the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-13

... innovations are driving transformative changes in toxicology and how safety testing is performed. The field of toxicology is evolving from a system based largely on animal testing toward one based on the integration of... methods that protect human and animal health and the environment while reducing, refining (enhancing...

Design and validation of an ontology-driven animal-free testing strategy for developmental neurotoxicity testing.

PubMed

Hessel, Ellen V S; Staal, Yvonne C M; Piersma, Aldert H

2018-03-13

Developmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of fundamental processes in neural tube formation, brain development and neural specification, aiming at illustrating complexity rather than comprehensiveness. We also give a flavor of the wealth of alternative methods in this area. Given the impressive progress in mechanistic knowledge of human biology and toxicology, the time is right for a conceptual approach for designing testing strategies that cover the integral mechanistic landscape of developmental neurotoxicity. The ontology approach provides a framework for defining this landscape, upon which an integral in silico model for predicting toxicity can be built. It subsequently directs the selection of in vitro assays for rate-limiting events in the biological network, to feed parameter tuning in the model, leading to prediction of the toxicological outcome. Validation of such models requires primary attention to coverage of the biological domain, rather than classical predictive value of individual tests. Proofs of concept for such an approach are already available. The challenge is in mining modern biology, toxicology and chemical information to feed intelligent designs, which will define testing strategies for neurodevelopmental toxicity testing. Copyright © 2018 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.

[Development and Application of Metabonomics in Forensic Toxicology].

PubMed

Yan, Hui; Shen, Min

2015-06-01

Metabonomics is an important branch of system biology following the development of genomics, transcriptomics and proteomics. It can perform high-throughput detection and data processing with multiple parameters, potentially enabling the identification and quantification of all small metabolites in a biological system. It can be used to provide comprehensive information on the toxicity effects, toxicological mechanisms and biomarkers, sensitively finding the unusual metabolic changes caused by poison. This article mainly reviews application of metabonomics in toxicological studies of abused drugs, pesticides, poisonous plants and poisonous animals, and also illustrates the new direction of forensic toxicology research.

PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

EPA Science Inventory

Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

Integrating informative priors from experimental research with Bayesian methods: an example from radiation epidemiology.

PubMed

Hamra, Ghassan; Richardson, David; Maclehose, Richard; Wing, Steve

2013-01-01

Informative priors can be a useful tool for epidemiologists to handle problems of sparse data in regression modeling. It is sometimes the case that an investigator is studying a population exposed to two agents, X and Y, where Y is the agent of primary interest. Previous research may suggest that the exposures have different effects on the health outcome of interest, one being more harmful than the other. Such information may be derived from epidemiologic analyses; however, in the case where such evidence is unavailable, knowledge can be drawn from toxicologic studies or other experimental research. Unfortunately, using toxicologic findings to develop informative priors in epidemiologic analyses requires strong assumptions, with no established method for its utilization. We present a method to help bridge the gap between animal and cellular studies and epidemiologic research by specification of an order-constrained prior. We illustrate this approach using an example from radiation epidemiology.

Integrating Informative Priors from Experimental Research with Bayesian Methods

PubMed Central

Hamra, Ghassan; Richardson, David; MacLehose, Richard; Wing, Steve

2013-01-01

Informative priors can be a useful tool for epidemiologists to handle problems of sparse data in regression modeling. It is sometimes the case that an investigator is studying a population exposed to two agents, X and Y, where Y is the agent of primary interest. Previous research may suggest that the exposures have different effects on the health outcome of interest, one being more harmful than the other. Such information may be derived from epidemiologic analyses; however, in the case where such evidence is unavailable, knowledge can be drawn from toxicologic studies or other experimental research. Unfortunately, using toxicologic findings to develop informative priors in epidemiologic analyses requires strong assumptions, with no established method for its utilization. We present a method to help bridge the gap between animal and cellular studies and epidemiologic research by specification of an order-constrained prior. We illustrate this approach using an example from radiation epidemiology. PMID:23222512

Developing Computational Tools for Application of Toxicogenomics to Environmental Regulations and Risk Assessment

EPA Science Inventory

Toxicogenomics is the study of changes in gene expression, protein, and metabolite profiles within cells and tissues, complementary to more traditional toxicological methods. Genomics tools provide detailed molecular data about the underlying biochemical mechanisms of toxicity, a...

Using pathway modules as targets for assay development in xenobiotic screening

EPA Science Inventory

Toxicology and pharmaceutical research is increasingly making use of high throughout-screening (HTS) methods to assess the effects of chemicals on molecular pathways, cells and tissues. Whole-genome microarray analysis provides broad information on the response of biological syst...

Detection of pyrethroid pesticides and their environmental degradation products in duplicate diet samples

EPA Science Inventory

The abstract is for an oral presentation at the Asilomar Conference on Mass Spectrometry: Mass Spectrometry in Environmental Chemistry, Toxicology, and Health. It describes analytical method development and sample results for determination of pyrethroid pesticides and environme...

Navigating through the domains of biology and chemistry

EPA Science Inventory

Developing computational toxicology methods to assist the risk assessment process has recently gained much attention both in regulatory agencies and industries. The FDA Center for Food Safety and Applied Nutrition’s Office of Food Additive Safety (CFSAN OFAS) uses (Q)SAR approach...

Development and Validation of a Computational Model for Androgen Receptor Activity

EPA Science Inventory

Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions of dollars and take decades to complete using current validated methods. High-throughput in vitro screening (HTS) and computational toxicology approaches can mo...

Evidence-based toxicology for the 21st century: opportunities and challenges.

PubMed

Stephens, Martin L; Andersen, Melvin; Becker, Richard A; Betts, Kellyn; Boekelheide, Kim; Carney, Ed; Chapin, Robert; Devlin, Dennis; Fitzpatrick, Suzanne; Fowle, John R; Harlow, Patricia; Hartung, Thomas; Hoffmann, Sebastian; Holsapple, Michael; Jacobs, Abigail; Judson, Richard; Naidenko, Olga; Pastoor, Tim; Patlewicz, Grace; Rowan, Andrew; Scherer, Roberta; Shaikh, Rashid; Simon, Ted; Wolf, Douglas; Zurlo, Joanne

2013-01-01

The Evidence-based Toxicology Collaboration (EBTC) was established recently to translate evidence-based approaches from medicine and health care to toxicology in an organized and sustained effort. The EBTC held a workshop on "Evidence-based Toxicology for the 21st Century: Opportunities and Challenges" in Research Triangle Park, North Carolina, USA on January 24-25, 2012. The presentations largely reflected two EBTC priorities: to apply evidence-based methods to assessing the performance of emerging pathway-based testing methods consistent with the 2007 National Research Council report on "Toxicity Testing in the 21st Century" as well as to adopt a governance structure and work processes to move that effort forward. The workshop served to clarify evidence-based approaches and to provide food for thought on substantive and administrative activities for the EBTC. Priority activities include conducting pilot studies to demonstrate the value of evidence-based approaches to toxicology, as well as conducting educational outreach on these approaches.

DockScreen: A database of in silico biomolecular interactions to support computational toxicology

EPA Science Inventory

We have developed DockScreen, a database of in silico biomolecular interactions designed to enable rational molecular toxicological insight within a computational toxicology framework. This database is composed of chemical/target (receptor and enzyme) binding scores calculated by...

Vision & Strategy: Predictive Ecotoxicology in the 21st Century

DTIC Science & Technology

2011-01-01

their relative abundance or modifications QSARs —Correlation of ecological or toxicological activity with chemical structure to understand or predict...data and collection methods. The dramatic increase in the amount of toxicological data we can collect and analyze is complemented by our improved...diverse disciplines such as biochemistry, ecology, molecular biology, toxicology , bioinformatics, and health and environmental risk assess- ment

Translational benchmark risk analysis

PubMed Central

Piegorsch, Walter W.

2010-01-01

Translational development – in the sense of translating a mature methodology from one area of application to another, evolving area – is discussed for the use of benchmark doses in quantitative risk assessment. Illustrations are presented with traditional applications of the benchmark paradigm in biology and toxicology, and also with risk endpoints that differ from traditional toxicological archetypes. It is seen that the benchmark approach can apply to a diverse spectrum of risk management settings. This suggests a promising future for this important risk-analytic tool. Extensions of the method to a wider variety of applications represent a significant opportunity for enhancing environmental, biomedical, industrial, and socio-economic risk assessments. PMID:20953283

COMPUTATIONAL TOXICOLOGY: FRAMEWORK, PARTNERSHIPS, AND PROGRAM DEVELOPMENT

EPA Science Inventory

Computational toxicology is a new research initiative being developed within the Office of Research and Development (ORD) of the US Environmental Protection Agency (EPA). Operationally, it is defined as the application of mathematical and computer models together with molecular c...

[Forensic medicine as the cradle of toxicology in Russia].

PubMed

Popov, V L; Grebeniuk, A N; Pigolkin, Iu I; Tolmachev, I A; Bozhchenko, A P; Timoshevskiĭ, A A

2013-01-01

Modern toxicology as a science and educational subject originated from forensic medicine in the middle of the XIXth century. In the beginning, selected toxicological problems were taught in the Emperor's Medical Surgical Academy (presently S.M. Kirov Military Medical Academy, Sankt-Peterburg) and at the Medical Faculty of the Moscow University (presently I.M. Sechenov First Moscow State Medical University, Moscow). The greatest contribution to the development of toxicology was made by such outstanding scientists as professors S.A. Gromov, P.P. Pelekhin, P.P. Zablotsky-Desyatovsky, E.V. Pelikan, Ya.A. Chistovich, G.I. Blosfel'd, I.M. Sorokin, D.P. Kosorotov, A.V. Grigoriev, V.V. Andreev, A.A. Glebovich, A.N. Grigoriev, B.I. Predtechensky, V.M. Rozhkov, S.S. Vail, M.N. Lubotsky, etc. The works of these researchers predetermined the further development of toxicology in this country, its main purpose being provision of medical aid in case of poisoning and diseases of chemical etiology. Another line of toxicological research became industrial and environmental toxicology having the purpose of hygienic rating and prevention of poisoning. Nevertheless, all aspects of the multifaceted science of toxicology are related to forensic medicine as the cradle in which it originated, evolved, and turned into a self-consistent science.

Development of an Analytical Procedure for the Determination of Multiclass Compounds for Forensic Veterinary Toxicology.

PubMed

Sell, Bartosz; Sniegocki, Tomasz; Zmudzki, Jan; Posyniak, Andrzej

2018-04-01

Reported here is a new analytical multiclass method based on QuEChERS technique, which has proven to be effective in diagnosing fatal poisoning cases in animals. This method has been developed for the determination of analytes in liver samples comprising rodenticides, carbamate and organophosphorus pesticides, coccidiostats and mycotoxins. The procedure entails addition of acetonitrile and sodium acetate to 2 g of homogenized liver sample. The mixture was shaken intensively and centrifuged for phase separation, which was followed by an organic phase transfer into a tube containing sorbents (PSA and C18) and magnesium sulfate, then it was centrifuged, the supernatant was filtered and analyzed by liquid chromatography tandem mass spectrometry. A validation of the procedure was performed. Repeatability variation coefficients <15% have been achieved for most of the analyzed substances. Analytical conditions allowed for a successful separation of variety of poisons with the typical screening detection limit at ≤10 μg/kg levels. The method was used to investigate more than 100 animals poisoning incidents and proved that is useful to be used in animal forensic toxicology cases.

The Center for Alternatives to Animal Testing - Europe (CAAT-EU): a transatlantic bridge for the paradigm shift in toxicology.

PubMed

Daneshian, Mardas; Leist, Marcel; Hartung, Thomas

2010-01-01

The Center for Alternatives to Animal Testing - Europe (CAAT-EU) was founded based collaboration between the Johns Hopkins Bloomberg School of Public Health and the University of Konstanz. CAAT-EU, housed at the University of Konstanz, will coordinate transatlantic activities to promote humane science in research and education, and participate, as partner or coordinator, in publicly and privately funded European projects. Thomas Hartung will serve as program liaison representing Johns Hopkins University and Marcel Leist as the University of Konstanz liaison. CAAT-EU aims to: 1) Set up transatlantic consortia for international research projects on alternative methods. 2) Establish a CAAT Europe faculty and advisory board composed of sponsor representatives and prominent academics from Europe . 3) Participate in the Transatlantic Think Tank for Toxicology (t4) devoted to conceptual work for the paradigm shift in toxicology. 4) Coordinate a series of information days in Europe on relevant developments in the US, similar to the 2009 series CAAT held in the US on EU issues (one on the 7th Amendment to the EU Cosmetics Directive and one on EU and US chemical regulation). 5) Support ALTEX as the official journal of CAAT and CAAT-EU. 6) Develop strategic projects with sponsors to promote humane science and new toxicology, especially with CAAT faculty members. 7) Develop a joint education program between Johns Hopkins and the University of Konstanz, such as e-courses and the existing Humane Science Certificate program developed by CAAT, a student exchange program, and collaboration with the International Graduate School "Cell-based Characterization of De- and Regeneration" in Konstanz.

Data-Driven Method to Estimate Nonlinear Chemical Equivalence.

PubMed

Mayo, Michael; Collier, Zachary A; Winton, Corey; Chappell, Mark A

2015-01-01

There is great need to express the impacts of chemicals found in the environment in terms of effects from alternative chemicals of interest. Methods currently employed in fields such as life-cycle assessment, risk assessment, mixtures toxicology, and pharmacology rely mostly on heuristic arguments to justify the use of linear relationships in the construction of "equivalency factors," which aim to model these concentration-concentration correlations. However, the use of linear models, even at low concentrations, oversimplifies the nonlinear nature of the concentration-response curve, therefore introducing error into calculations involving these factors. We address this problem by reporting a method to determine a concentration-concentration relationship between two chemicals based on the full extent of experimentally derived concentration-response curves. Although this method can be easily generalized, we develop and illustrate it from the perspective of toxicology, in which we provide equations relating the sigmoid and non-monotone, or "biphasic," responses typical of the field. The resulting concentration-concentration relationships are manifestly nonlinear for nearly any chemical level, even at the very low concentrations common to environmental measurements. We demonstrate the method using real-world examples of toxicological data which may exhibit sigmoid and biphasic mortality curves. Finally, we use our models to calculate equivalency factors, and show that traditional results are recovered only when the concentration-response curves are "parallel," which has been noted before, but we make formal here by providing mathematical conditions on the validity of this approach.

Biotransformation and ToxCast™

EPA Science Inventory

A major focus in toxicology research is the development of in vitro methods to predict in vivo chemical toxicity. Within the EPA ToxCast program, a broad range of in vitro biochemical and cellular assays have been deployed to profile the biological activity of 320 ToxCast Phase I...

Understanding the Biology and Technology of ToxCast and Tox21 Assays

EPA Science Inventory

The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...

DEVELOPMENT OF DNA MICROARRAYS FOR ECOLOGICAL EXPOSURE ASSESSMENT

EPA Science Inventory

EPA/ORD is moving forward with a computational toxicology initiative in FY 04 which aims to integrate genomics and computational methods to provide a mechanistic basis for prediction of exposure and effects of chemical stressors in the environment.

The goal of the presen...

Automated toxicological screening reports of modified Agilent MSD Chemstation combined with Microsoft Visual Basic application programs.

PubMed

Choe, Sanggil; Kim, Suncheun; Choi, Hyeyoung; Choi, Hwakyoung; Chung, Heesun; Hwang, Bangyeon

2010-06-15

Agilent GC-MS MSD Chemstation offers automated library search report for toxicological screening using total ion chromatogram (TIC) and mass spectroscopy in normal mode. Numerous peaks appear in the chromatogram of biological specimen such as blood or urine and often large migrating peaks obscure small target peaks, in addition, any target peaks of low abundance regularly give wrong library search result or low matching score. As a result, retention time and mass spectrum of all the peaks in the chromatogram have to be checked to see if they are relevant. These repeated actions are very tedious and time-consuming to toxicologists. MSD Chemstation software operates using a number of macro files which give commands and instructions on how to work on and extract data from the chromatogram and spectroscopy. These macro files are developed by the own compiler of the software. All the original macro files can be modified and new macro files can be added to the original software by users. To get more accurate results with more convenient method and to save time for data analysis, we developed new macro files for reports generation and inserted new menus in the Enhanced Data Analysis program. Toxicological screening reports generated by these new macro files are in text mode or graphic mode and these reports can be generated with three different automated subtraction options. Text reports have Brief mode and Full mode and graphic reports have the option with or without mass spectrum mode. Matched mass spectrum and matching score for detected compounds are printed in reports by modified library searching modules. We have also developed an independent application program named DrugMan. This program manages drug groups, lists and parameters that are in use in MSD Chemstation. The incorporation of DrugMan with modified macro modules provides a powerful tool for toxicological screening and save a lot of valuable time on toxicological work. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

TOXICOLOGICAL RESEARCH INVOLVING HUMANS: ETHICAL AND REGULATORY CONSIDERATIONS

EPA Science Inventory

This paper discusses the need for the Society of Toxicology (SOT) to develop a policy for ethical research in humans, and a review for publication of these studies. Observations on human beings have been the foundation upon which toxicologic knowledge has been built since the in...

The Whole Wildlife Toxicology Catalog: a Web Portal for Wildlife Toxicology Data

EPA Science Inventory

In 2007, the Smithsonian Institution sponsored a Wildlife Toxicology Workshop attended by over 50 scientists and administrators from academia, government and conservation entities, and the private sector. One of the action items from the meeting was to develop a web portal that ...

Development of a micropulverized extraction method for rapid toxicological analysis of methamphetamine in hair.

PubMed

Miyaguchi, Hajime; Kakuta, Masaya; Iwata, Yuko T; Matsuda, Hideaki; Tazawa, Hidekatsu; Kimura, Hiroko; Inoue, Hiroyuki

2007-09-07

We developed a rapid sample preparation method for the toxicological analysis of methamphetamine and amphetamine (the major metabolite of methamphetamine) in human hair by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), to facilitate fast screening and quantitation. Two milligrams of hair were mechanically micropulverized for 5 min in a 2-ml plastic tube together with 100 microl of an aqueous solvent containing 10% acetonitrile, 100 mM trifluoroacetic acid and the corresponding deuterium analogues as internal standards. The pulverizing highly disintegrated the hair components, simultaneously allowing the extraction of any drugs present in the hair. After filtering the suspension with a membrane-filter unit, the clear filtrate was directly analyzed by HPLC-MS/MS. No evaporation processes were required for sample preparation. Method optimization and validation study were carried out using real-case specimens and fortified samples in which the drugs had been artificially absorbed, respectively. Concentration ranges for quantitation were 0.040-125 and 0.040-25 ng/mg for methamphetamine and amphetamine, respectively. Real-case specimens were analyzed by the method presented here and by conventional ones to verify the applicability of our method to real-world analysis. Our method took less than 30 min for a set of chromatograms to be obtained from a washed hair sample.

Evaluation of sampling methods for toxicological testing of indoor air particulate matter.

PubMed

Tirkkonen, Jenni; Täubel, Martin; Hirvonen, Maija-Riitta; Leppänen, Hanna; Lindsley, William G; Chen, Bean T; Hyvärinen, Anne; Huttunen, Kati

2016-09-01

There is a need for toxicity tests capable of recognizing indoor environments with compromised air quality, especially in the context of moisture damage. One of the key issues is sampling, which should both provide meaningful material for analyses and fulfill requirements imposed by practitioners using toxicity tests for health risk assessment. We aimed to evaluate different existing methods of sampling indoor particulate matter (PM) to develop a suitable sampling strategy for a toxicological assay. During three sampling campaigns in moisture-damaged and non-damaged school buildings, we evaluated one passive and three active sampling methods: the Settled Dust Box (SDB), the Button Aerosol Sampler, the Harvard Impactor and the National Institute for Occupational Safety and Health (NIOSH) Bioaerosol Cyclone Sampler. Mouse RAW264.7 macrophages were exposed to particle suspensions and cell metabolic activity (CMA), production of nitric oxide (NO) and tumor necrosis factor (TNFα) were determined after 24 h of exposure. The repeatability of the toxicological analyses was very good for all tested sampler types. Variability within the schools was found to be high especially between different classrooms in the moisture-damaged school. Passively collected settled dust and PM collected actively with the NIOSH Sampler (Stage 1) caused a clear response in exposed cells. The results suggested the higher relative immunotoxicological activity of dust from the moisture-damaged school. The NIOSH Sampler is a promising candidate for the collection of size-fractionated PM to be used in toxicity testing. The applicability of such sampling strategy in grading moisture damage severity in buildings needs to be developed further in a larger cohort of buildings.

Implications of gender differences for human health risk assessment and toxicology

EPA Science Inventory

This paper from The Human Health working group of SGOMSEC 16 examines a broad range of issues on gender effects in toxicology. Gender differences in toxicology begin at the gamete and embryo stage, continuing through development and maturation and into old age. Sex influences exp...

77 FR 20022 - Substances To Be Evaluated for Set 26 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-03

...-275; Regulations.gov Docket: ATSDR-2012-0001] Substances To Be Evaluated for Set 26 Toxicological... Services (HHS). ACTION: Request for comments on the proposed substances to be evaluated for Set 26... on hazardous substances. ATSDR is initiating the development of its 26th set of toxicological...

Cavallin et al 2015

EPA Pesticide Factsheets

This study demonstrates the potential of whole-mount in situ hybridization (WISH), in conjunction with quantitative real-time polymerase chain reaction (QPCR) assays, to examine the mechanistic basis of the effects of toxicants on early-lifestage fathead minnows. Specifically, fathead minnow embryos were exposed to the environmentally-relevant estrogen receptor agonist, estrone, and the data show that: (1) the estrogen-responsive gene transcripts esr1, vtg, and cyp19b can be up-regulated in very early-lifestages of the fathead minnow, (2) WISH methods developed for zebrafish can also be applied successfully to fathead minnows, and (3) WISH has potential to be a useful tool for toxicological studies pertaining to early-lifestage development in the fathead minnow. This type of mechanistic information relative to spatial distribution of gene expression is important in determining potential biological pathways that may be impacted by targeted chemicals and the development of associated adverse outcome pathways.This dataset is associated with the following publication:Cavallin, J., A. Schroeder, K. Jensen , D. Villeneuve , B. Blackwell, K. Carlson, M. Kahl , C. LaLone , E. Randolph , and G. Ankley. Evaluation of whole-mount in situ hybridization as a tool for pathway-based toxicological research with early-life stage fathead minnows. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 169: 19-26, (2015).

The toxicological properties of petroleum gases.

PubMed

McKee, Richard H; Herron, Deborah; Saperstein, Mark; Podhasky, Paula; Hoffman, Gary M; Roberts, Linda

2014-01-01

To characterize the toxicological hazards of petroleum gases, 90-day inhalation toxicity (Organization for Economic Cooperation and Development [OECD] 413) and developmental toxicity (OECD 414) tests were conducted with liquefied propane gas (LPG) at concentrations of 1000, 5000, or 10,000 ppm. A micronucleus test (OECD 474) of LPG was also conducted. No systemic or developmental effects were observed; the overall no observed adverse effect concentration (NOAEC) was 10,000 ppm. Further, there was no effect of LPG exposure at levels up to 10,000 ppm on micronucleus induction and no evidence of bone marrow toxicity. Other alkane gases (ethane, propane, n-butane, and isobutane) were then evaluated in combined repeated exposure studies with reproduction/development toxicity screening tests (OECD 422). There were no toxicologically important changes in parameters relating to systemic toxicity or neurotoxicity for any of these gases at concentrations ranging from 9000 to 16,000 ppm. There was no evidence of effects on developmental or reproductive toxicity in the studies of ethane, propane, or n-butane at the highest concentrations tested. However, there was a reduction in mating in the high-exposure group (9000 ppm) of the isobutane study, which although not significantly different was outside the range previously observed in the testing laboratory. Assuming the reduction in mating to have been toxicologically significant, the NOAEC for the isobutane reproductive toxicity screening test was 3000 ppm (7125 mg/m(3)). A method is proposed by which the toxicity of any of the 106 complex petroleum gas streams can be estimated from its composition.

Mass Spectrometry Applications for Toxicology

PubMed Central

Mbughuni, Michael M.; Jannetto, Paul J.

2016-01-01

Toxicology is a multidisciplinary study of poisons, aimed to correlate the quantitative and qualitative relationships between poisons and their physiological and behavioural effects in living systems. Other key aspects of toxicology focus on elucidation of the mechanisms of action of poisons and development of remedies and treatment plans for associated toxic effects. In these endeavours, Mass spectrometry (MS) has become a powerful analytical technique with a wide range of application used in the Toxicological analysis of drugs, poisons, and metabolites of both. To date, MS applications have permeated all fields of toxicology which include; environmental, clinical, and forensic toxicology. While many different analytical applications are used in these fields, MS and its hyphenated applications such as; gas chromatography MS (GC-MS), liquid chromatography MS (LC-MS), inductively coupled plasma ionization MS (ICP-MS), tandem mass spectrometry (MS/MS and MSn) have emerged as powerful tools used in toxicology laboratories. This review will focus on these hyphenated MS technologies and their applications for toxicology. PMID:28149262

Aspects of matrix effects in applications of liquid chromatography-mass spectrometry to forensic and clinical toxicology--a review.

PubMed

Peters, Frank T; Remane, Daniela

2012-06-01

In the last decade, liquid chromatography coupled to (tandem) mass spectrometry (LC-MS(-MS)) has become a versatile technique with many routine applications in clinical and forensic toxicology. However, it is well-known that ionization in LC-MS(-MS) is prone to so-called matrix effects, i.e., alteration in response due to the presence of co-eluting compounds that may increase (ion enhancement) or reduce (ion suppression) ionization of the analyte. Since the first reports on such matrix effects, numerous papers have been published on this matter and the subject has been reviewed several times. However, none of the existing reviews has specifically addressed aspects of matrix effects of particular interest and relevance to clinical and forensic toxicology, for example matrix effects in methods for multi-analyte or systematic toxicological analysis or matrix effects in (alternative) matrices almost exclusively analyzed in clinical and forensic toxicology, for example meconium, hair, oral fluid, or decomposed samples in postmortem toxicology. This review article will therefore focus on these issues, critically discussing experiments and results of matrix effects in LC-MS(-MS) applications in clinical and forensic toxicology. Moreover, it provides guidance on performance of studies on matrix effects in LC-MS(-MS) procedures in systematic toxicological analysis and postmortem toxicology.

New Rotifer Bioassays for Aquatic Toxicology

DTIC Science & Technology

1991-07-01

Acute toxicity tests using rotifers. II. A freshwater test with Brachionus rubens. Aquatic Toxicology. 14: 81-92. Snell, T. W., B. D. Moffat, C. Janssen...24 hours with a sensitivity comparable to that of other aquatic invertebrates. 1. Standard Freshwater Medium Preparation: Carefully add 96 mg NaHCO3,60...rubens. Aquatic Toxicology. 14: 81-92. US Environmental Protection Agency 1985. Methods for measuring the acute toxicity of effluents to freshwater

Making Waves: New Developments in Toxicology With the Zebrafish.

PubMed

Horzmann, Katharine A; Freeman, Jennifer L

2018-05-01

The laboratory zebrafish (Danio rerio) is now an accepted model in toxicologic research. The zebrafish model fills a niche between in vitro models and mammalian biomedical models. The developmental characteristics of the small fish are strategically being used by scientists to study topics ranging from high-throughput toxicity screens to toxicity in multi- and transgenerational studies. High-throughput technology has increased the utility of zebrafish embryonic toxicity assays in screening of chemicals and drugs for toxicity or effect. Additionally, advances in behavioral characterization and experimental methodology allow for observation of recognizable phenotypic changes after xenobiotic exposure. Future directions in zebrafish research are predicted to take advantage of CRISPR-Cas9 genome editing methods in creating models of disease and interrogating mechanisms of action with fluorescent reporters or tagged proteins. Zebrafish can also model developmental origins of health and disease and multi- and transgenerational toxicity. The zebrafish has many advantages as a toxicologic model and new methodologies and areas of study continue to expand the usefulness and application of the zebrafish.

A bibliometric analysis of toxicology research productivity in Middle Eastern Arab countries during a 10-year period (2003-2012).

PubMed

Zyoud, Sa'ed H; Al-Jabi, Samah W; Sweileh, Waleed M; Awang, Rahmat

2014-01-21

Bibliometric studies are increasingly being used for research assessment by involving the application of statistical methods to scientific publications to obtain the bibliographics for each country. The main objective of this study was to analyse the research productivity originating from 13 Middle Eastern Arab (MEA) countries with articles published in toxicology journals. Data from January 1, 2003 till December 31, 2012 were searched for documents with specific words in the toxicology field as a "source title" in any one of the 13 MEA countries. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product (GDP) per capita. Documents (n = 1,240) were retrieved from 73 international peer-reviewed toxicology journals. The h-index of the retrieved documents was 39. Of the 73 journal titles, 52 (69.9%) have their IF listed in the ISI Journal Citation Reports 2012; 198 documents (16.0%) were published in journals that had no official IF. After adjusting for economy and population power, Egypt (193.6), Palestine (18.1), Kingdom of Saudi Arabia (KSA) (13.0), and Jordan (11.5) had the highest research productivity. Countries with large economies, such as the Kuwait, United Arab Emirates (UAE), and Oman, tended to rank relatively low after adjustment of GDP. The total number of citations at the time of data analysis (August 4, 2013) was 10,991, with a median (interquartile range) of 4 (1-11). MEA collaborated more with countries in the MEA regions (16.7%), especially KSA, Egypt, and UAE, followed by Europe (14.4%), especially with the United Kingdom and Germany. The present data show a promising rise and a good start for toxicology research activity in toxicology journals in the Arab world. Research output is low in some countries, which can be improved by investing in more international and national collaborative research projects in the field of toxicology.

Development and validation of an EI-GC-MS method for the determination of benzodiazepine drugs and their metabolites in blood: applications in clinical and forensic toxicology.

PubMed

Papoutsis, Ioannis I; Athanaselis, Sotirios A; Nikolaou, Panagiota D; Pistos, Constantinos M; Spiliopoulou, Chara A; Maravelias, Constantinos P

2010-08-01

Benzodiazepines are used widely in daily clinical practice, due to their multiple pharmacological actions. The frequent problems associated with the wide use of benzodiazepines, as well as the multiple incidents of poisonings, led to the necessity for the development of a precise, sensitive and rapid method for the simultaneous determination of the 23 most commonly used benzodiazepines (diazepam, nordiazepam, oxazepam, bromazepam, alprazolam, lorazepam, medazepam, flurazepam, fludiazepam, tetrazepam, chlordiazepoxide, clobazam, midazolam, flunitrazepam, 7-amino-flunitrazepam, triazolam, prazepam, nimetazepam, nitrazepam, temazepam, lormetazepam, clonazepam, camazepam) in blood. A gas chromatographic method combined with mass spectrometric detection was developed, optimized and validated for the determination of the above substances. This method includes liquid-liquid extraction with chloroform at pH 9 and two stages of derivatization using tetramethylammonium hydroxide and propyliodide (propylation), as well as a mixture of triethylamine:propionic anhydride (propionylation). The recoveries were higher than 74% for all the benzodiazepines. The calibration curves were linear within the dynamic range of each benzodiazepine with a correlation coefficient higher than 0.9981. The limits of detection and quantification for each analyte were statistically calculated from the relative calibration curves. Accuracy and precision were also calculated and were found to be less than 8.5% and 11.1%, respectively. The developed method was successfully applied for the investigation of both forensic and clinical toxicological cases of accidental and suicidal poisoning. Copyright (c) 2010 Elsevier B.V. All rights reserved.

The International Union of Toxicology (IUTOX): history and its role in information on toxicology.

PubMed

Schou, Jens S; Hodel, Christian M

2003-08-21

The International Union of Toxicology (IUTOX) was founded in 1980 in Brussels. The initiative was started by the Society of Toxicology (SOT), USA, and the European Society of Toxicology in 1975 (EST), and the foundation prepared by an Inter Society Liason Committee. Eight National Societies of Toxicology were founding members of IUTOX besides SOT and EST. It now comprises 43 national/regional Societies from all over the world, representing over 20,000 toxicologists. Information has always been a key element in toxicology. Information exchange in IUTOX has evolved from letters and phone calls to fax, e-mail and the use of the Internet. Initially, newsletters were created which were mailed and later displayed on the Web. The website has been developed as a major information tool with many useful links, thereby providing information for the scientific community, the media and the lay public.

Real-time prediction of Physicochemical and Toxicological Endpoints Using the Web-based CompTox Chemistry Dashboard (ACS Fall meeting) 10 of 12

EPA Science Inventory

The EPA CompTox Chemistry Dashboard developed by the National Center for Computational Toxicology (NCCT) provides access to data for ~750,000 chemical substances. The data include experimental and predicted data for physicochemical, environmental fate and transport and toxicologi...

COMPUTATIONAL TOXICOLOGY: FRAMEWORK, PARTNERSHIPS, AND PROGRAM DEVELOPMENT. SEPTEMBER 29-30, 2003, RESEARCH TRIANGLE PARK, NORTH CAROLINA

EPA Science Inventory

Abstract

The EPA sponsored a workshop held September 29-30, 2003 at the EPA in RTP that was focused on a proposal entitled "A Framework for a Computational Toxicology Research Program in ORD" (www.epa.gov/computox). Computational toxicology is a new research ini...

Advancing Toxicology Research Using In Vivo High Throughput Toxicology with Small Fish Models

PubMed Central

Planchart, Antonio; Mattingly, Carolyn J.; Allen, David; Ceger, Patricia; Casey, Warren; Hinton, David; Kanungo, Jyotshna; Kullman, Seth W.; Tal, Tamara; Bondesson, Maria; Burgess, Shawn M.; Sullivan, Con; Kim, Carol; Behl, Mamta; Padilla, Stephanie; Reif, David M.; Tanguay, Robert L.; Hamm, Jon

2017-01-01

Summary Small freshwater fish models, especially zebrafish, offer advantages over traditional rodent models, including low maintenance and husbandry costs, high fecundity, genetic diversity, physiology similar to that of traditional biomedical models, and reduced animal welfare concerns. The Collaborative Workshop on Aquatic Models and 21st Century Toxicology was held at North Carolina State University on May 5-6, 2014, in Raleigh, North Carolina, USA. Participants discussed the ways in which small fish are being used as models to screen toxicants and understand mechanisms of toxicity. Workshop participants agreed that the lack of standardized protocols is an impediment to broader acceptance of these models, whereas development of standardized protocols, validation, and subsequent regulatory acceptance would facilitate greater usage. Given the advantages and increasing application of small fish models, there was widespread interest in follow-up workshops to review and discuss developments in their use. In this article, we summarize the recommendations formulated by workshop participants to enhance the utility of small fish species in toxicology studies, as well as many of the advances in the field of toxicology that resulted from using small fish species, including advances in developmental toxicology, cardiovascular toxicology, neurotoxicology, and immunotoxicology. We also review many emerging issues that will benefit from using small fish species, especially zebrafish, and new technologies that will enable using these organisms to yield results unprecedented in their information content to better understand how toxicants affect development and health. PMID:27328013

MEETING IN CHARLOTTE: SOLID-PHASE EXTRACTION OF 35 DBPS WITH ANALYSIS BY GC/ECD AND GC/MS

EPA Science Inventory

An analytical method for 35 disinfection by-products (DBPs) was developed for a U.S. Environmental Protection Agency health effects study. A toxicological evaluation was conducted on drinking water that was scaled-up (using reverse osmosis) by concentrating the total organic car...

20180416 - Understanding the Biology and Technology of ToxCast and Tox21 Assays (SETAC Durham NC)

EPA Science Inventory

The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...

SOLID-PHASE EXTRACTION OF 35 DBPS WITH ANALYSIS BY GC/ECD AND GC/MS

EPA Science Inventory

An analytical method for 35 disinfection by-products (DBPs) was developed for a U.S. Environmental Protection Agency (EPA) health effects study. A toxicological evaluation was conducted on drinking water that was "scaled-up" using reverse osmosis (RO) by concentrating the total ...

SOLID-PHASE EXTRACTION OF 35 DBPS WITH ANALYSIS BY GC/ECD AND GC/MS

EPA Science Inventory

An analytical method for 35 disinfection by-products (DBPs) was developed for a U.S. Environmental Protection Agency (EPA) health effects study. A toxicological evaluation was conducted on drinking water that was ‘scaled-up’ using reverse osmosis (RO) by concentrating the total o...

SOLID-PHASE EXTRACTION OF 35 DBPS WITH ANALYSIS BY GC/ECD AND GC/MS 2007

EPA Science Inventory

An analytical method for 35 disinfection by-products (DBPs) was developed for a U.S. Environmental Protection Agency (EPA) health effects study. A toxicological evaluation was conducted on drinking water that was ‘scaled-up’ using reverse osmosis (RO) by concentrating the total o...

A brief review of the occurrence, use, and safety of food-related nanomaterials.

PubMed

Magnuson, Bernadene A; Jonaitis, Tomas S; Card, Jeffrey W

2011-08-01

Nanotechnology and nanomaterials have tremendous potential to enhance the food supply through novel applications, including nutrient and bioactive absorption and delivery systems; ingredient functionality; improved colors and flavors; microbial, allergen, and contaminant detection and control; and food packaging properties and performance. To determine the current state of knowledge regarding the safety of these potential uses of nanomaterials, an appraisal of the published literature on the safety of food-related nanomaterials was undertaken. A method of assessment of reliability of toxicology studies was developed to conduct this appraisal. The review of the toxicology literature on oral exposure to food-related nanomaterials found that the number of studies is limited. Exposure to nanomaterials in the human food chain may occur not only through intentional uses in food manufacturing, but also via uses in agricultural production and carry over from use in other industries. Although a number of analytical methods are useful in physicochemical characterization of manufactured nanomaterials, new methods may be needed to more fully detect and characterize nanomaterials incorporated into foods and in other media. There is a need for additional toxicology studies of sufficient quality and duration on different types of nanomaterials to further our understanding of the characteristics of nanomaterials that affect safety of oral exposure resulting from use in various food applications. © 2011 Institute of Food Technologists®

WORKSHOP REPORT: COMPUTATIONAL TOXICOLOGY: FRAMEWORK, PARTNERSHIPS, AND PROGRAM DEVELOPMENT, SEPTEMBER 29-30, 2003, RESEARCH TRIANGLE PARK, NORTH CAROLINA

EPA Science Inventory

Computational toxicology is a new research initiative being developed within the Office of Research and Development (ORD) of the US Environmental Protection Agency (EPA). Operationally, it is defined as the application of mathematical and computer models together with molecular c...

Systems Toxicology: From Basic Research to Risk Assessment

PubMed Central

2014-01-01

Systems Toxicology is the integration of classical toxicology with quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Society demands increasingly close scrutiny of the potential health risks associated with exposure to chemicals present in our everyday life, leading to an increasing need for more predictive and accurate risk-assessment approaches. Developing such approaches requires a detailed mechanistic understanding of the ways in which xenobiotic substances perturb biological systems and lead to adverse outcomes. Thus, Systems Toxicology approaches offer modern strategies for gaining such mechanistic knowledge by combining advanced analytical and computational tools. Furthermore, Systems Toxicology is a means for the identification and application of biomarkers for improved safety assessments. In Systems Toxicology, quantitative systems-wide molecular changes in the context of an exposure are measured, and a causal chain of molecular events linking exposures with adverse outcomes (i.e., functional and apical end points) is deciphered. Mathematical models are then built to describe these processes in a quantitative manner. The integrated data analysis leads to the identification of how biological networks are perturbed by the exposure and enables the development of predictive mathematical models of toxicological processes. This perspective integrates current knowledge regarding bioanalytical approaches, computational analysis, and the potential for improved risk assessment. PMID:24446777

Systems toxicology: from basic research to risk assessment.

PubMed

Sturla, Shana J; Boobis, Alan R; FitzGerald, Rex E; Hoeng, Julia; Kavlock, Robert J; Schirmer, Kristin; Whelan, Maurice; Wilks, Martin F; Peitsch, Manuel C

2014-03-17

Systems Toxicology is the integration of classical toxicology with quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Society demands increasingly close scrutiny of the potential health risks associated with exposure to chemicals present in our everyday life, leading to an increasing need for more predictive and accurate risk-assessment approaches. Developing such approaches requires a detailed mechanistic understanding of the ways in which xenobiotic substances perturb biological systems and lead to adverse outcomes. Thus, Systems Toxicology approaches offer modern strategies for gaining such mechanistic knowledge by combining advanced analytical and computational tools. Furthermore, Systems Toxicology is a means for the identification and application of biomarkers for improved safety assessments. In Systems Toxicology, quantitative systems-wide molecular changes in the context of an exposure are measured, and a causal chain of molecular events linking exposures with adverse outcomes (i.e., functional and apical end points) is deciphered. Mathematical models are then built to describe these processes in a quantitative manner. The integrated data analysis leads to the identification of how biological networks are perturbed by the exposure and enables the development of predictive mathematical models of toxicological processes. This perspective integrates current knowledge regarding bioanalytical approaches, computational analysis, and the potential for improved risk assessment.

Modern Instrumental Methods in Forensic Toxicology*

PubMed Central

Smith, Michael L.; Vorce, Shawn P.; Holler, Justin M.; Shimomura, Eric; Magluilo, Joe; Jacobs, Aaron J.; Huestis, Marilyn A.

2009-01-01

This article reviews modern analytical instrumentation in forensic toxicology for identification and quantification of drugs and toxins in biological fluids and tissues. A brief description of the theory and inherent strengths and limitations of each methodology is included. The focus is on new technologies that address current analytical limitations. A goal of this review is to encourage innovations to improve our technological capabilities and to encourage use of these analytical techniques in forensic toxicology practice. PMID:17579968

The Global Educational Toxicology Uniting Project (GETUP): an Analysis of the First Year of a Novel Toxicology Education Project.

PubMed

Wong, Anselm; Vohra, Rais; Ruha, Anne-Michelle; Koutsogiannis, Zeff; Graeme, Kimberlie; Dargan, Paul I; Wood, David M; Greene, Shaun L

2015-09-01

The international boundaries to medical education are becoming less marked as new technologies such as multiuser videoconferencing are developed and become more accessible to help bridge the communication gaps. The Global Educational Toxicology Uniting Project (GETUP) is aimed at connecting clinicians in countries with established clinical toxicology services to clinicians in countries without clinical toxicologists around the globe. Centers that manage or consult on toxicology cases were registered through the American College of Medical Toxicology website via Survey Monkey®. Data was analyzed retrospectively from February 2014 to January 2015. Google hangouts® was used as the main conferencing software, but some sites preferred the use of Skype®. Registration data included contact details and toxicology background and qualifications. Thirty sites in 19 different countries in Australasia, Europe, Africa, and America were registered. Twenty-eight (93 %) sites were located in a major urban center, one (3.5 %) site in a major rural center and one (3.5 %) a private practice. Expectations of GETUP included sharing toxicology cases and education (30, 100 % of sites), assistance with toxicology management guidelines (2, 7 %), assistance with providing a toxicology teaching curriculum in languages other than English (2, 7 %), and managing toxicology presentations in resource-poor settings, international collaboration, and toxicovigilance (2 sites, 7 %). Twenty-two conferences were performed during the first 12 months with a mean of 3 cases per conference. GETUP has connected countries and clinical units with and without toxicology services and will provide a platform to improve international collaboration in clinical toxicology.

Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing.

PubMed

Koch, Michael S; DeSesso, John M; Williams, Amy Lavin; Michalek, Suzanne; Hammond, Bruce

2016-01-01

To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods' (ECVAM) ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators.

Computer validation in toxicology: historical review for FDA and EPA good laboratory practice.

PubMed

Brodish, D L

1998-01-01

The application of computer validation principles to Good Laboratory Practice is a fairly recent phenomenon. As automated data collection systems have become more common in toxicology facilities, the U.S. Food and Drug Administration and the U.S. Environmental Protection Agency have begun to focus inspections in this area. This historical review documents the development of regulatory guidance on computer validation in toxicology over the past several decades. An overview of the components of a computer life cycle is presented, including the development of systems descriptions, validation plans, validation testing, system maintenance, SOPs, change control, security considerations, and system retirement. Examples are provided for implementation of computer validation principles on laboratory computer systems in a toxicology facility.

"Seeing is believing": perspectives of applying imaging technology in discovery toxicology.

PubMed

Xu, Jinghai James; Dunn, Margaret Condon; Smith, Arthur Russell

2009-11-01

Efficiency and accuracy in addressing drug safety issues proactively are critical in minimizing late-stage drug attritions. Discovery toxicology has become a specialty subdivision of toxicology seeking to effectively provide early predictions and safety assessment in the drug discovery process. Among the many technologies utilized to select safer compounds for further development, in vitro imaging technology is one of the best characterized and validated to provide translatable biomarkers towards clinically-relevant outcomes of drug safety. By carefully applying imaging technologies in genetic, hepatic, and cardiac toxicology, and integrating them with the rest of the drug discovery processes, it was possible to demonstrate significant impact of imaging technology on drug research and development and substantial returns on investment.

Historical milestones and discoveries that shaped the toxicology sciences.

PubMed

Hayes, Antoinette N; Gilbert, Steven G

2009-01-01

Knowledge of the toxic and healing properties of plants, animals, and minerals has shaped civilization for millennia. The foundations of modern toxicology are built upon the significant milestones and discoveries of serendipity and crude experimentation. Throughout the ages, toxicological science has provided information that has shaped and guided society. This chapter examines the development of the discipline of toxicology and its influence on civilization by highlighting significant milestones and discoveries related to toxicology. The examples shed light on the beginnings of toxicology, as well as examine lessons learned and re-learned. This chapter also examines how toxicology and the toxicologist have interacted with other scientific and cultural disciplines, including religion, politics, and the government. Toxicology has evolved to a true scientific discipline with its own dedicated scientists, educational institutes, sub-disciplines, professional societies, and journals. It now stands as its own entity while traversing such fields as chemistry, physiology, pharmacology, and molecular biology. We invite you to join us on a path of discovery and to offer our suggestions as to what are the most significant milestones and discoveries in toxicology. Additional information is available on the history section of Toxipedia (www.toxipedia.org).

Aerospace toxicology overview: aerial application and cabin air quality.

PubMed

Chaturvedi, Arvind K

2011-01-01

Aerospace toxicology is a rather recent development and is closely related to aerospace medicine. Aerospace toxicology can be defined as a field of study designed to address the adverse effects of medications, chemicals, and contaminants on humans who fly within or outside the atmosphere in aviation or on space flights. The environment extending above and beyond the surface of the Earth is referred to as aerospace. The term aviation is frequently used interchangeably with aerospace. The focus of the literature review performed to prepare this paper was on aerospace toxicology-related subject matters, aerial application and aircraft cabin air quality. Among the important topics addressed are the following: · Aerial applications of agricultural chemicals, pesticidal toxicity, and exposures to aerially applied mixtures of chemicals and their associated formulating solvents/surfactants The safety of aerially encountered chemicals and the bioanalytical methods used to monitor exposures to some of them · The presence of fumes and smoke, as well as other contaminants that may generally be present in aircraft/space vehicle cabin air · And importantly, the toxic effects of aerially encountered contaminants, with emphasis on the degradation products of oils, fluids, and lubricants used in aircraft, and finally · Analytical methods used for monitoring human exposure to CO and HCN are addressed in the review, as are the signs and symptoms associated with exposures to these combustion gases. Although many agricultural chemical monitoring studies have been published, few have dealt with the occurrence of such chemicals in aircraft cabin air. However, agricultural chemicals do appear in cabin air; indeed, attempts have been made to establish maximum allowable concentrations for several of the more potentially toxic ones that are found in aircraft cabin air. In this article, I emphasize the need for precautionary measures to be taken to minimize exposures to aerially encountered chemicals, or aircraft cabin air contaminants and point out the need for future research to better address toxicological evaluation of aircraft-engine oil additives.

Suspension characterization as important key for toxicological investigations

NASA Astrophysics Data System (ADS)

Meißner, Tobias; Potthoff, Annegret; Richter, Volkmar

2009-05-01

To assess potential health risks of nanoparticles by means of in vitro or in vivo assays and to determine dose-action curves a defined and reproducible method of particle administration is required. The interpretation of the toxicological results should be based on a comprehensive chemical-physical characterization of the particles used. Therefore, we developed a method to suspend nanoparticles stably and homogenously in physiological media. Our approach consist of three steps: (1) physical-chemical characterisation of the powders as delivered, (2) preparation and characterization of a non-physiological electro-statically stabilized nanoparticle suspension and (3) assessment of the nanoparticles behaviour in physiological media with or without proteins. This approach is demonstrated on a titanium dioxide and a tungsten carbide nanopowder. Results showed that particles agglomerate in protein-free medium within minutes, whereas in the presence of bovine serum albumin or foetal bovine serum an agglomeration is hindered.

A bibliometric analysis of research productivity of Malaysian publications in leading toxicology journals during a 10-year period (2003-2012).

PubMed

Zyoud, Sh; Al-Jabi, Sw; Sweileh, Wm; Awang, R

2014-12-01

Toxicology in Malaysia has experienced rapid development and made great progress in education and research in conjunction with economic development in Malaysia over the past two decades. The main objectives of this study were to analyse the research originating from Malaysia and published in toxicology journals and to examine the authorship pattern and the citations retrieved from the Scopus database. Data from 1 January 2003 till 31 December 2012 were searched for documents with specific words in the toxicology field as a 'source title' and Malaysia as an affiliation country. Research productivity was evaluated based on a methodology we developed and used in other bibliometric studies by analysing: (a) total and trends of contributions in toxicology fields between 2003 and 2012; (b) Malaysian authorship pattern and productivity; (c) collaboration patterns; (d) journals in which Malaysian researchers publish; (e) the classification of journals to Institute for Scientific Information (ISI) or non-ISI; (f) impact factors (IFs) of all publications; and (g) citations received by the publications. In total, 290 documents were retrieved from 55 international peer-reviewed toxicology journals. The quantity of publication increased by around 10-fold from 2003 to 2012. The h-index of the retrieved documents was 20. Of the 55 journal titles, 42 (76.4%) have their IF listed in the journal citation reports 2012. Forty-two documents (14.5%) were published in journals that had no official IF. The total number of citations, at the time of manuscript writing (5 August 2013), was 1707, with a median (interquartile range) of 3 (0-7). Malaysia collaborated mostly with countries in the Asia-Pacific regions (18.3%), especially India and Japan, followed by the Middle East and Africa (10.0%), especially Palestine and Yemen. The present data show a promising rise and a good start for toxicology research activity in Malaysia. The sharing of relevant research questions by developed and developing countries can lead to research opportunities in the field of toxicology. © The Author(s) 2014.

COMPUTATIONAL TOXICOLOGY - OBJECTIVE 2: DEVELOPING APPROACHES FOR PRIORITIZING CHEMICALS FOR SUBSEQUENT SCREENING AND TESTING

EPA Science Inventory

One of the strategic objectives of the Computational Toxicology Program is to develop approaches for prioritizing chemicals for subsequent screening and testing. Approaches currently available for this process require extensive resources. Therefore, less costly and time-extensi...

A framework program for the teaching of alternative methods (replacement, reduction, refinement) to animal experimentation.

PubMed

Daneshian, Mardas; Akbarsha, Mohammad A; Blaauboer, Bas; Caloni, Francesca; Cosson, Pierre; Curren, Rodger; Goldberg, Alan; Gruber, Franz; Ohl, Frauke; Pfaller, Walter; van der Valk, Jan; Vinardell, Pilar; Zurlo, Joanne; Hartung, Thomas; Leist, Marcel

2011-01-01

Development of improved communication and education strategies is important to make alternatives to the use of animals, and the broad range of applications of the 3Rs concept better known and understood by different audiences. For this purpose, the Center for Alternatives to Animal Testing in Europe (CAAT-Europe) together with the Transatlantic Think Tank for Toxicology (t(4)) hosted a three-day workshop on "Teaching Alternative Methods to Animal Experimentation". A compilation of the recommendations by a group of international specialists in the field is summarized in this report. Initially, the workshop participants identified the different audience groups to be addressed and also the communication media that may be used. The main outcome of the workshop was a framework for a comprehensive educational program. The modular structure of the teaching program presented here allows adaptation to different audiences with their specific needs; different time schedules can be easily accommodated on this basis. The topics cover the 3Rs principle, basic research, toxicological applications, method development and validation, regulatory aspects, case studies and ethical aspects of 3Rs approaches. This expert consortium agreed to generating teaching materials covering all modules and providing them in an open access online repository.

Evaluating the Impact of the U.S. National Toxicology Program: A Case Study on Hexavalent Chromium

PubMed Central

Xie, Yun; Holmgren, Stephanie; Andrews, Danica M. K.; Wolfe, Mary S.

2016-01-01

Background: Evaluating the impact of federally funded research with a broad, methodical, and objective approach is important to ensure that public funds advance the mission of federal agencies. Objectives: We aimed to develop a methodical approach that would yield a broad assessment of National Toxicology Program’s (NTP’s) effectiveness across multiple sectors and demonstrate the utility of the approach through a case study. Methods: A conceptual model was developed with defined activities, outputs (products), and outcomes (proximal, intermediate, distal) and applied retrospectively to NTP’s research on hexavalent chromium (CrVI). Proximal outcomes were measured by counting views of and requests for NTP’s products by external stakeholders. Intermediate outcomes were measured by bibliometric analysis. Distal outcomes were assessed through Web and LexisNexis searches for documents related to legislation or regulation changes. Results: The approach identified awareness of NTP’s work on CrVI by external stakeholders (proximal outcome) and citations of NTP’s research in scientific publications, reports, congressional testimonies, and legal and policy documents (intermediate outcome). NTP’s research was key to the nation’s first-ever drinking water standard for CrVI adopted by California in 2014 (distal outcome). By applying this approach to a case study, the utility and limitations of the approach were identified, including challenges to evaluating the outcomes of a research program. Conclusions: This study identified a broad and objective approach for assessing NTP’s effectiveness, including methodological needs for more thorough and efficient impact assessments in the future. Citation: Xie Y, Holmgren S, Andrews DMK, Wolfe MS. 2017. Evaluating the impact of the U.S. National Toxicology Program: a case study on hexavalent chromium. Environ Health Perspect 125:181–188; http://dx.doi.org/10.1289/EHP21 PMID:27483499

High-Throughput Toxicity Testing: New Strategies for ...

EPA Pesticide Factsheets

In recent years, the food industry has made progress in improving safety testing methods focused on microbial contaminants in order to promote food safety. However, food industry toxicologists must also assess the safety of food-relevant chemicals including pesticides, direct additives, and food contact substances. With the rapidly growing use of new food additives, as well as innovation in food contact substance development, an interest in exploring the use of high-throughput chemical safety testing approaches has emerged. Currently, the field of toxicology is undergoing a paradigm shift in how chemical hazards can be evaluated. Since there are tens of thousands of chemicals in use, many of which have little to no hazard information and there are limited resources (namely time and money) for testing these chemicals, it is necessary to prioritize which chemicals require further safety testing to better protect human health. Advances in biochemistry and computational toxicology have paved the way for animal-free (in vitro) high-throughput screening which can characterize chemical interactions with highly specific biological processes. Screening approaches are not novel; in fact, quantitative high-throughput screening (qHTS) methods that incorporate dose-response evaluation have been widely used in the pharmaceutical industry. For toxicological evaluation and prioritization, it is the throughput as well as the cost- and time-efficient nature of qHTS that makes it

ACToR – Aggregated Computational Toxicology Resource ...

EPA Pesticide Factsheets

ACToR (Aggregated Computational Toxicology Resource) is a collection of databases collated or developed by the US EPA National Center for Computational Toxicology (NCCT). More than 200 sources of publicly available data on environmental chemicals have been brought together and made searchable by chemical name and other identifiers, and by chemical structure. Data includes chemical structure, physico-chemical values, in vitro assay data and in vivo toxicology data. Chemicals include, but are not limited to, high and medium production volume industrial chemicals, pesticides (active and inert ingredients), and potential ground and drinking water contaminants.

COMPUTATIONAL TOXICOLOGY ADVANCES: EMERGING CAPABILITIES FOR DATA EXPLORATION AND SAR MODEL DEVELOPMENT

EPA Science Inventory

Computational Toxicology Advances: Emerging capabilities for data exploration and SAR model development
Ann M. Richard and ClarLynda R. Williams, National Health & Environmental Effects Research Laboratory, US EPA, Research Triangle Park, NC, USA; email: richard.ann@epa.gov

Bone development in laboratory mammals used in developmental toxicity studies.

PubMed

DeSesso, John M; Scialli, Anthony R

2018-06-19

Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings. © 2018 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

The United Kingdom and Ireland Association of Forensic Toxicologists; establishing best practice for professional training & development in forensic toxicology.

PubMed

Cosbey, Simon; Elliott, Simon; Paterson, Sue

2017-01-01

The current status of forensic toxicology in the United Kingdom is discussed with an emphasis on professional training and development. Best practice is proposed using a blend of modular foundation knowledge training, continuing professional development, academic study, research & development and ongoing analytical practice. The need for establishing a professional career structure is also discussed along with a suggested example of a suitable model. The issues discussed in this paper are intended to provoke discussion within the forensic toxicology community, industry regulators and other government bodies responsible for the administration of justice. Copyright © 2016 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.

Development of a simple and sensitive liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method for the determination of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and its metabolites in rat whole blood after oral administration of a single high dose of CBD.

PubMed

Palazzoli, Federica; Citti, Cinzia; Licata, Manuela; Vilella, Antonietta; Manca, Letizia; Zoli, Michele; Vandelli, Maria Angela; Forni, Flavio; Cannazza, Giuseppe

2018-02-20

The investigation of the possible conversion of cannabidiol (CBD) into Δ 9 -tetrahydrocannabinol (THC) in vivo after oral administration of CBD is reported herein since recent publications suggested a rapid conversion in simulated gastric fluid. To this end, single high dose of CBD (50mg/kg) was administered orally to rats and their blood was collected after 3 and 6h. A highly sensitive and selective LC-MS/MS method was developed and fully validated in compliance with the Scientific Working Group of Forensic Toxicology (SWGTOX) standard practices for method validation in forensic toxicology. This method also involved the optimization of cannabinoids and their metabolites extraction in order to remove co-eluting phospholipids and increase the sensitivity of the MS detection. Neither THC nor its metabolites were detected in rat whole blood after 3 or 6h from CBD administration. After oral administration, the amount of CBD dissolved in olive oil was higher than that absorbed from an ethanolic solution. This could be explained by the protection of lipid excipients towards CBD from acidic gastric juice. Copyright © 2017 Elsevier B.V. All rights reserved.

Successful validation of in vitro methods in toxicology by ZEBET, the National Centre for Alternatives in Germany at the BfR (Federal Institute for Risk Assessment).

PubMed

Spielmann, Horst; Grune, Barbara; Liebsch, Manfred; Seiler, Andrea; Vogel, Richard

2008-06-01

A short description of the history of the 3Rs concept is given, which was developed as the scientific concept to refine, reduce and replace animal experiments by Russel and Burch more than 40 years ago. In addition, the legal framework in Europe for developing alternatives to animal experiments is given and the current status of in vitro systems in pharmacology and toxicology is described including an update on metabolising systems. The decrease in experimental animal numbers during the past decade in Europe is illustrated by the situation in Germany and the contribution of international harmonisation of test guidelines on reducing animal numbers in regulatory testing is described. A review of the development of the principles of experimental validation is given and the 3T3 NRU in vitro phototoxicity test is used as an example for a successful validation study, which led to the acceptance of the first in vitro toxicity test for regulatory purposes by the OECD. Finally, the currently accepted alternative methods for standardisation and safety testing of drugs, biologicals and medical devices are summarised.

Fatal overdose from Bendectin.

PubMed

Bayley, M; Walsh, F M; Valaske, M J

1975-05-01

A three-year old male ingested approximately 100 tablets of Bendectin. He developed tonic-clonic seizures followed by cardiac arrest. Toxicologic analysis yielded high levels of doxylamine, dicyclomine, and pyridoxine in blood, peritoneal fluid, and tissue homogenates. The antihistamine, doxylamine succinate appears to be the toxic constituent. Analytical methods used to document the case are herein described.

The SEURAT-1 approach towards animal free human safety assessment.

PubMed

Gocht, Tilman; Berggren, Elisabet; Ahr, Hans Jürgen; Cotgreave, Ian; Cronin, Mark T D; Daston, George; Hardy, Barry; Heinzle, Elmar; Hescheler, Jürgen; Knight, Derek J; Mahony, Catherine; Peschanski, Marc; Schwarz, Michael; Thomas, Russell S; Verfaillie, Catherine; White, Andrew; Whelan, Maurice

2015-01-01

SEURAT-1 is a European public-private research consortium that is working towards animal-free testing of chemical compounds and the highest level of consumer protection. A research strategy was formulated based on the guiding principle to adopt a toxicological mode-of-action framework to describe how any substance may adversely affect human health.The proof of the initiative will be in demonstrating the applicability of the concepts on which SEURAT-1 is built on three levels:(i) Theoretical prototypes for adverse outcome pathways are formulated based on knowledge already available in the scientific literature on investigating the toxicological mode-of-actions leading to adverse outcomes (addressing mainly liver toxicity);(ii)adverse outcome pathway descriptions are used as a guide for the formulation of case studies to further elucidate the theoretical model and to develop integrated testing strategies for the prediction of certain toxicological effects (i.e., those related to the adverse outcome pathway descriptions);(iii) further case studies target the application of knowledge gained within SEURAT-1 in the context of safety assessment. The ultimate goal would be to perform ab initio predictions based on a complete understanding of toxicological mechanisms. In the near-term, it is more realistic that data from innovative testing methods will support read-across arguments. Both scenarios are addressed with case studies for improved safety assessment. A conceptual framework for a rational integrated assessment strategy emerged from designing the case studies and is discussed in the context of international developments focusing on alternative approaches for evaluating chemicals using the new 21st century tools for toxicity testing.

SAR/QSAR methods in public health practice

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

Demchuk, Eugene, E-mail: edemchuk@cdc.gov; Ruiz, Patricia; Chou, Selene

2011-07-15

Methods of (Quantitative) Structure-Activity Relationship ((Q)SAR) modeling play an important and active role in ATSDR programs in support of the Agency mission to protect human populations from exposure to environmental contaminants. They are used for cross-chemical extrapolation to complement the traditional toxicological approach when chemical-specific information is unavailable. SAR and QSAR methods are used to investigate adverse health effects and exposure levels, bioavailability, and pharmacokinetic properties of hazardous chemical compounds. They are applied as a part of an integrated systematic approach in the development of Health Guidance Values (HGVs), such as ATSDR Minimal Risk Levels, which are used to protectmore » populations exposed to toxic chemicals at hazardous waste sites. (Q)SAR analyses are incorporated into ATSDR documents (such as the toxicological profiles and chemical-specific health consultations) to support environmental health assessments, prioritization of environmental chemical hazards, and to improve study design, when filling the priority data needs (PDNs) as mandated by Congress, in instances when experimental information is insufficient. These cases are illustrated by several examples, which explain how ATSDR applies (Q)SAR methods in public health practice.« less

Adverse outcome pathways (AOPs): A framework to support predictive toxicology

EPA Science Inventory

High throughput and in silico methods are providing the regulatory toxicology community with capacity to rapidly and cost effectively generate data concerning a chemical’s ability to initiate one or more biological perturbations that may culminate in an adverse ecological o...

A UNIFYING CONCEPT FOR ASSESSING TOXICOLOGICAL INTERACTIONS: CHANGES IN SLOPE

EPA Science Inventory

Robust statistical methods are important to the evaluation of interactions among chemicals in a mixture. However, different concepts of interaction as applied to the statistical analysis of chemical mixture toxicology data or as used in environmental risk assessment often can ap...

The startle response and toxicology: Methods, use and interpretation.

EPA Science Inventory

The startle response (SR) is a sensory-evoked motor reflex that has been used successfully in toxicology for decades. Advantages of this procedure include: rapidly objective measurement of a defined neural circuit, measurement of habituation of the response, and a high potential ...

Toward the Replacement of Animal Experiments through the Bioinformatics-driven Analysis of 'Omics' Data from Human Cell Cultures.

PubMed

Grafström, Roland C; Nymark, Penny; Hongisto, Vesa; Spjuth, Ola; Ceder, Rebecca; Willighagen, Egon; Hardy, Barry; Kaski, Samuel; Kohonen, Pekka

2015-11-01

This paper outlines the work for which Roland Grafström and Pekka Kohonen were awarded the 2014 Lush Science Prize. The research activities of the Grafström laboratory have, for many years, covered cancer biology studies, as well as the development and application of toxicity-predictive in vitro models to determine chemical safety. Through the integration of in silico analyses of diverse types of genomics data (transcriptomic and proteomic), their efforts have proved to fit well into the recently-developed Adverse Outcome Pathway paradigm. Genomics analysis within state-of-the-art cancer biology research and Toxicology in the 21st Century concepts share many technological tools. A key category within the Three Rs paradigm is the Replacement of animals in toxicity testing with alternative methods, such as bioinformatics-driven analyses of data obtained from human cell cultures exposed to diverse toxicants. This work was recently expanded within the pan-European SEURAT-1 project (Safety Evaluation Ultimately Replacing Animal Testing), to replace repeat-dose toxicity testing with data-rich analyses of sophisticated cell culture models. The aims and objectives of the SEURAT project have been to guide the application, analysis, interpretation and storage of 'omics' technology-derived data within the service-oriented sub-project, ToxBank. Particularly addressing the Lush Science Prize focus on the relevance of toxicity pathways, a 'data warehouse' that is under continuous expansion, coupled with the development of novel data storage and management methods for toxicology, serve to address data integration across multiple 'omics' technologies. The prize winners' guiding principles and concepts for modern knowledge management of toxicological data are summarised. The translation of basic discovery results ranged from chemical-testing and material-testing data, to information relevant to human health and environmental safety. 2015 FRAME.

Toxicogenomics and clinical toxicology: an example of the connection between basic and applied sciences.

PubMed

Ferrer-Dufol, Ana; Menao-Guillen, Sebastian

2009-04-10

The relationship between basic research and its potential clinical applications is often a difficult subject. Clinical toxicology has always been very dependent on experimental research whose usefulness has been impaired by the existence of huge differences in the toxicity expression of different substances, inter- and intra-species which make it difficult to predict clinical effects in humans. The new methods in molecular biology developed in the last decades are furnishing very useful tools to study some of the more relevant molecules implied in toxicokinetic and toxicodynamic processes. We aim to show some meaningful examples of how recent research developments with genes and proteins have clear applications to understand significant clinical matters, such as inter-individual variations in susceptibility to chemicals, and other phenomena related to the way some substances act to induce variations in the expression and functionality of these targets.

78 FR 4147 - Notice of Development of Set 26 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-18

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [ATSDR-277] Notice of Development of Set 26 Toxicological Profiles AGENCY: Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services (HHS). ACTION: Notice. SUMMARY: This...

77 FR 6800 - Notice of Development of Set 25 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [ATSDR-273] Notice of Development of Set 25 Toxicological Profiles AGENCY: Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services (DHHS). ACTION: Notice. SUMMARY: This...

Bridging the divide between human and environmental nanotoxicology

NASA Astrophysics Data System (ADS)

Malysheva, Anzhela; Lombi, Enzo; Voelcker, Nicolas H.

2015-10-01

The need to assess the human and environmental risks of nanoscale materials has prompted the development of new metrological tools for their detection, quantification and characterization. Some of these methods have tremendous potential for use in various scenarios of nanotoxicology. However, in some cases, the limited dialogue between environmental scientists and human toxicologists has hampered the full exploitation of these resources. Here we review recent progress in the development of methods for nanomaterial analysis and discuss the use of these methods in environmental and human toxicology. We highlight the opportunities for collaboration between these two research areas.

Course constructions: A case-base of forensic toxicology.

PubMed

Zhou, Nan; Wu, Yeda; Su, Terry; Zhang, Liyong; Yin, Kun; Zheng, Da; Zheng, Jingjing; Huang, Lei; Wu, Qiuping; Cheng, Jianding

2017-08-01

Forensic toxicology education in China is limited by insufficient teaching methods and resources, resulting in students with adequate theoretical principles but lacking practice experience. Typical cases used as teaching materials vividly represent intoxication and provide students with an opportunity to practice and hone resolving skills. In 2013, the Department of Forensic Pathology at Zhongshan School of Medicine began to construct top-quality courses in forensic toxicology, with its first step, creating a base containing typical cases of intoxication. This essay reviews the construction process of said cases-base, which is intended to set an example of forensic toxicology education. Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

PubMed

Bercu, J P; Galloway, S M; Parris, P; Teasdale, A; Masuda-Herrera, M; Dobo, K; Heard, P; Kenyon, M; Nicolette, J; Vock, E; Ku, W; Harvey, J; White, A; Glowienke, S; Martin, E A; Custer, L; Jolly, R A; Thybaud, V

2018-04-01

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. Copyright © 2018. Published by Elsevier Inc.

Overview of the "epigenetic end points in toxicologic pathology and relevance to human health" session of the 2014 Society Of Toxicologic Pathology Annual Symposium.

PubMed

Hoenerhoff, Mark J; Hartke, James

2015-01-01

The theme of the Society of Toxicologic Pathology 2014 Annual Symposium was "Translational Pathology: Relevance of Toxicologic Pathology to Human Health." The 5th session focused on epigenetic end points in biology, toxicity, and carcinogenicity, and how those end points are relevant to human exposures. This overview highlights the various presentations in this session, discussing integration of epigenetics end points in toxicologic pathology studies, investigating the role of epigenetics in product safety assessment, epigenetic changes in cancers, methodologies to detect them, and potential therapies, chromatin remodeling in development and disease, and epigenomics and the microbiome. The purpose of this overview is to discuss the application of epigenetics to toxicologic pathology and its utility in preclinical or mechanistic based safety, efficacy, and carcinogenicity studies. © 2014 by The Author(s).

Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions.

PubMed

Tralau, Tewes; Oelgeschläger, Michael; Gürtler, Rainer; Heinemeyer, Gerhard; Herzler, Matthias; Höfer, Thomas; Itter, Heike; Kuhl, Thomas; Lange, Nikola; Lorenz, Nicole; Müller-Graf, Christine; Pabel, Ulrike; Pirow, Ralph; Ritz, Vera; Schafft, Helmut; Schneider, Heiko; Schulz, Thomas; Schumacher, David; Zellmer, Sebastian; Fleur-Böl, Gaby; Greiner, Matthias; Lahrssen-Wiederholt, Monika; Lampen, Alfonso; Luch, Andreas; Schönfelder, Gilbert; Solecki, Roland; Wittkowski, Reiner; Hensel, Andreas

2015-06-01

The advent of new testing systems and "omics"-technologies has left regulatory toxicology facing one of the biggest challenges for decades. That is the question whether and how these methods can be used for regulatory purposes. The new methods undoubtedly enable regulators to address important open questions of toxicology such as species-specific toxicity, mixture toxicity, low-dose effects, endocrine effects or nanotoxicology, while promising faster and more efficient toxicity testing with the use of less animals. Consequently, the respective assays, methods and testing strategies are subject of several research programs worldwide. On the other hand, the practical application of such tests for regulatory purposes is a matter of ongoing debate. This document summarizes key aspects of this debate in the light of the European "regulatory status quo", while elucidating new perspectives for regulatory toxicity testing.

Adverse outcome pathways (AOPs): A framework to support predictive toxicology (presentation)

EPA Science Inventory

High throughput and in silico methods are providing the regulatory toxicology community with capacity to rapidly and cost effectively generate data concerning a chemical’s ability to initiate one or more biological perturbations that may culminate in an adverse ecological o...

Expert consensus on an in vitro approach to assess ...

EPA Pesticide Factsheets

Report from an international workshop with the goal of reviewing the state-of-the-science and determine the technical needs to develop an in vitro system that will reduce and eventually replace the use of animals for evaluating the potential inhalation toxicity of nanomaterials (NMs) in a regulatory setting. Workshop was co-organized in February 2015 by the PETA International Science Consortium Ltd. with the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods an international workshop that was attended by representatives from industry, government, academia, and non-governmental organizations with expertise in in vivo and in vitro lung systems, respiratory toxicology, inhalation particle dosimetry, nanotoxicology, and hazard and human health risk analysis. This report provides an overview of the presentations, discussions, and recommendations of the participants on the design of an in vitro system for the prediction of pulmonary fibrosis. The workshop participants identified multi-walled carbon nanotubes (MWCNTs), which have been shown to induce fibrosis in animal experiments and represent an important commercial nanomaterial class, as representative pro-fibrogenic NMs to use for the development of an in vitro test system. Recommendations were made for designing a system using lung relevant cells co-cultured at the air-liquid interface to assess the pro-fibrogenic potential of aerosolized MWCNTs, while consider

Predicting Chemical Toxicity from Proteomics and Computational Chemistry

DTIC Science & Technology

2008-07-30

similarity spaces, BD Gute and SC Basak, SAR QSAR Environ. Res., 17, 37-51 (2006). Predicting pharmacological and toxicological activity of heterocyclic...affinity of dibenzofurans: a hierarchical QSAR approach, authored jointly by Basak and Mills; Division of Chemical Toxicology iii. Prediction of blood...biodescriptors vis-ä-vis chemodescriptors in predictive toxicology e) Development of integrated QSTR models using the combined set of chemodescriptors and

Exploration of the Chemical Space of Public Genomic ...

EPA Pesticide Factsheets

The current project aims to chemically index the content of public genomic databases to make these data accessible in relation to other publicly available, chemically-indexed toxicological information. By evaluating the chemical space of public genomic data in relation to public toxicological data, it is possible to identify classes of chemicals on which to develop methodologies for the integration of chemogenomic data into predictive toxicology.

75 FR 16108 - Science Advisory Board Staff Office; Notification of a Public Teleconference and Public Meeting...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-31

... Information System (IRIS) is an electronic database containing descriptive and quantitative toxicological... Office of Research and Development (ORD). In 2001, ORD developed a draft IRIS Toxicological Assessment..., the National Research Council (NRC) was requested to provide a scientific consultation on key...

IRIS Toxicological Review and Summary Documents for Vinyl Chloride (External Review Draft)

EPA Science Inventory

The Draft Toxicological Review was developed to evaluate both the cancer and non cancer human health risks from environmental exposure to vinyl chloride. A reference concentration (RfC), and a reference dose (RfD) were developed based upon induction of liver cell polymorphism in ...

A primer on systematic reviews in toxicology.

PubMed

Hoffmann, Sebastian; de Vries, Rob B M; Stephens, Martin L; Beck, Nancy B; Dirven, Hubert A A M; Fowle, John R; Goodman, Julie E; Hartung, Thomas; Kimber, Ian; Lalu, Manoj M; Thayer, Kristina; Whaley, Paul; Wikoff, Daniele; Tsaioun, Katya

2017-07-01

Systematic reviews, pioneered in the clinical field, provide a transparent, methodologically rigorous and reproducible means of summarizing the available evidence on a precisely framed research question. Having matured to a well-established approach in many research fields, systematic reviews are receiving increasing attention as a potential tool for answering toxicological questions. In the larger framework of evidence-based toxicology, the advantages and obstacles of, as well as the approaches for, adapting and adopting systematic reviews to toxicology are still being explored. To provide the toxicology community with a starting point for conducting or understanding systematic reviews, we herein summarized available guidance documents from various fields of application. We have elaborated on the systematic review process by breaking it down into ten steps, starting with planning the project, framing the question, and writing and publishing the protocol, and concluding with interpretation and reporting. In addition, we have identified the specific methodological challenges of toxicological questions and have summarized how these can be addressed. Ultimately, this primer is intended to stimulate scientific discussions of the identified issues to fuel the development of toxicology-specific methodology and to encourage the application of systematic review methodology to toxicological issues.

Quantitative measurement of XLR11 and UR-144 in oral fluid by LC-MS-MS.

PubMed

Amaratunga, Piyadarsha; Thomas, Christopher; Lemberg, Bridget Lorenz; Lemberg, Dave

2014-01-01

Availability and consumption of synthetic cannabinoids have risen recently in the USA and Europe. These drugs have adverse effects, including acute psychosis and bizarre behavior. In 2012, the United States Drug Enforcement Agency permanently banned five of the synthetic cannabinoids and in 2013, temporarily added XLR11, UR-144 and AKB48 to Schedule I of the Controlled Substances Act. As synthetic cannabinoid strains are added to the Schedule I list, new strains are being introduced into the market. XLR11 and UR-144 are two of the most recent additions to the synthetic cannabinoid drug class. To test collected oral fluid samples for XLR11 and UR-144, we developed a bioanalytical method that initially purifies the sample with solid-phase extraction and then quantitatively identifies the drugs with ultra-high-performance liquid chromatography-tandem mass spectrometry. The method was validated according to United States Food and Drug Administration guidelines and Scientific Working Group for Forensic Toxicology guidelines and the validation data showed that the method is an accurate, precise, robust and efficient method suited for high-throughput toxicological screening applications. We tested human subject samples with the developed method and found the presence of parent drugs (XLR11 and UR-144), their metabolites and their pyrolysis products in oral fluid. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Alarms about structural alerts.

PubMed

Alves, Vinicius; Muratov, Eugene; Capuzzi, Stephen; Politi, Regina; Low, Yen; Braga, Rodolpho; Zakharov, Alexey V; Sedykh, Alexander; Mokshyna, Elena; Farag, Sherif; Andrade, Carolina; Kuz'min, Victor; Fourches, Denis; Tropsha, Alexander

2016-08-21

Structural alerts are widely accepted in chemical toxicology and regulatory decision support as a simple and transparent means to flag potential chemical hazards or group compounds into categories for read-across. However, there has been a growing concern that alerts disproportionally flag too many chemicals as toxic, which questions their reliability as toxicity markers. Conversely, the rigorously developed and properly validated statistical QSAR models can accurately and reliably predict the toxicity of a chemical; however, their use in regulatory toxicology has been hampered by the lack of transparency and interpretability. We demonstrate that contrary to the common perception of QSAR models as "black boxes" they can be used to identify statistically significant chemical substructures (QSAR-based alerts) that influence toxicity. We show through several case studies, however, that the mere presence of structural alerts in a chemical, irrespective of the derivation method (expert-based or QSAR-based), should be perceived only as hypotheses of possible toxicological effect. We propose a new approach that synergistically integrates structural alerts and rigorously validated QSAR models for a more transparent and accurate safety assessment of new chemicals.

Laboratory for Energy-Related Health Research: Annual report, fiscal year 1987

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

Abell, D.L.

1989-04-01

The laboratory's research objective is to provide new knowledge for an improved understanding of the potential bioenvironmental and occupational health problems associated with energy utilization. Our purpose is to contribute to the safe and healthful development of energy resources for the benefit of mankind. This research encompasses several areas of basic investigation that relate to toxicological and biomedical problems associated with potentially toxic chemical and radioactive substances and ionizing radiation, with particular emphasis on carcinogenicity. Studies of systemic injury and nuclear-medical diagnostic and therapeutic methods are also involved. This program is interdisciplinary; it involves physics, chemistry, environmental engineering, biophysics andmore » biochemistry, cellular and molecular biology, physiology, immunology, toxicology, both human and veterinary medicine, nuclear medicine, pathology, hematology, radiation biology, reproductive biology, oncology, biomathematics, and computer science. The principal themes of the research at LEHR center around the biology, radiobiology, and health status of the skeleton and its blood-forming constituents; the toxicology and properties of airborne materials; the beagle as an experimental animal model; carcinogenesis; and the scaling of the results from laboratory animal studies to man for appropriate assessment of risk.« less

Using Pareto points for model identification in predictive toxicology

PubMed Central

2013-01-01

Predictive toxicology is concerned with the development of models that are able to predict the toxicity of chemicals. A reliable prediction of toxic effects of chemicals in living systems is highly desirable in cosmetics, drug design or food protection to speed up the process of chemical compound discovery while reducing the need for lab tests. There is an extensive literature associated with the best practice of model generation and data integration but management and automated identification of relevant models from available collections of models is still an open problem. Currently, the decision on which model should be used for a new chemical compound is left to users. This paper intends to initiate the discussion on automated model identification. We present an algorithm, based on Pareto optimality, which mines model collections and identifies a model that offers a reliable prediction for a new chemical compound. The performance of this new approach is verified for two endpoints: IGC50 and LogP. The results show a great potential for automated model identification methods in predictive toxicology. PMID:23517649

Principles and procedures in forensic toxicology.

PubMed

Wyman, John F

2012-09-01

The principles and procedures employed in a modern forensic toxicology lab are detailed in this review. Aspects of Behavioral and Postmortem toxicology, including certification of analysts and accreditation of labs, chain of custody requirements, typical testing services provided, rationale for specimen selection, and principles of quality assurance are discussed. Interpretation of toxicology results in postmortem specimens requires the toxicologist and pathologist to be cognizant of drug-drug interactions, drug polymorphisms and pharmacogenomics, the gross signs of toxic pathology, postmortem redistribution, confirmation of systemic toxicity in suspected overdoses, the possibility of developed tolerance, and the effects of decomposition on drug concentration.

Proceedings of the Conference on Environmental Toxicology (11th), 18-20 November 1980, Dayton, OH

DTIC Science & Technology

1981-06-01

here to enrich your own understanding, to infuse new ideas and, I believe, ultimately to develop practical solutions to the problem of ensuring human...behavioral batteries evaluate the development of various reflexes and complex behaviors and usually include time of appearance of developmental landmarks...that there has been tremendous effort expended in the development of research methods for use with rats. I also see a number of problems and I’m

A review on phytochemistry, pharmacology and toxicology studies of Aconitum.

PubMed

Nyirimigabo, Eric; Xu, Yanyan; Li, Yubo; Wang, Yuming; Agyemang, Kojo; Zhang, Yanjun

2015-01-01

A number of species belonging to herbal genus Aconitum are well-known and popular for their medicinal benefits in Indian, Vietnamese, Korean, Japanese, Tibetan and Chinese systems of medicine. It is a valuable drug as well as an unpredictable toxic material. It is therefore imperative to understand and control the toxic potential of herbs from this genus. In this review, the ethnomedicinal, phytochemistry, pharmacology, structure activity relationship and toxicology studies of Aconitum were presented to add to knowledge for their safe application. A total of about 76 of all aconite species growing in China and surrounding far-east and Asian countries are used for various medical purposes. The main ingredients of aconite species are alkaloids, flavonoids, free fatty acids and polysaccharides. The tuberous roots of genus Aconitum are commonly applied for various diseases such as rheumatic fever, painful joints and some endocrinal disorders. It stimulates the tip of sensory nerve fibres. These tubers of Aconitum are used in the herbal medicines only after processing. There remain high toxicological risks of the improper medicinal applications of Aconitum. The cardio and neurotoxicities of this herb are potentially lethal. Many analytical methods have been reported for quantitatively and qualitatively characterization of Aconitum. Aconitum is a plant of great importance both in traditional medicine in general and in TCM in particular. Much attention should be put on Aconitum because of its narrow therapeutic range. However, Aconitum's toxicity can be reduced using different techniques and then benefit from its pharmacological activities. New methods, approaches and techniques should be developed for chemical and toxicological analysis to improve its quality and safety. © 2014 Royal Pharmaceutical Society.

Discovery, identification and mitigation of isobaric sulfate metabolite interference to a phosphate prodrug in LC-MS/MS bioanalysis: Critical role of method development in ensuring assay quality.

PubMed

Yuan, Long; Ji, Qin C

2018-06-05

Metabolite interferences represent a major risk of inaccurate quantification when using LC-MS/MS bioanalytical assays. During LC-MS/MS bioanalysis of BMS-919194, a phosphate ester prodrug, in plasma samples from rat and monkey GLP toxicology studies, an unknown peak was detected in the MRM channel of the prodrug. This peak was not observed in previous discovery toxicology studies, in which a fast gradient LC-MS/MS method was used. We found out that this unknown peak would co-elute with the prodrug peak when the discovery method was used, therefore, causing significant overestimation of the exposure of the prodrug in the discovery toxicology studies. To understand the nature of this interfering peak and its impact to bioanalytical assay, we further investigated its formation and identification. The interfering compound and the prodrug were found to be isobaric and to have the same major product ions in electrospray ionization positive mode, thus, could not be differentiated using a triple quadrupole mass spectrometer. By using high-resolution mass spectrometry (HRMS), the interfering metabolite was successfully identified to be an isobaric sulfate metabolite of BMS-919194. To the best of our knowledge, this is the first report that a phosphate prodrug was metabolized in vivo to an isobaric sulfate metabolite, and this metabolite caused significant interference to the analysis of the prodrug. This work demonstrated the presence of the interference risk from isobaric sulfate metabolites to the bioanalysis of phosphate prodrugs in real samples. It is critical to evaluate and mitigate potential metabolite interferences during method development, therefore, minimize the related bioanalytical risks and ensure assay quality. Our work also showed the unique advantages of HRMS in identifying potential metabolite interference during LC-MS/MS bioanalysis. Copyright © 2018 Elsevier B.V. All rights reserved.

IRIS TOXICOLOGICAL REVIEW AND SUMMARY ...

EPA Pesticide Factsheets

Trichloroacetic acid is a crystalline solid with sharp, pungent odor. It is used as a soil sterilizer; and as a laboratory intermediate or reagent in the synthesis of a variety of medicinal products and organic chemicals. Trichloroacetic acid is also used industrially as an etching and pickling agent for the surface treatment of metals and as a solvent in the plastics industry. Trichloroacetic acid can be formed as a combustion byproduct of organic compounds in the presence of chlorine. It is also formed as a disinfection byproduct during water chlorination. The existing IRIS entry was added to the IRIS data base between 1994 and 1996. No RfD was developed. The IRIS program is updating the IRIS assessment for Trichloroacetic Acid. This update will incorporate health effects information published since the last assessment was prepared as well as new risk assessment methods. The IRIS assessment for Trichloroacetic Acid will consist of a Toxicological Review and IRIS Summary. The Toxicological Review is a critical review of the physicochemical and toxicokinetic properties of the chemical and its toxicity in humans and experimental systems. The assessment will present reference value for noncancer effects of Trichloroacetic Acid (RfD) and a cancer assessment. The Toxicological Review and IRIS Summary will be subject to internal peer consultation, Agency review and external scientific peer review. The final products will constitute the Agency's opinion on the

Risk, Uncertainty and Precaution in Science: The Threshold of the Toxicological Concern Approach in Food Toxicology.

PubMed

Bschir, Karim

2017-04-01

Environmental risk assessment is often affected by severe uncertainty. The frequently invoked precautionary principle helps to guide risk assessment and decision-making in the face of scientific uncertainty. In many contexts, however, uncertainties play a role not only in the application of scientific models but also in their development. Building on recent literature in the philosophy of science, this paper argues that precaution should be exercised at the stage when tools for risk assessment are developed as well as when they are used to inform decision-making. The relevance and consequences of this claim are discussed in the context of the threshold of the toxicological concern approach in food toxicology. I conclude that the approach does not meet the standards of an epistemic version of the precautionary principle.

Modeling Biotransformation Using In Vitro Data on Parent-Metabolite Pairs within the ToxCast Phase I Chemical Set

EPA Science Inventory

A major focus in toxicology research is the development of new in vitro methods to predict in vivo chemical toxicity. Within the EPA ToxCast program, a broad range of in vitro biochemical and cellular assays have been deployed to profile the biological activity of 320 Phase I che...

Workgroup II Synopsis: Containment Fate and Effects in Freshwater Wetlands

Treesearch

A. Dennis Lemly; G. Ronnie Best; Wiliam G. Crumpton; Mary G. Henry; Donald D. Hook; Greg Linder; Patrick H. Masscheleyn; Hans G. Peterson; Terrence Salt; Ralph G. Stahl

1999-01-01

Pollution ecology is one of the few disciplines in biology that grew out of a societal need to fix a problem. The research community was forming questions as well as simultaneously developing methods, both toxicological and analytical, to address the questions in a cultural framework that demanded immediate answers. Aquatic toxicologists wrestled with pollution issues...

Computational Toxicology as Implemented by the US EPA ...

EPA Pesticide Factsheets

Computational toxicology is the application of mathematical and computer models to help assess chemical hazards and risks to human health and the environment. Supported by advances in informatics, high-throughput screening (HTS) technologies, and systems biology, the U.S. Environmental Protection Agency EPA is developing robust and flexible computational tools that can be applied to the thousands of chemicals in commerce, and contaminant mixtures found in air, water, and hazardous-waste sites. The Office of Research and Development (ORD) Computational Toxicology Research Program (CTRP) is composed of three main elements. The largest component is the National Center for Computational Toxicology (NCCT), which was established in 2005 to coordinate research on chemical screening and prioritization, informatics, and systems modeling. The second element consists of related activities in the National Health and Environmental Effects Research Laboratory (NHEERL) and the National Exposure Research Laboratory (NERL). The third and final component consists of academic centers working on various aspects of computational toxicology and funded by the U.S. EPA Science to Achieve Results (STAR) program. Together these elements form the key components in the implementation of both the initial strategy, A Framework for a Computational Toxicology Research Program (U.S. EPA, 2003), and the newly released The U.S. Environmental Protection Agency's Strategic Plan for Evaluating the T

Latin America's present and future challenges in toxicology education

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

Rojas, M.

2005-09-01

Industrialization that Latin America has experienced during the past 50 years, the increase of population and the growth of chemical-related industries has generated a variety of environmental problems that must be addressed. After assessing these profound changes, greater emphasis should be placed on the study of environmental health and toxicology. Latin American countries face many problems that are common to other developing nations. Therefore, there is a demand for safety assessment and regulatory control of chemicals that create a need for increasing numbers of toxicologists. To meet this demand, educational programs in toxicology have to be designed. This paper utilizesmore » a consultation questionnaire that includes toxicology-network members, scientists and educational institutions where toxicology is taught. An analysis of the information collected is made, with an emphasis on what we currently lack and on future challenges for toxicology professionals. Although the response from the study institutions was 65% (13 countries out of 20), the paper aims to assess the present situation of toxicology. The convenience for a certification/recognition for toxicologists is also evaluated. Action needs to be taken to promote scientific development based on regional specific needs that require increasing at the number of toxicology programs, and promoting of cooperation between academics and researchers. Among the limitations we have are the variability of curricula, objectives and priorities. The increasing globalization of markets and regulations requires the harmonization of graduate/postgraduate programs to ensure that risk assessment and management are dealt with uniformly. Cooperation among our countries and international assistance should play a more prominent role in the promotion of regional integration and the more efficient utilization of international experience in defining educational policies.« less

Predictive Toxicology and In Vitro to In Vivo Extrapolation (AsiaTox2015)

EPA Science Inventory

A significant challenge in toxicology is the “too many chemicals” problem. Humans and environmental species are exposed to as many as tens of thousands of chemicals, few of which have been thoroughly tested using standard in vivo test methods. This talk will discuss several appro...

Toxicoproteomics in Aquatic Toxicology: iTRAQ Reveals Insight into Proteins Affected by 17alpha-ethinylestradiol, Dieldrin, and 17â-trenbolone

EPA Science Inventory

Toxicoproteomics is an emerging discipline in toxicology for characterizing chemical modes of action at the molecular level. We have successfully utilized a quantitative proteomics method termed isobaric tagging for relative and absolute quantitation (iTRAQ) to measure protein re...

Toxicology in Australia: a key component of environmental health.

PubMed

Priestly, Brian G; Di Marco, Peter; Sim, Malcolm; Moore, Michael R; Langley, Andrew

2007-10-01

Managing public concerns relating to chemical exposures can consume substantial public health resources, particularly as the scientific basis around these issues is often contentious. Toxicology remains underrecognized as a public health discipline in Australia, although Australian toxicologists are making significant contributions from academia, government, and the commercial sector toward assessing the level of risk and protecting the community from environmental hazards. Internationally, the growth of environmental toxicology and the promotion of sound science in risk assessment as a basis for making regulatory decisions have been, to some extent, driven by the outcomes of the 1992 UNCED Conference on Sustainable Development (Rio Summit) and its Chapter 19 Agenda 21 activities. The promotion of safe chemical management practices and the need for global strengthening of capabilities in toxicology are among the initiatives of the Intergovernmental Forum on Chemical Safety (IFCS), which was formed after the Rio Summit to manage these programs. This article describes some of the initiatives in capacity building that marked the development of environmental toxicology in Australia since 1992 in response to these international environmental health initiatives.

Multifaceted toxicity assessment of catalyst composites in transgenic zebrafish embryos.

PubMed

Jang, Gun Hyuk; Lee, Keon Yong; Choi, Jaewon; Kim, Sang Hoon; Lee, Kwan Hyi

2016-09-01

Recent development in the field of nanomaterials has given rise into the inquiries regarding the toxicological characteristics of the nanomaterials. While many individual nanomaterials have been screened for their toxicological effects, composites that accompany nanomaterials are not common subjects to such screening through toxicological assessment. One of the widely used composites that accompany nanomaterials is catalyst composite used to reduce air pollution, which was selected as a target composite with nanomaterials for the multifaceted toxicological assessment. As existing studies did not possess any significant data regarding such catalyst composites, this study focuses on investigating toxicological characteristics of catalyst composites from various angles in both in-vitro and in-vivo settings. Initial toxicological assessment on catalyst composites was conducted using HUVECs for cell viability assays, and subsequent in-vivo assay regarding their direct influence on living organisms was done. The zebrafish embryo and its transgenic lines were used in the in-vivo assays to obtain multifaceted analytic results. Data obtained from the in-vivo assays include blood vessel formation, mutated heart morphology, and heart functionality change. Our multifaceted toxicological assessment pointed out that chemical composites augmented with nanomaterials can too have toxicological threat as much as individual nanomaterials do and alarms us with their danger. This manuscript provides a multifaceted assessment for composites augmented with nanomaterials, of which their toxicological threats have been overlooked. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Toxicity Data Landscape for Environmental Chemicals

PubMed Central

Judson, Richard; Richard, Ann; Dix, David J.; Houck, Keith; Martin, Matthew; Kavlock, Robert; Dellarco, Vicki; Henry, Tala; Holderman, Todd; Sayre, Philip; Tan, Shirlee; Carpenter, Thomas; Smith, Edwin

2009-01-01

Objective Thousands of chemicals are in common use, but only a portion of them have undergone significant toxicologic evaluation, leading to the need to prioritize the remainder for targeted testing. To address this issue, the U.S. Environmental Protection Agency (EPA) and other organizations are developing chemical screening and prioritization programs. As part of these efforts, it is important to catalog, from widely dispersed sources, the toxicology information that is available. The main objective of this analysis is to define a list of environmental chemicals that are candidates for the U.S. EPA screening and prioritization process, and to catalog the available toxicology information. Data sources We are developing ACToR (Aggregated Computational Toxicology Resource), which combines information for hundreds of thousands of chemicals from > 200 public sources, including the U.S. EPA, National Institutes of Health, Food and Drug Administration, corresponding agencies in Canada, Europe, and Japan, and academic sources. Data extraction ACToR contains chemical structure information; physical–chemical properties; in vitro assay data; tabular in vivo data; summary toxicology calls (e.g., a statement that a chemical is considered to be a human carcinogen); and links to online toxicology summaries. Here, we use data from ACToR to assess the toxicity data landscape for environmental chemicals. Data synthesis We show results for a set of 9,912 environmental chemicals being considered for analysis as part of the U.S. EPA ToxCast screening and prioritization program. These include high-and medium-production-volume chemicals, pesticide active and inert ingredients, and drinking water contaminants. Conclusions Approximately two-thirds of these chemicals have at least limited toxicity summaries available. About one-quarter have been assessed in at least one highly curated toxicology evaluation database such as the U.S. EPA Toxicology Reference Database, U.S. EPA Integrated Risk Information System, and the National Toxicology Program. PMID:19479008

Imaging mass spectrometry in drug development and toxicology.

PubMed

Karlsson, Oskar; Hanrieder, Jörg

2017-06-01

During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.

Impact of online toxicology training on health professionals: the Global Educational Toxicology Uniting Project (GETUP).

PubMed

Wong, Anselm; Vohra, Rais; Dawson, Andrew H; Stolbach, Andrew

2017-11-01

The Global Educational Toxicology Uniting Project (GETUP), supported by the American College of Medical Toxicology, links countries with and without toxicology services via distance education with the aim to improve education. Due to the lack of toxicology services in some countries there is a knowledge gap in the management of poisonings. We describe our experience with the worldwide delivery of an online introductory toxicology curriculum to emergency doctors and other health professionals treating poisoned patients. We delivered a 15-module introductory Internet-based toxicology curriculum to emergency doctors and health professionals, conducted from August to December 2016. This Internet-based curriculum was adapted from one used to teach emergency residents toxicology in the United States. Modules covered themes such as pharmaceutical (n = 8), toxidromes (n = 2) and agrochemicals (n = 5) poisoning. Participants completed pre-test and post-test multiple choice questions (MCQs) before and after completing the online module, respectively, throughout the course. We collected information on participant demographics, education and training, and perception of relevance of the curriculum. Participants gave feedback on the course and how it affected their practice. One hundred and thirty-six health professionals from 33 countries participated in the course: 98 emergency doctors/medical officers, 25 physicians, eight pharmacists/poisons information specialists, two toxicologists, two medical students and one nurse. Median age of participants was 34 years. Median number of years postgraduate was seven. Ninety (65%) had access to either a poisons information centre over the phone or toxicologist and 48 (35%) did not. All participants expected the course to help improve their knowledge. Overall median pre-module MCQ scores were 56% (95%CI: 38, 75%) compared to post-module MCQ scores median 89% (95% CI: 67, 100%) (p < .0001). Our participants demonstrated an increase in medical knowledge based on performance on MCQs. An online toxicology curriculum is an effective way to deliver education to health professionals treating poisoned patients and can help to bridge the knowledge gap and change practice in developed and developing countries.

[Clinical and analytical toxicology of opiate, cocaine and amphetamine].

PubMed

Feliu, Catherine; Fouley, Aurélie; Millart, Hervé; Gozalo, Claire; Marty, Hélène; Djerada, Zoubir

2015-01-01

In several circumstances, determination and quantification of illicit drugs in biological fluids are determinant. Contexts are varied such as driving under influence, traffic accident, clinical and forensic toxicology, doping analysis, chemical submission. Whole blood is the favoured matrix for the quantification of illicit drugs. Gas chromatography coupled with mass spectrometry (GC-MS) is the gold standard for these analyses. All methods developed must be at least equivalent to gas chromatography coupled with a mass spectrometer. Nowadays, new technologies are available to biologists and clinicians: liquid chromatography coupled with a mass spectrometry (LC/MS) or coupled with a tandem mass spectrometer (LC/MS/MS). The aim of this paper is to describe the state of the art regarding techniques of confirmation by mass spectrometry used for quantification of conventional drugs except cannabis.

IRIS Toxicological Review of Dichloromethane (Methylene ...

EPA Pesticide Factsheets

EPA is releasing the draft report, Toxicological Review of Dichloromethane, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Comments received from other Federal agencies and White House Offices are provided below with external peer review panel comments. The draft Toxicological Review of Dichloromethane provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to dichloromethane.

IRIS Toxicological Review of Urea (Interagency Science ...

EPA Pesticide Factsheets

EPA is releasing the draft report, Toxicological Review of Urea,, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Comments received from other Federal agencies and White House Offices are provided below with external peer review panel comments. The draft Toxicological Review of Urea provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to Urea.

Environmental toxicology and risk assessment: Standardization of biomarkers for endocrine disruption and environmental assessment: Eighth volume. Special technical publication 1364

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

Henshel, D.S.; Black, M.C.; Harrass, M.C.

1999-07-01

This conference was held April 20--22, 1998 in Atlanta, Georgia. The purpose of this conference was to provide a multidisciplinary forum for exchange of state-of-the-art information on biological markers in toxicology and risk assessment, including endocrine disrupter screening assays. Attention is focused on the following: aquatic toxicology; behavioral toxicology; biochemical indicators; developmental indicators; endocrine indicators; biodegradation and fate of chemicals; quality assurance and quality control within laboratory and field studies; risk assessment and communication, and harmonization of standards development. Individual papers have been processed separately for inclusion in the appropriate data bases.

Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology.

PubMed

Kiyosawa, Naoki; Manabe, Sunao

2016-01-01

Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.

Cost analysis in the toxicology laboratory.

PubMed

Travers, E M

1990-09-01

The process of determining laboratory sectional and departmental costs and test costs for instrument-generated and manually generated reportable results for toxicology laboratories has been outlined in this article. It is hoped that the basic principles outlined in the preceding text will clarify and elucidate one of the most important areas needed for laboratory fiscal integrity and its survival in these difficult times for health care providers. The following general principles derived from this article are helpful aids for managers of toxicology laboratories. 1. To manage a cost-effective, efficient toxicology laboratory, several factors must be considered: the laboratory's instrument configuration, test turnaround time needs, the test menu offered, the analytic methods used, the cost of labor based on time expended and the experience and educational level of the staff, and logistics that determine specimen delivery time and costs. 2. There is a wide variation in costs for toxicologic methods, which requires that an analysis of capital (equipment) purchase and operational (test performance) costs be performed to avoid waste, purchase wisely, and determine which tests consume the majority of the laboratory's resources. 3. Toxicologic analysis is composed of many complex steps. Each step must be individually cost-accounted. Screening test results must be confirmed, and the cost for both steps must be included in the cost per reportable result. 4. Total costs will vary in the same laboratory and between laboratories based on differences in salaries paid to technical staff, differences in reagent/supply costs, the number of technical staff needed to operate the analyzer or perform the method, and the inefficient use of highly paid staff to operate the analyzer or perform the method. 5. Since direct test costs vary directly with the type and number of analyzers or methods and are dependent on the operational mode designed by the manufacturer, laboratory managers should construct an actual test-cost data base for instrument or method in use to accurately compare costs using the "bottom-up" approach. 6. Laboratory expenses can be examined from three perspectives: total laboratory, laboratory section, and subsection workstation. The objective is to track all laboratory expenses through each of these levels. 7. In the final analysis, a portion of total laboratory expenses must be allocated to each unit of laboratory output--the billable procedure or, in laboratories where tests are not billed, the tests produced.(ABSTRACT TRUNCATED AT 400 WORDS)

75 FR 54889 - Development of Set 24 Toxicological Profiles

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-09

... these documents will be available at the ATSDR Web site: http://www.atsdr.cdc.gov/toxpro2.html . Set 24... toxicological profiles for each substance included on the Priority List of Hazardous Substances ( http://www...

Techniques and Protocols for Dispersing Nanoparticle Powders in Aqueous Media-Is there a Rationale for Harmonization?

PubMed

Hartmann, Nanna B; Jensen, Keld Alstrup; Baun, Anders; Rasmussen, Kirsten; Rauscher, Hubert; Tantra, Ratna; Cupi, Denisa; Gilliland, Douglas; Pianella, Francesca; Riego Sintes, Juan M

2015-01-01

Selecting appropriate ways of bringing engineered nanoparticles (ENP) into aqueous dispersion is a main obstacle for testing, and thus for understanding and evaluating, their potential adverse effects to the environment and human health. Using different methods to prepare (stock) dispersions of the same ENP may be a source of variation in the toxicity measured. Harmonization and standardization of dispersion methods applied in mammalian and ecotoxicity testing are needed to ensure a comparable data quality and to minimize test artifacts produced by modifications of ENP during the dispersion preparation process. Such harmonization and standardization will also enhance comparability among tests, labs, and studies on different types of ENP. The scope of this review was to critically discuss the essential parameters in dispersion protocols for ENP. The parameters are identified from individual scientific studies and from consensus reached in larger scale research projects and international organizations. A step-wise approach is proposed to develop tailored dispersion protocols for ecotoxicological and mammalian toxicological testing of ENP. The recommendations of this analysis may serve as a guide to researchers, companies, and regulators when selecting, developing, and evaluating the appropriateness of dispersion methods applied in mammalian and ecotoxicity testing. However, additional experimentation is needed to further document the protocol parameters and investigate to what extent different stock dispersion methods affect ecotoxicological and mammalian toxicological responses of ENP.

Electronic cigarettes in the USA: a summary of available toxicology data and suggestions for the future.

PubMed

Orr, Michael S

2014-05-01

To review the available evidence evaluating the toxicological profiles of electronic cigarettes (e-cigarettes) in order to understand the potential impact of e-cigarettes on individual users and the public health. Systematic literature searches were conducted between October 2012 and October 2013 using five electronic databases. Search terms such as 'e-cigarettes' and 'electronic delivery devices' were used to identify the toxicology information for e-cigarettes. As of October 2013, the scientific literature contains very limited information regarding the toxicity of e-cigarettes commercially available in the USA. While some preliminary toxicology data suggests that e-cigarette users are exposed to lower levels of toxicants relative to cigarette smokers, the data available is extremely limited at this time. At present, there is insufficient toxicological data available to perform thorough risk assessment analyses for e-cigarettes; few toxicology studies evaluating e-cigarettes have been conducted to date, and standard toxicological testing paradigms have not been developed for comparing disparate types of tobacco products such as e-cigarettes and traditional cigarettes. Overall, the limited toxicology data on e-cigarettes in the public domain is insufficient to allow a thorough toxicological evaluation of this new type of tobacco product. In the future, the acquisition of scientific datasets that are derived from scientifically robust standard testing paradigms, include comprehensive chemical characterisation of the aerosol, provide information on users' toxicant exposure levels, and from studies replicated by independent researchers will improve the scientific community's ability to perform robust toxicological evaluations of e-cigarettes.

NONYLPHENOL AND ATRAZINE INDUCE INVERSE EFFECTS ON MAMMARY GLAND DEVELOPMENT IN FEMALE RATS EXPOSED IN UTERO

EPA Science Inventory

Nonylphenol and Atrazine Induce Inverse Effects on Mammary Gland Development in Female Rats Exposed In Utero.
HJ Moon1, SY Han1, CC Davis2, and SE Fenton2
1 Department of Toxicology, NITR, Korea FDA, 5Nokbun-Dong, Eunpyung-Gu, Seoul, Korea and 2 Reproductive Toxicology Divi...

Do prevailing XAD extraction methods used to generate extracts from disinfected water adequately link extract toxicology to disinfected water chemistry?

EPA Science Inventory

Motivation: It is common to use XAD resins to extract disinfection byproducts (DBPs) from disinfected water. The resulting extract is used in toxicological assays to study the effects of DBP mixtures and has been considered representative of the original disinfected water. Howeve...

DIGGING DEEPER INTO DEEP DATA: MOLECULAR DOCKING AS A HYPOTHESIS-DRIVEN BIOPHYSICAL INTERROGATION SYSTEM IN COMPUTATIONAL TOXICOLOGY.

EPA Science Inventory

Developing and evaluating prediactive strategies to elucidate the mode of biological activity of environmental chemicals is a major objective of the concerted efforts of the US-EPA's computational toxicology program.

AN AUTOMATED MONITORING SYSTEM FOR FISH PHYSIOLOGY AND TOXICOLOGY

EPA Science Inventory

This report describes a data acquisition and control (DAC) system that was constructed to manage selected physiological measurements and sample control for aquatic physiology and toxicology. Automated DAC was accomplished with a microcomputer running menu-driven software develope...

Fast determination of ethylene glycol, 1,2-propylene glycol and glycolic acid in blood serum and urine for emergency and clinical toxicology by GC-FID.

PubMed

Hložek, Tomáš; Bursová, Miroslava; Čabalaa, Radomír

2014-12-01

A simple, cost effective, and fast gas chromatography method with flame ionization detection (GC-FID) for simultaneous measurement of ethylene glycol, 1,2-propylene glycol and glycolic acid was developed and validated for clinical toxicology purposes. This new method employs a relatively less used class of derivatization agents - alkyl chloroformates, allowing the efficient and rapid derivatization of carboxylic acids within seconds while glycols are simultaneously derivatized by phenylboronic acid. The entire sample preparation procedure is completed within 10 min. To avoid possible interference from naturally occurring endogenous acids and quantitation errors 3-(4-chlorophenyl) propionic acid was chosen as an internal standard. The significant parameters of the derivatization have been found using chemometric procedures and these parameters were optimized using the face-centered central composite design. The calibration dependence of the method was proved to be quadratic in the range of 50-5000 mg mL(-1), with adequate accuracy (92.4-108.7%) and precision (9.4%). The method was successfully applied to quantify the selected compounds in serum of patients from emergency units. Copyright © 2014 Elsevier B.V. All rights reserved.

Cheminformatics Analysis of EPA ToxCast Chemical Libraries to Identify Domains of Applicability for Predictive Toxicity Models and Prioritize Compounds for Toxicity Testing

EPA Science Inventory

An important goal of toxicology research is the development of robust methods that use in vitro and chemical structure information to predict in vivo toxicity endpoints. The US EPA ToxCast program is addressing this goal using ~600 in vitro assays to create bioactivity profiles o...

Military Psychology: An Overview,

DTIC Science & Technology

1984-05-01

intelligence tests that were widely used in World War I and also served as the models for most group intelligence tests developed after the war for military and...in such areas as supervision, job satisfaction, organizational climate , and work-group effectiveness. For more information write: LMDC/AN, Maxwell Air...primate. Animal models and methods from the disciplines of behavioral toxicology, behavioral pharmacology, physiological psychology, and neurophysiology

Designing monitoring programs for chemicals of emerging concern in potable reuse--what to include and what not to include?

PubMed

Drewes, J E; Anderson, P; Denslow, N; Olivieri, A; Schlenk, D; Snyder, S A; Maruya, K A

2013-01-01

This study discussed a proposed process to prioritize chemicals for reclaimed water monitoring programs, selection of analytical methods required for their quantification, toxicological relevance of chemicals of emerging concern regarding human health, and related issues. Given that thousands of chemicals are potentially present in reclaimed water and that information about those chemicals is rapidly evolving, a transparent, science-based framework was developed to guide prioritization of which compounds of emerging concern (CECs) should be included in reclaimed water monitoring programs. The recommended framework includes four steps: (1) compile environmental concentrations (e.g., measured environmental concentration or MEC) of CECs in the source water for reuse projects; (2) develop a monitoring trigger level (MTL) for each of these compounds (or groups thereof) based on toxicological relevance; (3) compare the environmental concentration (e.g., MEC) to the MTL; CECs with a MEC/MTL ratio greater than 1 should be prioritized for monitoring, compounds with a ratio less than '1' should only be considered if they represent viable treatment process performance indicators; and (4) screen the priority list to ensure that a commercially available robust analytical method is available for that compound.

Poisonings and clinical toxicology: a template for Ireland.

PubMed

Tormey, W P; Moore, T

2013-03-01

Poisons information is accessed around the clock in the British Isles from six centres of which two are in Ireland at Dublin and Belfast accompanied by consultant toxicologist advisory service. The numbers of calls in Ireland are down to about 40 per day due to easy access to online data bases. Access to Toxbase, the clinical toxicology database of the National Poisons Information Service is available to National Health Service (NHS) health professionals and to Emergency Departments and Intensive Care units in the Republic of Ireland. There are 59 Toxbase users in the Republic of Ireland and 99 % of activity originates in Emergency Departments. All United States Poison Control Centres primarily use Poisindex which is a commercial database from Thomson Reuters. Information on paracetamol, diazepam, analgesics and psycho-active compounds are the commonest queries. Data from telephone and computer accesses provide an indicator of future trends in both licit and illicit drug poisons which may direct laboratory analytical service developments. Data from National Drug-Related Deaths Index is the most accurate information on toxicological deaths in Ireland. Laboratory toxicology requirements to support emergency departments are listed. Recommendations are made for a web-based open access Toxbase or equivalent; for a co-location of poisons information and laboratory clinical toxicology; for the establishment of a National Clinical Toxicology Institute for Ireland; for a list of accredited medical advisors in clinical toxicology; for multidisciplinary case conferences in complex toxicology cases for coroners; for the establishment of a national clinical toxicology referral out-patients service in Ireland.

Assessment of Environmental and Occupational Health Impacts in Munitions and Weapon Systems Development: A Phased Approach

DTIC Science & Technology

2010-12-01

Human Health Impacts of New Energetic Compounds. • Models – QSARs • In vitro toxicology • In vivo toxicology • Aligned with RDT&E level of...D.A.B.T. Health Effects Research Program Directorate of Toxicology Army Institute of Public Health UNCLASSIFIED Report Documentation Page Form...program. Early in the research stage models are primarily relied upon (e.g. QSAR approaches) and as the technology progresses, a greater reliance is

lazar: a modular predictive toxicology framework

PubMed Central

Maunz, Andreas; Gütlein, Martin; Rautenberg, Micha; Vorgrimmler, David; Gebele, Denis; Helma, Christoph

2013-01-01

lazar (lazy structure–activity relationships) is a modular framework for predictive toxicology. Similar to the read across procedure in toxicological risk assessment, lazar creates local QSAR (quantitative structure–activity relationship) models for each compound to be predicted. Model developers can choose between a large variety of algorithms for descriptor calculation and selection, chemical similarity indices, and model building. This paper presents a high level description of the lazar framework and discusses the performance of example classification and regression models. PMID:23761761

Acute Oral Toxicity of 3-Chloro-4,4-dimethyl-2-oxazolidinone (Compound 1) in ICR Mice

DTIC Science & Technology

1990-10-01

number) FIELD GROUP SUB-GROUP Acute Oral Toxicity, N- Chloramine , Mouse, Mammalian Toxicology, Water Disinfectant , 3-Chloro-4, 4 -dimethyl-2...Amer Ind Hyg Assoc Q 1943; 10:93-96. 7. Mora EC, Kohl HH, Wheatley WB, et al. Properties or a new chloramine disinfectant and detoxicant. Poultry Sci...ORGANIZATION Mammalian Toxicology (If applicable) US Army Biomedical Research Division of Toxicology SGRD-ULE- T and Development Laboratory 6c. ADDRESS

Collection analysis techniques used to evaluate a graduate-level toxicology collection.

PubMed

Crawley-Low, Jill V

2002-07-01

Collections librarians from academic libraries are often asked, on short notice, to evaluate whether their collections are able to support changes in their institutions' curricula, such as new programs or courses or revisions to existing programs or courses. With insufficient time to perform an exhaustive critique of the collection and a need to prepare a report for faculty external to the library, a selection of reliable but brief qualitative and quantitative tests is needed. In this study, materials-centered and use-centered methods were chosen to evaluate the toxicology collection of the University of Saskatchewan (U of S) Library. Strengths and weaknesses of the techniques are reviewed, along with examples of their use in evaluating the toxicology collection. The monograph portion of the collection was evaluated using list checking, citation analysis, and classified profile methods. Cost-effectiveness and impact factor data were compiled to rank journals from the collection. Use-centered methods such as circulation and interlibrary loan data identified highly used items that should be added to the collection. Finally, although the data were insufficient to evaluate the toxicology electronic journals at the U of S, a brief discussion of three initiatives that aim to assist librarians as they evaluate the use of networked electronic resources in their collections is presented.

The principle of safety evaluation in medicinal drug - how can toxicology contribute to drug discovery and development as a multidisciplinary science?

PubMed

Horii, Ikuo

2016-01-01

Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as "biological responses to foreign substances." This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of "on-target" or "off-target", and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of "how can multidisciplinary toxicology contribute to innovative drug discovery and development?" And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision medicine are to be addressed for the new aspect of efficacy and safety evaluation.

[Contaminants from food packaging : New developments in risk assessment].

PubMed

Pfaff, Karla; Wölfle, Detlef; Luch, Andreas

2017-07-01

Diverse materials intended for contact with food are important sources of food contamination. Harmonised European regulations including whitelists (so-called "positive lists") of substances along with migration limits and restrictions exist for plastics and regenerated cellulose films only. The European Food Safety Authority (EFSA) is responsible for the risk assessment of substances prior to their authorization and inclusion into the positive lists. In 2016 the EFSA issued an opinion on recent developments in the risk assessment of substances migrating into food for public consideration. Also migration related to non-intentionally added substances (NIASs), e. g. impurities, degradations products or oligomers, may be relevant for risk assessment. For substances migrating in quantities up to 50 ppb the requested data are restricted to genotoxicity testing based on a tiered approach for toxicological data requirements. In the case of higher migration levels (>50 ppb) experimental animal studies are also requested. Along with an evaluation of the available information, toxicological data on structurally similar substances may be used for the assessment if sufficiently justified with the aim to reduce animal studies as far as possible. For the risk assessment of NIASs it is possible to apply in silico methods in the absence of experimental toxicological data. Additionally, new technologies such as the use of nanomaterials, active and intelligent packaging and recycled plastics are challenging tasks in EFSA's risk assessment in accordance with the regulations by the European Commission.

Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2).

PubMed

Khan, Mohammad Firoz; Nahar, Nusrat; Rashid, Ridwan Bin; Chowdhury, Akhtaruzzaman; Rashid, Mohammad A

2018-02-02

Betulinic acid (BA) is a natural triterpenoid compound and exhibits a wide range of biological and medicinal properties including anti-inflammatory activity. Therefore, this theoretical investigation is performed to evaluate (a) physicochemical properties such as acid dissociation constant (pKa), distribution coefficient (logD), partition coefficient (logP), aqueous solubility (logS), solvation free energy, dipole moment, polarizability, hyperpolarizability and different reactivity descriptors, (b) pharmacokinetic properties like human intestinal absorption (HIA), cellular permeability, skin permeability (P Skin ), plasma protein binding (PPB), penetration of the blood brain barrier (BBB), (c) toxicological properties including mutagenicity, carcinogenicity, risk of inhibition of hERG gene and (d) molecular mechanism of anti-inflammatory action which will aid the development of analytical method and the synthesis of BA derivatives. The physicochemical properties were calculated using MarvinSketch 15.6.29 and Gaussian 09 software package. The pharmacokinetic and toxicological properties were calculated on online server PreADMET. Further, the molecular docking study was conducted on AutoDock vina in PyRx 0.8. The aqueous solubility increased with increasing pH due to the ionization of BA leading to decrease in distribution coefficient. The solvation energies in water, dimethyl sulfoxide (DMSO), acetonitrile, n-octanol, chloroform and carbon tetrachloride were - 41.74 kJ/mol, - 53.80 kJ/mol, - 66.27 kJ/mol, - 69.64 kJ/mol, - 65.96 kJ/mol and - 60.13 kJ/mol, respectively. From the results of polarizability and softness, it was clear that BA is less stable and hence, kinetically more reactive in water. BA demonstrated good human intestinal absorption (HIA) and moderate cellular permeability. Further, BA also exhibited positive CNS activity due to high permeability through BBB. The toxicological study revealed that BA was a mutagenic compound but noncarcinogenic in mice model. Moreover, molecular docking study of BA with PLA2 revealed that BA interacts with GLY22 & GLY29 through hydrogen bond formation and LEU2, PHE5, HIS6, ALA17, ALA18, HIS47 and TYR51 through different types of hydrophobic interactions. The binding affinity of BA was - 41.00 kJ/mol which is comparable to the binding affinity of potent inhibitor 6-Phenyl-4(R)-(7-Phenyl-heptanoylamino)-hexanoic acid (BR4) (- 33.89 kJ/mol). Our computed properties may assist the development of analytical method to assay BA or to develop BA derivatives with better pharmacokinetic and toxicological profile.

Building shared experience to advance practical application of pathway-based toxicology: liver toxicity mode-of-action.

PubMed

Willett, Catherine; Caverly Rae, Jessica; Goyak, Katy O; Minsavage, Gary; Westmoreland, Carl; Andersen, Melvin; Avigan, Mark; Duché, Daniel; Harris, Georgina; Hartung, Thomas; Jaeschke, Hartmut; Kleensang, Andre; Landesmann, Brigitte; Martos, Suzanne; Matevia, Marilyn; Toole, Colleen; Rowan, Andrew; Schultz, Terry; Seed, Jennifer; Senior, John; Shah, Imran; Subramanian, Kalyanasundaram; Vinken, Mathieu; Watkins, Paul

2014-01-01

A workshop sponsored by the Human Toxicology Project Consortium (HTPC), "Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action" brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is extremely helpful. In addition, it is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered.

Nano-technology and nano-toxicology.

PubMed

Maynard, Robert L

2012-01-01

Rapid developments in nano-technology are likely to confer significant benefits on mankind. But, as with perhaps all new technologies, these benefits are likely to be accompanied by risks, perhaps by new risks. Nano-toxicology is developing in parallel with nano-technology and seeks to define the hazards and risks associated with nano-materials: only when risks have been identified they can be controlled. This article discusses the reasons for concern about the potential effects on health of exposure to nano-materials and relates these to the evidence of the effects on health of the ambient aerosol. A number of hypotheses are proposed and the dangers of adopting unsubstantiated hypotheses are stressed. Nano-toxicology presents many challenges and will need substantial financial support if it is to develop at a rate sufficient to cope with developments in nano-technology.

Nano-technology and nano-toxicology

PubMed Central

Maynard, Robert L.

2012-01-01

Rapid developments in nano-technology are likely to confer significant benefits on mankind. But, as with perhaps all new technologies, these benefits are likely to be accompanied by risks, perhaps by new risks. Nano-toxicology is developing in parallel with nano-technology and seeks to define the hazards and risks associated with nano-materials: only when risks have been identified they can be controlled. This article discusses the reasons for concern about the potential effects on health of exposure to nano-materials and relates these to the evidence of the effects on health of the ambient aerosol. A number of hypotheses are proposed and the dangers of adopting unsubstantiated hypotheses are stressed. Nano-toxicology presents many challenges and will need substantial financial support if it is to develop at a rate sufficient to cope with developments in nano-technology. PMID:22662021

Public Databases Supporting Computational Toxicology

EPA Science Inventory

A major goal of the emerging field of computational toxicology is the development of screening-level models that predict potential toxicity of chemicals from a combination of mechanistic in vitro assay data and chemical structure descriptors. In order to build these models, resea...

IRIS Toxicological Review of Hexachloroethane (Interagency Science Consultation Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Hexachloroethane, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Comments received from other Federal agencies a...

MODELING CHEMICAL FATE AND METABOLISM FOR COMPUTATIONAL TOXICOLOGY

EPA Science Inventory

The goal of ORD's Computational Toxicology initiative is to develop the science for EPA to prioritize toxicity-testing requirements for chemicals subject to regulation. Many toxic effects, however, result from metabolism of parent chemicals to form metabolites that are much more...

IRIS Toxicological Review of Trichloroethylene (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Trichloroethylene, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Comments received from other Federal agencies ...

Recent Developments in Toxico-Cheminformatics: A New Frontier for Predictive Toxicology

EPA Science Inventory

Efforts to improve public access to chemical toxicity information resources, coupled with new high-throughput screening (HTS) data and efforts to systematize legacy toxicity studies, have the potential to significantly improve predictive capabilities in toxicology. Important rec...

Evaluating the Impact of the U.S. National Toxicology Program: A Case Study on Hexavalent Chromium.

PubMed

Xie, Yun; Holmgren, Stephanie; Andrews, Danica M K; Wolfe, Mary S

2017-02-01

Evaluating the impact of federally funded research with a broad, methodical, and objective approach is important to ensure that public funds advance the mission of federal agencies. We aimed to develop a methodical approach that would yield a broad assessment of National Toxicology Program's (NTP's) effectiveness across multiple sectors and demonstrate the utility of the approach through a case study. A conceptual model was developed with defined activities, outputs (products), and outcomes (proximal, intermediate, distal) and applied retrospectively to NTP's research on hexavalent chromium (CrVI). Proximal outcomes were measured by counting views of and requests for NTP's products by external stakeholders. Intermediate outcomes were measured by bibliometric analysis. Distal outcomes were assessed through Web and LexisNexis searches for documents related to legislation or regulation changes. The approach identified awareness of NTP's work on CrVI by external stakeholders (proximal outcome) and citations of NTP's research in scientific publications, reports, congressional testimonies, and legal and policy documents (intermediate outcome). NTP's research was key to the nation's first-ever drinking water standard for CrVI adopted by California in 2014 (distal outcome). By applying this approach to a case study, the utility and limitations of the approach were identified, including challenges to evaluating the outcomes of a research program. This study identified a broad and objective approach for assessing NTP's effectiveness, including methodological needs for more thorough and efficient impact assessments in the future. Citation: Xie Y, Holmgren S, Andrews DMK, Wolfe MS. 2017. Evaluating the impact of the U.S. National Toxicology Program: a case study on hexavalent chromium. Environ Health Perspect 125:181-188; http://dx.doi.org/10.1289/EHP21.

Aggregating Data for Computational Toxicology Applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System

PubMed Central

Judson, Richard S.; Martin, Matthew T.; Egeghy, Peter; Gangwal, Sumit; Reif, David M.; Kothiya, Parth; Wolf, Maritja; Cathey, Tommy; Transue, Thomas; Smith, Doris; Vail, James; Frame, Alicia; Mosher, Shad; Cohen Hubal, Elaine A.; Richard, Ann M.

2012-01-01

Computational toxicology combines data from high-throughput test methods, chemical structure analyses and other biological domains (e.g., genes, proteins, cells, tissues) with the goals of predicting and understanding the underlying mechanistic causes of chemical toxicity and for predicting toxicity of new chemicals and products. A key feature of such approaches is their reliance on knowledge extracted from large collections of data and data sets in computable formats. The U.S. Environmental Protection Agency (EPA) has developed a large data resource called ACToR (Aggregated Computational Toxicology Resource) to support these data-intensive efforts. ACToR comprises four main repositories: core ACToR (chemical identifiers and structures, and summary data on hazard, exposure, use, and other domains), ToxRefDB (Toxicity Reference Database, a compilation of detailed in vivo toxicity data from guideline studies), ExpoCastDB (detailed human exposure data from observational studies of selected chemicals), and ToxCastDB (data from high-throughput screening programs, including links to underlying biological information related to genes and pathways). The EPA DSSTox (Distributed Structure-Searchable Toxicity) program provides expert-reviewed chemical structures and associated information for these and other high-interest public inventories. Overall, the ACToR system contains information on about 400,000 chemicals from 1100 different sources. The entire system is built using open source tools and is freely available to download. This review describes the organization of the data repository and provides selected examples of use cases. PMID:22408426

Aggregating data for computational toxicology applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System.

PubMed

Judson, Richard S; Martin, Matthew T; Egeghy, Peter; Gangwal, Sumit; Reif, David M; Kothiya, Parth; Wolf, Maritja; Cathey, Tommy; Transue, Thomas; Smith, Doris; Vail, James; Frame, Alicia; Mosher, Shad; Cohen Hubal, Elaine A; Richard, Ann M

2012-01-01

Computational toxicology combines data from high-throughput test methods, chemical structure analyses and other biological domains (e.g., genes, proteins, cells, tissues) with the goals of predicting and understanding the underlying mechanistic causes of chemical toxicity and for predicting toxicity of new chemicals and products. A key feature of such approaches is their reliance on knowledge extracted from large collections of data and data sets in computable formats. The U.S. Environmental Protection Agency (EPA) has developed a large data resource called ACToR (Aggregated Computational Toxicology Resource) to support these data-intensive efforts. ACToR comprises four main repositories: core ACToR (chemical identifiers and structures, and summary data on hazard, exposure, use, and other domains), ToxRefDB (Toxicity Reference Database, a compilation of detailed in vivo toxicity data from guideline studies), ExpoCastDB (detailed human exposure data from observational studies of selected chemicals), and ToxCastDB (data from high-throughput screening programs, including links to underlying biological information related to genes and pathways). The EPA DSSTox (Distributed Structure-Searchable Toxicity) program provides expert-reviewed chemical structures and associated information for these and other high-interest public inventories. Overall, the ACToR system contains information on about 400,000 chemicals from 1100 different sources. The entire system is built using open source tools and is freely available to download. This review describes the organization of the data repository and provides selected examples of use cases.

New challenges and innovation in forensic toxicology: focus on the "New Psychoactive Substances".

PubMed

Favretto, Donata; Pascali, Jennifer P; Tagliaro, Franco

2013-04-26

In the recent years, new molecules have appeared in the illicit market, claimed to contain "non-illegal" compounds, although exhibiting important psychoactive effects; this heterogeneous and rapidly evolving class of compounds are commonly known as "New Psychoactive Substances" or, less properly, "Smart Drugs" and are easily distributed through the e-commerce or in the so-called "Smart Shops". They include, among other, synthetic cannabinoids, cathinones and tryptamine analogs of psylocin. Whereas cases of intoxication and death have been reported, the phenomenon appears to be largely underestimated and is a matter of concern for Public Health. One of the major points of concern depends on the substantial ineffectiveness of the current methods of toxicological screening of biological samples to identify the new compounds entering the market. These limitations emphasize an urgent need to increase the screening capabilities of the toxicology laboratories, and to develop rapid, versatile yet specific assays able to identify new molecules. The most recent advances in mass spectrometry technology, introducing instruments capable of detecting hundreds of compounds at nanomolar concentrations, are expected to give a fundamental contribution to broaden the diagnostic spectrum of the toxicological screening to include not only all these continuously changing molecules but also their metabolites. In the present paper a critical overview of the opportunities, strengths and limitations of some of the newest analytical approaches is provided, with a particular attention to liquid phase separation techniques coupled to high accuracy, high resolution mass spectrometry. Copyright © 2012 Elsevier B.V. All rights reserved.

Quantitative analysis of unconjugated and total bisphenol A in human urine using solid-phase extraction and UPLC-MS/MS: method implementation, method qualification and troubleshooting.

PubMed

Buscher, Brigitte; van de Lagemaat, Dick; Gries, Wolfgang; Beyer, Dieter; Markham, Dan A; Budinsky, Robert A; Dimond, Stephen S; Nath, Rajesh V; Snyder, Stephanie A; Hentges, Steven G

2015-11-15

The aim of the presented investigation was to document challenges encountered during implementation and qualification of a method for bisphenol A (BPA) analysis and to develop and discuss precautions taken to avoid and to monitor contamination with BPA during sample handling and analysis. Previously developed and published HPLC-MS/MS methods for the determination of unconjugated BPA (Markham et al. Journal of Analytical Toxicology, 34 (2010) 293-303) [17] and total BPA (Markham et al. Journal of Analytical Toxicology, 38 (2014) 194-203) [20] in human urine were combined and transferred into another laboratory. The initial method for unconjugated BPA was developed and evaluated in two independent laboratories simultaneously. The second method for total BPA was developed and evaluated in one of these laboratories to conserve resources. Accurate analysis of BPA at sub-ppb levels is a challenging task as BPA is a widely used material and is ubiquitous in the environment at trace concentrations. Propensity for contamination of biological samples with BPA is reported in the literature during sample collection, storage, and/or analysis. Contamination by trace levels of BPA is so pervasive that even with extraordinary care, it is difficult to completely exclude the introduction of BPA into biological samples and, consequently, contamination might have an impact on BPA biomonitoring data. The applied UPLC-MS/MS method was calibrated from 0.05 to 25ng/ml. The limit of quantification was 0.1ng/ml for unconjugated BPA and 0.2ng/ml for total BPA, respectively, in human urine. Finally, the method was applied to urine samples derived from 20 volunteers. Overall, BPA can be analyzed in human urine with acceptable recovery and repeatability if sufficient measures are taken to avoid contamination throughout the procedure from sample collection until UPLC-MS/MS analysis. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

IRIS Toxicological Review of Benzo[a]pyrene (Interagency ...

EPA Pesticide Factsheets

On August 21, 2013, the draft Toxicological Review of Benzo[a]pyrene and the draft charge to external peer reviewers were released for public review and comment. 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 Benzo[a]pyrene and the charge to external peer reviewers, are posted on this site. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for benzo[a]pyrene (BaP). The outcome of this project is an updated Toxicological Review and IRIS Summary for BaP that will be entered into the IRIS database.

IRIS Toxicological Review of 1,4-Dioxane (with Inhalation ...

EPA Pesticide Factsheets

On September 9, 2011, the Toxicological Review of 1,4-Dioxane (inhalation) (External Review Draft) was posted for external peer review and public comment. Subsequently, the Toxicological Review and IRIS Summary were reviewed internally by EPA and by other federal agencies and Executive Office of the President before final public release. Based on the 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and the Executive Office of the President will be made publicly available. Accordingly, interagency comments with EPA's response and the interagency science discussion draft of the IRIS Toxicological Review of 1,4-dioxane (with inhalation update) and the draft IRIS Summary are posted on this site. The Toxicological Review of 1,4-dioxane provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to 1,4-dioxane.

From the Cover: Development and Application of a Dual Rat and Human AHR Activation Assay.

PubMed

Brown, Martin R; Garside, Helen; Thompson, Emma; Atwal, Saseela; Bean, Chloe; Goodall, Tony; Sullivan, Michael; Graham, Mark J

2017-12-01

Significant prolonged aryl hydrocarbon receptor (AHR) activation, classically exhibited following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin, can cause a variety of undesirable toxicological effects. Novel pharmaceutical chemistries also have the potential to cause activation of AHR and consequent toxicities in pre-clinical species and man. Previous methods either employed relatively expensive and low-throughput primary hepatocyte dosing with PCR endpoint, or low resolution overexpressing reporter gene assays. We have developed, validated and applied an in vitro microtitre plate imaging-based medium throughput screening assay for the assessment of endogenous species-specific AHR activation potential via detection of induction of the surrogate transcriptional target Cytochrome P450 CYP1A1. Routine testing of pharmaceutical drug development candidate chemistries using this assay can influence the chemical design process and highlight AHR liabilities. This assay should be introduced such that human AHR activation liability is flagged early for confirmatory testing. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Understanding the toxicological potential of aerosol organic compounds using informatics based screening

NASA Astrophysics Data System (ADS)

Topping, David; Decesari, Stefano; Bassan, Arianna; Pavan, Manuela; Ciacci, Andrea

2016-04-01

Exposure to atmospheric particulate matter is responsible for both short-term and long-term adverse health effects. So far, all efforts spent in achieving a systematic epidemiological evidence of specific aerosol compounds determining the overall aerosol toxicity were unsuccessful. The results of the epidemiological studies apparently conflict with the laboratory toxicological analyses which have highlighted very different chemical and toxicological potentials for speciated aerosol compounds. Speciation remains a problem, especially for organic compounds: it is impossible to conduct screening on all possible molecular species. At the same time, research on toxic compounds risks to be biased towards the already known compounds, such as PAHs and dioxins. In this study we present results from an initial assessment of the use of in silico methods (i.e. (Q)SAR, read-across) to predict toxicity of atmospheric organic compounds including evaluation of applicability of a variety of popular tools (e.g. OECD QSAR Toolbox) for selected endpoints (e.g. genotoxicity). Compounds are categorised based on the need of new experimental data for the development of in silico approaches for toxicity prediction covering this specific chemical space, namely the atmospheric aerosols. Whilst only an initial investigation, we present recommendations for continuation of this work.

Toxcast and the Use of Human Relevant In Vitro Exposures: Incorporating High-Throughput Exposure and Toxicity Testing Data for 21st Century Risk Assessments (British Toxicological Society Annual Congress)

EPA Science Inventory

The path for incorporating new approach methods and technologies into quantitative chemical risk assessment poses a diverse set of scientific challenges. These challenges include sufficient coverage of toxicological mechanisms to meaningfully interpret negative test results, dev...

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

Selkirk, J.K.

The National Toxicology Program (NTP) was organized to support national public health programs by initiating research designed to understand the physiological, metabolic, and genetic basis for chemical toxicity. The primary mandated responsibilities of NTP were in vivo and vitro toxicity testing of potentially hazardous chemicals; broadening the spectrum of toxicological information on known hazardous chemicals; validating current toxicological assay systems as well as developing new and innovative toxicity testing technology; and rapidly communicating test results to government agencies with regulatory responsibilities and to the medical and scientific communities. 2 figs.

IRIS Toxicological Review of Trichloroacetic Acid (TCA) ...

EPA Pesticide Factsheets

EPA is releasing the draft report, Toxicological Review of Trichloroacetic Acid (TCA), that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Comments received from other Federal agencies and White House Offices are provided below with external peer review panel comments. The draft Toxicological Review of Trichloroacetic Acid provides scientific support and rationale for the hazard identification and dose-response assessment pertaining to chronic exposure to trichloroacetic acid.

Advancing the adverse outcome pathway framework: An international horizon scanning approach

EPA Science Inventory

In 2016, an international multi-sector steering committee focusing on the development of a Society of Environmental Toxicology & Chemistry (SETAC) Pellston™ Workshop reached out to the membership of the Society of Toxicology, as well as other national and internatio...

IRIS Toxicological Review of Trimethylbenzenes (Interagency Science Discussion Draft)

EPA Science Inventory

In September 2016, EPA finalized the IRIS assessment of Trimethylbenzenes. The Toxicological Review was reviewed internally by EPA and by other federal agencies and White House Offices before public release in June 2016. Consistent with the May 2009 IRIS assessment development pr...

IRIS Toxicological Review for Carbon Tetrachloride (Interagency Science Discussion Draft)

EPA Science Inventory

EPA released the draft report,Toxicological Review for Carbon Tetrachloride(Interagency Science Discussion Draft), that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Co...

Systems Toxicology of Embryo Development (9th Copenhagen Workshop)

EPA Science Inventory

An important consideration for predictive toxicology is to identify developmental hazards utilizing mechanism-based in vitro assays (e.g., ToxCast) and in silico multiscale models. Steady progress has been made with agent-based models that recapitulate morphogenetic drivers for a...

IRIS Toxicological Review of Biphenyl (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Biphenyl, that was distributed to other federal agencies and the Executive Office of the President for comment during Interagency Science Discussion (IASD) (Step 6b) of the IRIS assessment development process. Interagenc...

Wiki-based Data Management to Support Systems Toxicology*

EPA Science Inventory

As the field of toxicology relies more heavily on systems approaches for mode of action discovery, evaluation, and modeling, the need for integrated data management is greater than ever. To meet these needs, we developed a flexible data management system that assists scientists ...

Incorporating exposure information into the toxicological prioritization index decision support framework

EPA Science Inventory

The Toxicological Prioritization Index (ToxPi) decision support framework was previously developed to facilitate incorporation of diverse data to prioritize chemicals based on potential hazard. This ToxPi index was demonstrated by considering results of bioprofiling related to po...

Research Models in Developmental Behavioral Toxicology.

ERIC Educational Resources Information Center

Dietrich, Kim N.; Pearson, Douglas T.

Developmental models currently used by child behavioral toxicologists and teratologists are inadequate to address current issues in these fields. Both child behavioral teratology and toxicology scientifically study the impact of exposure to toxic agents on behavior development: teratology focuses on prenatal exposure and postnatal behavior…

Comprehensive summary--Predict-IV: A systems toxicology approach to improve pharmaceutical drug safety testing.

PubMed

Mueller, Stefan O; Dekant, Wolfgang; Jennings, Paul; Testai, Emanuela; Bois, Frederic

2015-12-25

This special issue of Toxicology in Vitro is dedicated to disseminating the results of the EU-funded collaborative project "Profiling the toxicity of new drugs: a non animal-based approach integrating toxicodynamics and biokinetics" (Predict-IV; Grant 202222). The project's overall aim was to develop strategies to improve the assessment of drug safety in the early stage of development and late discovery phase, by an intelligent combination of non animal-based test systems, cell biology, mechanistic toxicology and in silico modeling, in a rapid and cost effective manner. This overview introduces the scope and overall achievements of Predict-IV. Copyright © 2014 Elsevier Ltd. All rights reserved.

Computational toxicology: Its essential role in reducing drug attrition.

PubMed

Naven, R T; Louise-May, S

2015-12-01

Predictive toxicology plays a critical role in reducing the failure rate of new drugs in pharmaceutical research and development. Despite recent gains in our understanding of drug-induced toxicity, however, it is urgent that the utility and limitations of our current predictive tools be determined in order to identify gaps in our understanding of mechanistic and chemical toxicology. Using recently published computational regression analyses of in vitro and in vivo toxicology data, it will be demonstrated that significant gaps remain in early safety screening paradigms. More strategic analyses of these data sets will allow for a better understanding of their domain of applicability and help identify those compounds that cause significant in vivo toxicity but which are currently mis-predicted by in silico and in vitro models. These 'outliers' and falsely predicted compounds are metaphorical lighthouses that shine light on existing toxicological knowledge gaps, and it is essential that these compounds are investigated if attrition is to be reduced significantly in the future. As such, the modern computational toxicologist is more productively engaged in understanding these gaps and driving investigative toxicology towards addressing them. © The Author(s) 2015.

Use of Non-Apical Assay Data in an Integrated Approach to ...

EPA Pesticide Factsheets

This speaker abstract is part of a session proposal for the 2018 Society of Toxicology annual meeting. I am proposing to speak about the use of new approach methods and data, such as AOPs, in mixtures risk assessment. I have developed an innovative approach called AOP footprinting that I intend to present at this meeting. This speaker abstract is part of a session proposal for the 2018 Society of Toxicology annual meeting. Drs. Margaret Pratt (NCEA-IRIS) and Cynthia Rider (NIEHS) are the co-chairs of the proposed session which is designed to present information related to mixtures risk assessment of environmental chemicals, such as PAHs. I have specifically been asked to speak about the use of 21st century toxicity information in human health assessment (e.g., assay data from novel data streams).

Toxcast and the Use of Human Relevant In Vitro Exposures ...

EPA Pesticide Factsheets

The path for incorporating new approach methods and technologies into quantitative chemical risk assessment poses a diverse set of scientific challenges. These challenges include sufficient coverage of toxicological mechanisms to meaningfully interpret negative test results, development of increasingly relevant test systems, computational modeling to integrate experimental data, putting results in a dose and exposure context, characterizing uncertainty, and efficient validation of the test systems and computational models. The presentation will cover progress at the U.S. EPA in systematically addressing each of these challenges and delivering more human-relevant risk-based assessments. This abstract does not necessarily reflect U.S. EPA policy. Presentation at the British Toxicological Society Annual Congress on ToxCast and the Use of Human Relevant In Vitro Exposures: Incorporating high-throughput exposure and toxicity testing data for 21st century risk assessments .

QSAR Methods.

PubMed

Gini, Giuseppina

2016-01-01

In this chapter, we introduce the basis of computational chemistry and discuss how computational methods have been extended to some biological properties and toxicology, in particular. Since about 20 years, chemical experimentation is more and more replaced by modeling and virtual experimentation, using a large core of mathematics, chemistry, physics, and algorithms. Then we see how animal experiments, aimed at providing a standardized result about a biological property, can be mimicked by new in silico methods. Our emphasis here is on toxicology and on predicting properties through chemical structures. Two main streams of such models are available: models that consider the whole molecular structure to predict a value, namely QSAR (Quantitative Structure Activity Relationships), and models that find relevant substructures to predict a class, namely SAR. The term in silico discovery is applied to chemical design, to computational toxicology, and to drug discovery. We discuss how the experimental practice in biological science is moving more and more toward modeling and simulation. Such virtual experiments confirm hypotheses, provide data for regulation, and help in designing new chemicals.

Identification and assessment of hazardous compounds in drinking water.

PubMed

Fawell, J K; Fielding, M

1985-12-01

The identification of organic chemicals in drinking water and their assessment in terms of potential hazardous effects are two very different but closely associated tasks. In relation to both continuous low-level background contamination and specific, often high-level, contamination due to pollution incidents, the identification of contaminants is a pre-requisite to evaluation of significant hazards. Even in the case of the rapidly developing short-term bio-assays which are applied to water to indicate a potential genotoxic hazard (for example Ames tests), identification of the active chemicals is becoming a major factor in the further assessment of the response. Techniques for the identification of low concentrations of organic chemicals in drinking water have developed remarkably since the early 1970s and methods based upon gas chromatography-mass spectrometry (GC-MS) have revolutionised qualitative analysis of water. Such techniques are limited to "volatile" chemicals and these usually constitute a small fraction of the total organic material in water. However, in recent years there have been promising developments in techniques for "non-volatile" chemicals in water. Such techniques include combined high-performance liquid chromatography-mass spectrometry (HPLC-MS) and a variety of MS methods, involving, for example, field desorption, fast atom bombardment and thermospray ionisation techniques. In the paper identification techniques in general are reviewed and likely future developments outlined. The assessment of hazards associated with chemicals identified in drinking and related waters usually centres upon toxicology - an applied science which involves numerous disciplines. The paper examines the toxicological information needed, the quality and deployment of such information and discusses future research needs. Application of short-term bio-assays to drinking water is a developing area and one which is closely involved with, and to some extent dependent on, powerful methods of identification. Recent developments are discussed.

Use of Non-Apical Assay Data in an Integrated Approach to Testing and Assessment of Chemical Mixtures in the Environment: the Advent of Adverse Outcome Pathway Footprinting

EPA Science Inventory

This speaker abstract is part of a session proposal for the 2018 Society of Toxicology annual meeting. I am proposing to speak about the use of new approach methods and data, such as AOPs, in mixtures risk assessment. I have developed an innovative approach called AOP footprint...

IRIS Toxicological Review of Chloroprene (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Chloroprene, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Co...

IRIS Toxicological Review of Hexachloroethane (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Hexachloroethane, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Pro...

Role of adverse outcome pathways in developing computational models for regulatory toxicology

EPA Science Inventory

Regulatory toxicology for both human health and the environment increasingly is moving from a sole reliance on direct observation of apical toxicity outcomes in whole organism toxicity tests, to predictive approaches in which unacceptable outcomes and risk are inferred from mecha...

DEVELOPMENTAL TOXICOLOGY EVALUATIONS -- ISSUES WITH INCLUDING NEUROTOXICOLOGY AND IMMUNOTOXICOLOGY ASSESSMENTS IN REPRODUCTIVE TOXICOLOGY STUDIES

EPA Science Inventory

Developmental and reproductive toxixology (DART) has routinely been a part of safety assessment. Attention is now focused on the effects of chemicals on the developing nervous and immune systems. This focus on developmental neurotoxicology (DNT) and developmental immunotoxicolo...

IRIS Toxicological Review of Pentachlorophenol (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Pentachlorophenol, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Pr...

Application of Signaling Pathway-Based Adverse Outcome Pathways and High Throughput Toxicokinetic-PBPK for Developmental Cardiac Malformations

EPA Science Inventory

Associating putative molecular initiating events (MIE) with downstream cell signaling pathways and modeling fetal exposure kinetics is an important challenge for integration in developmental systems toxicology. Here, we describe an integrative systems toxicology model for develop...

A FRAMEWORK FOR A COMPUTATIONAL TOXICOLOGY RESEARCH PROGRAM IN ORD

EPA Science Inventory

"A Framework for a Computational Toxicology Research Program in ORD" was drafted by a Technical Writing Team having representatives from all of ORD's Laboratories and Centers. The document describes a framework for the development of an program within ORD to utilize approaches d...

Wiki-Based Data Management to Support Systems Toxicology

EPA Science Inventory

As the field of toxicology relies more heavily on systems approaches for mode of action discovery, evaluation, and modeling, the need for integrated data management is greater than ever. To meet these needs, we have developed a flexible system that assists individual or multiple...

Measuring Impact of EPAs Computational Toxicology Research (BOSC)

EPA Science Inventory

Computational Toxicology (CompTox) research at the EPA was initiated in 2005. Since 2005, CompTox research efforts have made tremendous advances in developing new approaches to evaluate thousands of chemicals for potential health effects. The purpose of this case study is to trac...

IRIS Toxicological Review for Acrylamide (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review for Acrylamide, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process<...

Recent Developments in Toxico-Cheminformatics; Supporting a New Paradigm for Predictive Toxicology

EPA Science Inventory

EPA's National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction through the harnessing of legacy toxicity data, creation of data linkages, and generation of new high-content and high-thoughput screening d...

IRIS Toxicological Review of Dichloromethane (Methylene Chloride) (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Dichloromethane, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Proc...

Adverse Outcome Pathways: Moving from a scientific concept to a globally accepted framework

EPA Science Inventory

In 2016, an international multi-sector steering committee focusing on the development of a Society of Environmental Toxicology (SETAC) Pellston Workshop reached out to the membership of the Society of Toxicology as well as other national and international scientific and regulator...

IRIS Toxicological Review of Tetrahydrofuran (THF) (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Tetrahydrofuran, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Proc...

Toxicological assessment of particulate emissions from the exhaust of old and new model heavy- and light-duty vehicles.

DOT National Transportation Integrated Search

2011-06-01

The primary objective of this project is to develop an improved understanding of the factors affecting the toxicology of particulate exhaust emissions. Diesel particulate matter is a known carcinogen, and particulate exhaust emissions from both light...

IRIS Toxicological Review of Urea (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Urea,, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. C...

CUMULATIVE RISK ASSESSMENT: GETTING FROM TOXICOLOGY TO QUANTITATIVE ANALYSIS

EPA Science Inventory

INTRODUCTION: GETTING FROM TOXICOLOGY TO QUANTITATIVE ANALYSIS FOR CUMULATIVE RISK

Hugh A. Barton1 and Carey N. Pope2
1US EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC
2Department of...

Using in vitro Dose-Response Profiles to Enhance QSAR Modeling of in vivo Toxicity

EPA Science Inventory

To develop effective means for rapid toxicity evaluation of environmental chemicals, the Tox21 partnership among the National Toxicology Program (NTP), NIH Chemical Genomics Center, and National Center for Computational Toxicology (NCCT) at the US EPA are conducting a number of ...

A conceptual framework to advance exposure science research and complement the Adverse Outcome Pathway framework

EPA Science Inventory

A tremendous amount of data on environmental stressors has been accumulated in exposure science, epidemiology, and toxicology, yet most of these data reside in different silos. The Adverse Outcome Pathway (AOP) framework was developed as an organizing principle for toxicological ...

IRIS Toxicological Review of Benzo[a]pyrene (Interagency Science Discussion Draft)

EPA Science Inventory

In January 2017, EPA finalized the IRIS assessment of Benzo[a]pyrene. The Toxicological Review was 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...

ACToR Chemical Structure processing using Open Source ChemInformatics Libraries (FutureToxII)

EPA Science Inventory

ACToR (Aggregated Computational Toxicology Resource) is a centralized database repository developed by the National Center for Computational Toxicology (NCCT) at the U.S. Environmental Protection Agency (EPA). Free and open source tools were used to compile toxicity data from ove...

Wiki-based Data Management System for Toxicogenomics

EPA Science Inventory

We are developing a data management system to enable systems-based toxicology at the US EPA. This is built upon the WikiLIMS platform and is capabale of housing not just genomics data but also a wide variety of toxicology data and associated experimental design information. Thi...

Combustion toxicology of epoxy/carbon fiber composites

NASA Technical Reports Server (NTRS)

Cagliostro, D. E.

1981-01-01

A combustion toxicology test was developed to screen materials for aerospace applications. The system is called the radiant panel test facility. A description of the facility and some preliminary results from tests on a Navy 3501-6AS composite, a typical composite for fighter aircraft, are presented.

The ToxCast Chemical Prioritization Program at the US EPA (UCLA Molecular Toxicology Program)

EPA Science Inventory

To meet the needs of chemical regulators reviewing large numbers of data-poor chemicals for safety, the EPA's National Center for Computational Toxicology is developing a means of efficiently testing thousands of compounds for potential toxicity. High-throughput bioactivity profi...

IRIS Toxicological Review of Trichloroacetic Acid (TCA) (Interagency Science Discussion Draft)

EPA Science Inventory

EPA is releasing the draft report, Toxicological Review of Trichloroacetic Acid (TCA), that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development ...

Computational Toxicology - A State of the Science Mini Review

EPA Science Inventory

This mini-review is based on presentations and discussions at the International Science Forum on Computational Toxicology that was sponsored by the Office of Research and Development of the US Environmental Protection Agency and held in Research Triangle Park, NC on May 21-23, 20...

COMPUTATIONAL TOXICOLOGY: AN IN SILLICO DOSIMETRY MODEL FOR THE ASSESSMENT OF AIR POLLUTANTS

EPA Science Inventory

To accurately assess the threat to human health presented by airborne contaminants, it is necessary to know the deposition patterns of particulate matter (PM) within the respiratory system. To provide a foundation for computational toxicology, we have developed an in silico model...

Computational toxicology as implemented by the U.S. EPA: providing high throughput decision support tools for screening and assessing chemical exposure, hazard and risk.

PubMed

Kavlock, Robert; Dix, David

2010-02-01

Computational toxicology is the application of mathematical and computer models to help assess chemical hazards and risks to human health and the environment. Supported by advances in informatics, high-throughput screening (HTS) technologies, and systems biology, the U.S. Environmental Protection Agency EPA is developing robust and flexible computational tools that can be applied to the thousands of chemicals in commerce, and contaminant mixtures found in air, water, and hazardous-waste sites. The Office of Research and Development (ORD) Computational Toxicology Research Program (CTRP) is composed of three main elements. The largest component is the National Center for Computational Toxicology (NCCT), which was established in 2005 to coordinate research on chemical screening and prioritization, informatics, and systems modeling. The second element consists of related activities in the National Health and Environmental Effects Research Laboratory (NHEERL) and the National Exposure Research Laboratory (NERL). The third and final component consists of academic centers working on various aspects of computational toxicology and funded by the U.S. EPA Science to Achieve Results (STAR) program. Together these elements form the key components in the implementation of both the initial strategy, A Framework for a Computational Toxicology Research Program (U.S. EPA, 2003), and the newly released The U.S. Environmental Protection Agency's Strategic Plan for Evaluating the Toxicity of Chemicals (U.S. EPA, 2009a). Key intramural projects of the CTRP include digitizing legacy toxicity testing information toxicity reference database (ToxRefDB), predicting toxicity (ToxCast) and exposure (ExpoCast), and creating virtual liver (v-Liver) and virtual embryo (v-Embryo) systems models. U.S. EPA-funded STAR centers are also providing bioinformatics, computational toxicology data and models, and developmental toxicity data and models. The models and underlying data are being made publicly available through the Aggregated Computational Toxicology Resource (ACToR), the Distributed Structure-Searchable Toxicity (DSSTox) Database Network, and other U.S. EPA websites. While initially focused on improving the hazard identification process, the CTRP is placing increasing emphasis on using high-throughput bioactivity profiling data in systems modeling to support quantitative risk assessments, and in developing complementary higher throughput exposure models. This integrated approach will enable analysis of life-stage susceptibility, and understanding of the exposures, pathways, and key events by which chemicals exert their toxicity in developing systems (e.g., endocrine-related pathways). The CTRP will be a critical component in next-generation risk assessments utilizing quantitative high-throughput data and providing a much higher capacity for assessing chemical toxicity than is currently available.

Development of a High-Performance Liquid Chromatography–Tandem Mass Spectrometry Method for the Identification and Quantification of CP-47,497, CP-47,497-C8 and JWH-250 in Mouse Brain

PubMed Central

Samano, Kimberly L.; Poklis, Justin L.; Lichtman, Aron H.; Poklis, Alphonse

2014-01-01

While Marijuana continues to be the most widely used illicit drug, abuse of synthetic cannabinoid (SCB) compounds in ‘Spice’ or ‘K2’ herbal incense products has emerged as a significant public health concern in many European countries and in the USA. Several of these SCBs have been declared Schedule I controlled substances but detection and quantification in biological samples remain a challenge. Therefore, we present a liquid chromatography–tandem mass spectrometry method after liquid–liquid extraction for the quantitation of CP-47,497, CP-47,497-C8 and JWH-250 in mouse brain. We report data for linearity, limit of quantification, accuracy/bias, precision, recovery, selectivity, carryover, matrix effects and stability experiments which were developed and fully validated based on Scientific Working Group for Forensic Toxicology guidelines for forensic toxicology method validation. Acceptable coefficients of variation for accuracy/bias, within- and between-run precision and selectivity were determined, with all values within ±15% of the target concentration. Validation experiments revealed degradation of CP-47, 497 and CP-47,497-C8 at different temperatures, and significant ion suppression was produced in brain for all compounds tested. The method was successfully applied to detect and quantify CP-47,497 in brains from mice demonstrating significant cannabimimetic behavioral effects as assessed by the classical tetrad paradigm. PMID:24816398

Zebrafish neurobehavioral phenomics for aquatic neuropharmacology and toxicology research.

PubMed

Kalueff, Allan V; Echevarria, David J; Homechaudhuri, Sumit; Stewart, Adam Michael; Collier, Adam D; Kaluyeva, Aleksandra A; Li, Shaomin; Liu, Yingcong; Chen, Peirong; Wang, JiaJia; Yang, Lei; Mitra, Anisa; Pal, Subharthi; Chaudhuri, Adwitiya; Roy, Anwesha; Biswas, Missidona; Roy, Dola; Podder, Anupam; Poudel, Manoj K; Katare, Deepshikha P; Mani, Ruchi J; Kyzar, Evan J; Gaikwad, Siddharth; Nguyen, Michael; Song, Cai

2016-01-01

Zebrafish (Danio rerio) are rapidly emerging as an important model organism for aquatic neuropharmacology and toxicology research. The behavioral/phenotypic complexity of zebrafish allows for thorough dissection of complex human brain disorders and drug-evoked pathological states. As numerous zebrafish models become available with a wide spectrum of behavioral, genetic, and environmental methods to test novel drugs, here we discuss recent zebrafish phenomics methods to facilitate drug discovery, particularly in the field of biological psychiatry. Additionally, behavioral, neurological, and endocrine endpoints are becoming increasingly well-characterized in zebrafish, making them an inexpensive, robust and effective model for toxicology research and pharmacological screening. We also discuss zebrafish behavioral phenotypes, experimental considerations, pharmacological candidates and relevance of zebrafish neurophenomics to other 'omics' (e.g., genomic, proteomic) approaches. Finally, we critically evaluate the limitations of utilizing this model organism, and outline future strategies of research in the field of zebrafish phenomics. Copyright © 2015 Elsevier B.V. All rights reserved.

[Toxicological analysis of biological material originating from the body of general Władysław Sikorski for organic poisons].

PubMed

Lechowicz, Wojciech

2009-01-01

Toxicological analyses performed in individuals who died in unclear circumstances constitute a key element of research aiming at providing a complete explanation of cause of death. The entire panel of examinations of the corpse of general Sikorski also included toxicological analyses for drugs and organic poisons of synthetic and natural origin. Attention was focused on fast-acting and potent poisons known and used in the forties of the century. The internal organs (stomach, liver, lung, brain) and hair, as well as other materials collected from the body and found in the coffin were analyzed. The classic method of sample preparation, i.e. homogenization, deproteinization, headspace and liquid-liquid extraction were applied. Hyphenated methods, mainly chromatographic with mass spectrometry were used for identification of the analytes. Organic poisons were not identified in the material as a result of the research.

Clinical and anatomic pathology effects of serial blood sampling in rat toxicology studies, using conventional or microsampling methods.

PubMed

Caron, Alexis; Lelong, Christine; Bartels, T; Dorchies, O; Gury, T; Chalier, Catherine; Benning, Véronique

2015-08-01

As a general practice in rodent toxicology studies, satellite animals are used for toxicokinetic determinations, because of the potential impact of serial blood sampling on toxicological endpoints. Besides toxicological and toxicokinetic determinations, blood samples obtained longitudinally from a same animal may be used for the assessment of additional parameters (e.g., metabolism, pharmacodynamics, safety biomarkers) to maximize information that can be deduced from rodents. We investigated whether removal of up to 6 × 200 μL of blood over 24h can be applied in GLP rat toxicology studies without affecting the scientific outcome. 8 week-old female rats (200-300 g) were dosed for up to 1 month with a standard vehicle and subjected or not (controls) to serial blood sampling for sham toxicokinetic/ancillary determinations, using miniaturized methods allowing collection of 6 × 50, 100 or 200 μL over 24h. In-life endpoints, clinical pathology parameters and histopathology of organs sensitive to blood volume reduction were evaluated at several time points after completion of sampling. In sampled rats, minimal and reversible changes in red blood cell mass (maximally 15%) and subtle variations in liver enzymes, fibrinogen and neutrophils were not associated with any organ/tissue macroscopic or microscopic correlate. Serial blood sampling (up to 6 × 200 μL over 24h) is compatible with the assessment of standard toxicity endpoints in adult rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Integrating Personalized Technology in Toxicology: Sensors, Smart Glass, and Social Media Applications in Toxicology Research.

PubMed

Carreiro, Stephanie; Chai, Peter R; Carey, Jennifer; Chapman, Brittany; Boyer, Edward W

2017-06-01

Rapid proliferation of mobile technologies in social and healthcare spaces create an opportunity for advancement in research and clinical practice. The application of mobile, personalized technology in healthcare, referred to as mHealth, has not yet become routine in toxicology. However, key features of our practice environment, such as frequent need for remote evaluation, unreliable historical data from patients, and sensitive subject matter, make mHealth tools appealing solutions in comparison to traditional methods that collect retrospective or indirect data. This manuscript describes the features, uses, and costs associated with several of common sectors of mHealth research including wearable biosensors, ingestible biosensors, head-mounted devices, and social media applications. The benefits and novel challenges associated with the study and use of these applications are then discussed. Finally, opportunities for further research and integration are explored with a particular focus on toxicology-based applications.

Quantification of paracetamol and 5-oxoproline in serum by capillary electrophoresis: Implication for clinical toxicology.

PubMed

Hložek, Tomáš; Křížek, Tomáš; Tůma, Petr; Bursová, Miroslava; Coufal, Pavel; Čabala, Radomír

2017-10-25

High anion gap metabolic acidosis frequently complicates acute paracetamol overdose and is generally attributed to lactic acidosis or compromised hepatic function. However, metabolic acidosis can also be caused by organic acid 5-oxoproline (pyroglutamic acid). Paracetamol's toxic intermediate, N-acetyl-p-benzoquinoneimine irreversibly binds to glutathione and its depletion leads to subsequent disruption of the gamma glutamyl cycle and an excessive 5-oxoproline generation. This is undoubtedly an underdiagnosed condition because measurement of serum 5-oxoproline level is not readily available. A simple, cost effective, and fast capillary electrophoresis method with diode array detection (DAD) for simultaneous measurement of both paracetamol (acetaminophen) and 5-oxoproline in serum was developed and validated. This method is highly suitable for clinical toxicology laboratory diagnostic, allowing rapid quantification of acidosis inducing organic acid 5-oxoproline present in cases of paracetamol overdose. The calibration dependence of the method was proved to be linear in the range of 1.3-250μgmL -1 , with adequate accuracy (96.4-107.8%) and precision (12.3%). LOQ equaled 1.3μgmL -1 for paracetamol and 4.9μgmL -1 for 5-oxoproline. Copyright © 2017 Elsevier B.V. All rights reserved.

Toxicogenomics concepts and applications to study hepatic effects of food additives and chemicals

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

Stierum, Rob; Heijne, Wilbert; Kienhuis, Anne

2005-09-01

Transcriptomics, proteomics and metabolomics are genomics technologies with great potential in toxicological sciences. Toxicogenomics involves the integration of conventional toxicological examinations with gene, protein or metabolite expression profiles. An overview together with selected examples of the possibilities of genomics in toxicology is given. The expectations raised by toxicogenomics are earlier and more sensitive detection of toxicity. Furthermore, toxicogenomics will provide a better understanding of the mechanism of toxicity and may facilitate the prediction of toxicity of unknown compounds. Mechanism-based markers of toxicity can be discovered and improved interspecies and in vitro-in vivo extrapolations will drive model developments in toxicology. Toxicologicalmore » assessment of chemical mixtures will benefit from the new molecular biological tools. In our laboratory, toxicogenomics is predominantly applied for elucidation of mechanisms of action and discovery of novel pathway-supported mechanism-based markers of liver toxicity. In addition, we aim to integrate transcriptome, proteome and metabolome data, supported by bioinformatics to develop a systems biology approach for toxicology. Transcriptomics and proteomics studies on bromobenzene-mediated hepatotoxicity in the rat are discussed. Finally, an example is shown in which gene expression profiling together with conventional biochemistry led to the discovery of novel markers for the hepatic effects of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole.« less

Systematic approaches to toxicology in the zebrafish.

PubMed

Peterson, Randall T; Macrae, Calum A

2012-01-01

As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology.

IRIS Toxicological Review of 1,1,2,2-Tetrachloroethane ...

EPA Pesticide Factsheets

EPA is releasing the draft report, Toxicological Review of 1,1,2,2-Tetrachloroethane, that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Comments received from other Federal agencies and White House Offices are provided below with external peer review panel comments. The draft Toxicological Review of 1,1,2,2-Tetrachloroethane provides scientific support and rationale for the hazard and dose-response assessment pertaining to subchronic and chronic exposure to 1,1,2,2-Tetrachloroethane.

Guidelines for developing spacecraft maximum allowable concentrations for Space Station contaminants

NASA Technical Reports Server (NTRS)

1992-01-01

The National Aeronautics and Space Administration (NASA) is preparing to launch a manned space station by the year 1996. Because of concerns about the health, safety, and functioning abilities of the crews, NASA has requested that the National Research Council (NRC) through the Board on Environmental Studies and Toxicology (BEST) provide advice on toxicological matters for the space-station program. The Subcommittee on Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants was established by the Committee on Toxicology (COT) to address NASA's concerns. Spacecraft maximum allowable concentrations (SMAC's) are defined as the maximum concentrations of airborne substances (such as gas, vapor, or aerosol) that will not cause adverse health effects, significant discomfort, or degradation in crew performance.

Quantitative systems toxicology

PubMed Central

Bloomingdale, Peter; Housand, Conrad; Apgar, Joshua F.; Millard, Bjorn L.; Mager, Donald E.; Burke, John M.; Shah, Dhaval K.

2017-01-01

The overarching goal of modern drug development is to optimize therapeutic benefits while minimizing adverse effects. However, inadequate efficacy and safety concerns remain to be the major causes of drug attrition in clinical development. For the past 80 years, toxicity testing has consisted of evaluating the adverse effects of drugs in animals to predict human health risks. The U.S. Environmental Protection Agency recognized the need to develop innovative toxicity testing strategies and asked the National Research Council to develop a long-range vision and strategy for toxicity testing in the 21st century. The vision aims to reduce the use of animals and drug development costs through the integration of computational modeling and in vitro experimental methods that evaluates the perturbation of toxicity-related pathways. Towards this vision, collaborative quantitative systems pharmacology and toxicology modeling endeavors (QSP/QST) have been initiated amongst numerous organizations worldwide. In this article, we discuss how quantitative structure-activity relationship (QSAR), network-based, and pharmacokinetic/pharmacodynamic modeling approaches can be integrated into the framework of QST models. Additionally, we review the application of QST models to predict cardiotoxicity and hepatotoxicity of drugs throughout their development. Cell and organ specific QST models are likely to become an essential component of modern toxicity testing, and provides a solid foundation towards determining individualized therapeutic windows to improve patient safety. PMID:29308440

Recent developments in urinalysis of metabolites of new psychoactive substances using LC-MS.

PubMed

Peters, Frank T

2014-08-01

In the last decade, an ever-increasing number of new psychoactive substances (NPSs) have appeared on the recreational drug market. To account for this development, analytical toxicologists have to continuously adapt their methods to encompass the latest NPSs. Urine is the preferred biological matrix for screening analysis in different areas of analytical toxicology. However, the development of urinalysis procedures for NPSs is complicated by the fact that generally little or no information on urinary excretion patterns of such drugs exists when they first appear on the market. Metabolism studies are therefore a prerequisite in the development of urinalysis methods for NPSs. In this article, the literature on the urinalysis of NPS metabolites will be reviewed, focusing on articles published after 2008.

Distance learning in toxicology: Resident and remote; Scotland, IPCS, IUPAC, and the world

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

Duffus, John H.

2005-09-01

Globally, very few college or university chemistry courses incorporate toxicology although public perception of chemicals and the chemical industry as threats to health and the environment has had an adverse effect on chemistry and on the use of its products. The International Union for Pure and Applied Chemistry (IUPAC) through its Commission on Toxicology recognized this and, with the support of the Committee on the Teaching of Chemistry has used the IUPAC web site to promote distance learning in toxicology for chemists. After preparation of a thoroughly refereed consensus Glossary of Terms for Chemists of Terms Used in Toxicology, amore » textbook Fundamental Toxicology for Chemists and a set of educational modules entitled Essential Toxicology were compiled and put through the normal thorough review procedure of IUPAC before being approved by the organization. There is now an additional Glossary of Terms Used in Toxicokinetics. The modules are freely downloadable in Adobe PDF format and are designed to be used both by educators and by students. Educators are asked to select whatever is appropriate to their students and to use the material as they wish, adding content specifically relevant to their circumstances. For self-study, the web modules have self-assessment questions and model answers. Currently the original Glossary for Chemists of Terms Used in Toxicology is being revised and it is expected that this will lead to further developments. The currently available components of the IUPAC programme may be accessed through the IUPAC website at the Subcommittee on Toxicology and Risk Assessment page: http://www.iupac.org/divisions/VII/VII.C.2/index.html.« less

The underlying toxicological mechanism of chemical mixtures: A case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum

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

Tian, Dayong; Department of Chemical and Environmental Engineering, Anyang Institute of Technology, Anyang 455000; Lin, Zhifen, E-mail: lzhifen@tongji.edu.cn

Intracellular chemical reaction of chemical mixtures is one of the main reasons that cause synergistic or antagonistic effects. However, it still remains unclear what the influencing factors on the intracellular chemical reaction are, and how they influence on the toxicological mechanism of chemical mixtures. To reveal this underlying toxicological mechanism of chemical mixtures, a case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum was employed, and both their joint effects and mixture toxicity were observed. Then series of two-step linear regressions were performed to describe the relationships between joint effects, the expected additive toxicities and descriptorsmore » of individual chemicals (including concentrations, binding affinity to receptors, octanol/water partition coefficients). Based on the quantitative relationships, the underlying joint toxicological mechanisms were revealed. The result shows that, for mixtures with their joint effects resulting from intracellular chemical reaction, their underlying toxicological mechanism depends on not only their interaction with target proteins, but also their transmembrane actions and their concentrations. In addition, two generic points of toxicological mechanism were proposed including the influencing factors on intracellular chemical reaction and the difference of the toxicological mechanism between single reactive chemicals and their mixtures. This study provided an insight into the understanding of the underlying toxicological mechanism for chemical mixtures with intracellular chemical reaction. - Highlights: • Joint effects of nitriles and aldehydes at non-equitoxic ratios were determined. • A novel descriptor, ligand–receptor interaction energy (E{sub binding}), was employed. • Quantitative relationships for mixtures were developed based on a novel descriptor. • The underlying toxic mechanism was revealed based on quantitative relationships. • Two generic points of toxicological mechanism were elucidated.« less

Dried blood spots combined to an UPLC-MS/MS method for the simultaneous determination of drugs of abuse in forensic toxicology.

PubMed

Sadler Simões, Susana; Castañera Ajenjo, Antonio; Dias, Mário João

2018-01-05

A method for the simultaneous determination of 11 illicit drugs, using the dried blood spot (DBS) sampling technique combined with the UPLC-MS/MS technology was developed to study its applicability within the forensic toxicology. The DBS samples, prepared from a blood volume of 50μL and using the Whatman® BFC 180 bloodstain cards, were extracted with a methanol/acetonitrile mixture. The chromatographic separation was performed using an Acquity UPLC ® HSS T3 column (100mm×2.1mm, 1.8μm) and an acetonitrile/2mM ammonium formate (0.1% formic acid) gradient. The detection was accomplished with a TQ Detector, operating in the ESI+ and MRM modes. The method was validated in terms of selectivity, matrix effect, extraction recovery (42%-91%), carryover, LOD and LOQ (0.5-1ng/mL and 1-5ng/mL, respectively), linearity (LOQ to 500ng/mL), intraday and interday precision (3.8-14% and 5.3-13%, respectively), accuracy (-9.3% to 7.9%) and dilution integrity. An eight months stability study at room temperature, 2-8°C and -10°C, was also performed, with the best results obtained at -10°C. The procedure was applied to 64 real samples (92 positive results for substances included in this study). The results were compared with the methodologies routinely applied in the laboratory and the statistical analysis allowed to establish an acceptable correlation. This study permitted to determine that the DBS can represent an alternative or a complement to conventional analytical and sampling techniques, responding to some of the present issues concerning the different forensic toxicology applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Toxicological characteristics of edible insects in China: A historical review.

PubMed

Gao, Yu; Wang, Di; Xu, Meng-Lei; Shi, Shu-Sen; Xiong, Jin-Feng

2018-04-10

Edible insects are ideal food sources, which contain important nutrients and health-promoting compounds. With a rapid development of industrial insect farming, insect-derived food is a novel and emerging food industry. Edible insects have been traditionally consumed in various communities, while continuously gaining relevance in today's society; however, they currently remain underutilized. Although there are a large number of literature on edible insects, these literature primarily focus on the nutritional value edible insects. The toxicity assessment data of edible insects remain incomprehensive, especially for the new national standard that is currently in effect; and many data and conclusions are not accurately specified/reported. Therefore, we performed a literature review and summarized the data on the toxicological assessment of edible insects in China. The review first describes the research progress on safety toxicological assessment, and then offers references regarding the development of 34 edible insect species in China. These data can be a platform for the development of future toxicological assessment strategies, which can be carried out by a multidisciplinary team, possibly consisting of food engineers, agronomists, farmers, and so on, to improve the acceptability of edible insects. Copyright © 2018 Elsevier Ltd. All rights reserved.

Using energy budgets to combine ecology and toxicology in a mammalian sentinel species

NASA Astrophysics Data System (ADS)

Desforges, Jean-Pierre W.; Sonne, Christian; Dietz, Rune

2017-04-01

Process-driven modelling approaches can resolve many of the shortcomings of traditional descriptive and non-mechanistic toxicology. We developed a simple dynamic energy budget (DEB) model for the mink (Mustela vison), a sentinel species in mammalian toxicology, which coupled animal physiology, ecology and toxicology, in order to mechanistically investigate the accumulation and adverse effects of lifelong dietary exposure to persistent environmental toxicants, most notably polychlorinated biphenyls (PCBs). Our novel mammalian DEB model accurately predicted, based on energy allocations to the interconnected metabolic processes of growth, development, maintenance and reproduction, lifelong patterns in mink growth, reproductive performance and dietary accumulation of PCBs as reported in the literature. Our model results were consistent with empirical data from captive and free-ranging studies in mink and other wildlife and suggest that PCB exposure can have significant population-level impacts resulting from targeted effects on fetal toxicity, kit mortality and growth and development. Our approach provides a simple and cross-species framework to explore the mechanistic interactions of physiological processes and ecotoxicology, thus allowing for a deeper understanding and interpretation of stressor-induced adverse effects at all levels of biological organization.

Cadmium-containing nanoparticles: Perspectives on pharmacology and toxicology of quantum dots

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

Rzigalinski, Beverly A.; Strobl, Jeannine S.

2009-08-01

The field of nanotechnology is rapidly expanding with the development of novel nanopharmaceuticals that have potential for revolutionizing medical treatment. The rapid pace of expansion in this field has exceeded the pace of pharmacological and toxicological research on the effects of nanoparticles in the biological environment. The development of cadmium-containing nanoparticles, known as quantum dots, show great promise for treatment and diagnosis of cancer and targeted drug delivery, due to their size-tunable fluorescence and ease of functionalization for tissue targeting. However, information on pharmacology and toxicology of quantum dots needs much further development, making it difficult to assess the risksmore » associated with this new nanotechnology. Further, nanotechnology poses yet another risk for toxic cadmium, which will now enter the biological realm in nano-form. In this review, we discuss cadmium-containing quantum dots and their physicochemical properties at the nano-scale. We summarize the existing work on pharmacology and toxicology of cadmium-containing quantum dots and discuss perspectives in their utility in disease treatment. Finally, we identify critical gaps in our knowledge of cadmium quantum dot toxicity, and how these gaps need to be assessed to enable quantum dot nanotechnology to transit safely from bench to bedside.« less

Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action

PubMed Central

Willett, Catherine; Rae, Jessica Caverly; Goyak, Katy O.; Minsavage, Gary; Westmoreland, Carl; Andersen, Melvin; Avigan, Mark; Duché, Daniel; Harris, Georgina; Hartung, Thomas; Jaeschke, Hartmut; Kleensang, Andre; Landesmann, Brigitte; Martos, Suzanne; Matevia, Marilyn; Toole, Colleen; Rowan, Andrew; Schultz, Terry; Seed, Jennifer; Senior, John; Shah, Imran; Subramanian, Kalyanasundaram; Vinken, Mathieu; Watkins, Paul

2016-01-01

Summary A workshop sponsored by the Human Toxicology Project Consortium (HTPC), “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action” brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is helpful. It is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered. PMID:24535319

Estimation of the upper bound of predictive performance for alternative models that use in vivo reference data (OpenTox USA 2017)

EPA Science Inventory

The number of chemicals with limited toxicological information for chemical safety decision-making has accelerated alternative model development, which often are evaluated via referencing animal toxicology studies. In vivo studies are generally considered the standard for hazard ...

The EPA ToxCast Program: Developing Predictive Bioactivity Signatures for Chemicals

EPA Science Inventory

There are tens of thousands of chemicals used in the environment for which little or no toxicology information is known. Current testing paradigms that use large numbers of animals to perform in vivo toxicology are too slow and expensive to apply to this large number of chemicals...

ANALYSIS OF FLOW THROUGH A HUMAN ORAL MODEL FOR USE IN INHALATION TOXICOLOGY AND AEROSOL THERAPY PROTOCOLS

EPA Science Inventory

RATIONALE
Understanding the transport and deposition of inhaled aerosols is of fundamental importance to inhalation toxicology and aerosol therapy. Herein, we focus on the development of a computer based oral morphology and related computational fluid dynamics (CFD) studi...

Inter-connections between human health and ecological integrity: An organizational framework for research and development

EPA Science Inventory

A Pellston workshop entitled, Interconnections between Human Health and Ecological Integrity, was held in 2000. Jointly sponsored by the Society of Environmental Toxicology and Chemistry (SETAC) and the Society of Toxicology (SOT), the workshop was motivated by the concern of hum...

How adverse outcome pathways can aid the development and use of computational prediction models for regulatory toxicology

EPA Science Inventory

Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumu...

A Bachelor of Science Toxicology Program: Description, Resources, Student Profiles and Graduate Placement.

ERIC Educational Resources Information Center

Ferguson, Paul W.; And Others

1991-01-01

The nine-year experience of the Northeast Louisiana University School of Pharmacy in developing an undergraduate toxicology program is described. A survey of 128 graduates revealed student characteristics and graduate employment and/or education patterns. Common job duties included industrial hygiene, analytical chemistry, technical writing,…

New developments in delivering public access to data from the National Center for Computational Toxicology at the EPA

EPA Science Inventory

Researchers at EPA’s National Center for Computational Toxicology integrate advances in biology, chemistry, and computer science to examine the toxicity of chemicals and help prioritize chemicals for further research based on potential human health risks. The goal of this researc...

The Accidental Toxicologist: A Career in the Science of Poisons (Health Science career presentation to HS Students)

EPA Science Inventory

This product is a powerpoint presentation. The presentation describes the science of toxicology and basic concepts in dose-response analysis. The presentation provides an example of computational toxicology approaches used to develop toxicity data for thousands of chemicals. The ...

75 FR 16106 - Draft Toxicological Review of Dichloromethane: In Support of Summary Information on the...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-31

... science-based human health assessments to support the Agency's regulatory activities. The IRIS database... for the external review draft human health assessment titled, ``Toxicological Review of... developing human health assessments for inclusion in the IRIS database. The purpose of the listening session...

Application of Computational Toxicological Approaches in Supporting Human Health Risk Assessment, Project Summary

EPA Science Inventory

Summary

ToxPi Prioritization and Profiling of 1060 ToxCast Chemicals Across Multiple Sectors of Toxicological Concern

EPA Science Inventory

The Toxicological Prioritization Index (ToxPi™) framework was developed as a decision-support tool to aid in the prioritization of chemicals for integrated toxicity testing. ToxPi consolidates information from multiple domains - including ToxCast™ in vitro bioactivity profiles (a...

IRIS Toxicological Review of Ethylene Glycol Mono-Butyl Ether (Egbe) (Interagency Science Discussion Draft)

EPA Science Inventory

EPA released the draft report, Toxicological Review for Ethylene Glycol Mono-Butyl Ether , that was distributed to Federal agencies and White House Offices for comment during the Science Discussion step of the IRIS Assessment Development Process. Comments received from ot...

Recent Developments in Toxico-Cheminformatics and Progress Towards a New Paradigm for Predictive Toxicology (2)

EPA Science Inventory

EPAs National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction through harnessing of legacy toxicity data, creation of data linkages, and generation of new in vitro screening data. In association with EPA...

Recent Developments in Toxico-Cheminformatics and Progress Towards a New Paradigm for Predictive Toxicology

EPA Science Inventory

EPA’s Computational Toxicology Center is building capabilities to support a new paradigm for toxicity screening and prediction through harnessing of legacy toxicity data, creation of data linkages, and generation of new in vitro screening data. In association with EPA’s ToxCastTM...

Data Aggregation, Curation and Modeling Approaches to Deliver Prediction Models to Support Computational Toxicology at the EPA (ACS Fall meeting)

EPA Science Inventory

The U.S. Environmental Protection Agency (EPA) Computational Toxicology Program develops and utilizes QSAR modeling approaches across a broad range of applications. In terms of physical chemistry we have a particular interest in the prediction of basic physicochemical parameters ...

Primary Care Providers’ Experiences with Urine Toxicology Tests to Manage Prescription Opioid Misuse and Substance Use Among Chronic Non-Cancer Pain Patients in Safety Net Healthcare Settings

PubMed Central

Ceasar, Rachel; Chang, Jamie; Zamora, Kara; Hurstak, Emily; Kushel, Margot; Miaskowski, Christine; Knight, Kelly

2016-01-01

Background Guideline recommendations to reduce prescription opioid misuse among patients with chronic non-cancer pain include the routine use of urine toxicology tests for high-risk patients. Yet little is known about how the implementation of urine toxicology tests among patients with co-occurring chronic non-cancer pain and substance use impacts primary care providers’ management of misuse. In this paper, we present clinicians’ perspectives on the benefits and challenges of implementing urine toxicology tests in the monitoring of opioid misuse and substance use in safety net healthcare settings. Methods We interviewed 23 primary care providers from six safety net healthcare settings whose patients had a diagnosis of co-occurring chronic non-cancer pain and substance use. We transcribed, coded, and analyzed interviews using grounded theory methodology. Results The benefits of implementing urine toxicology tests for primary care providers included less reliance on intuition to assess for misuse and the ability to identify unknown opioid misuse and/or substance use. The challenges of implementing urine toxicology tests included insufficient education and training about how to interpret and implement tests, and a lack of clarity on how and when to act on tests that indicated misuse and/or substance use. Conclusions These data suggest that primary care clinicians’ lack of education and training to interpret and implement urine toxicology tests may impact their management of patient opioid misuse and/or substance use. Clinicians may benefit from additional education and training about the clinical implementation and use of urine toxicology tests. Additional research is needed on how primary care providers implementation and use of urine toxicology tests impacts chronic non-cancer pain management in primary care and safety net healthcare settings among patients with co-occurring chronic non-cancer pain and substance use. PMID:26682471

IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5 ...

EPA Pesticide Factsheets

On March 10, 2016, the public comment draft Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine and the draft charge to external peer reviewers were released for public review and comment. 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 Hexahydro-1,3,5-trinitro-1,3,5-triazine and the charge to external peer reviewers, are posted on this site. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for RDX. The outcome of this project is an updated Toxicological Review and IRIS Summary for RDX that will be entered into the IRIS database.

Web tools for predictive toxicology model building.

PubMed

Jeliazkova, Nina

2012-07-01

The development and use of web tools in chemistry has accumulated more than 15 years of history already. Powered by the advances in the Internet technologies, the current generation of web systems are starting to expand into areas, traditional for desktop applications. The web platforms integrate data storage, cheminformatics and data analysis tools. The ease of use and the collaborative potential of the web is compelling, despite the challenges. The topic of this review is a set of recently published web tools that facilitate predictive toxicology model building. The focus is on software platforms, offering web access to chemical structure-based methods, although some of the frameworks could also provide bioinformatics or hybrid data analysis functionalities. A number of historical and current developments are cited. In order to provide comparable assessment, the following characteristics are considered: support for workflows, descriptor calculations, visualization, modeling algorithms, data management and data sharing capabilities, availability of GUI or programmatic access and implementation details. The success of the Web is largely due to its highly decentralized, yet sufficiently interoperable model for information access. The expected future convergence between cheminformatics and bioinformatics databases provides new challenges toward management and analysis of large data sets. The web tools in predictive toxicology will likely continue to evolve toward the right mix of flexibility, performance, scalability, interoperability, sets of unique features offered, friendly user interfaces, programmatic access for advanced users, platform independence, results reproducibility, curation and crowdsourcing utilities, collaborative sharing and secure access.

THE FUTURE OF TOXICOLOGY-PREDICTIVE TOXICOLOGY ...

EPA Pesticide Factsheets

A chemistry approach to predictive toxicology relies on structure−activity relationship (SAR) modeling to predict biological activity from chemical structure. Such approaches have proven capabilities when applied to well-defined toxicity end points or regions of chemical space. These approaches are less well-suited, however, to the challenges of global toxicity prediction, i.e., to predicting the potential toxicity of structurally diverse chemicals across a wide range of end points of regulatory and pharmaceutical concern. New approaches that have the potential to significantly improve capabilities in predictive toxicology are elaborating the “activity” portion of the SAR paradigm. Recent advances in two areas of endeavor are particularly promising. Toxicity data informatics relies on standardized data schema, developed for particular areas of toxicological study, to facilitate data integration and enable relational exploration and mining of data across both historical and new areas of toxicological investigation. Bioassay profiling refers to large-scale high-throughput screening approaches that use chemicals as probes to broadly characterize biological response space, extending the concept of chemical “properties” to the biological activity domain. The effective capture and representation of legacy and new toxicity data into mineable form and the large-scale generation of new bioassay data in relation to chemical toxicity, both employing chemical stru

The Impact of Novel Assessment Methodologies in Toxicology on Green Chemistry and Chemical Alternatives.

PubMed

Rusyn, Ivan; Greene, Nigel

2018-02-01

The field of experimental toxicology is rapidly advancing by incorporating novel techniques and methods that provide a much more granular view into the mechanisms of potential adverse effects of chemical exposures on human health. The data from various in vitro assays and computational models are useful not only for increasing confidence in hazard and risk decisions, but also are enabling better, faster and cheaper assessment of a greater number of compounds, mixtures, and complex products. This is of special value to the field of green chemistry where design of new materials or alternative uses of existing ones is driven, at least in part, by considerations of safety. This article reviews the state of the science and decision-making in scenarios when little to no data may be available to draw conclusions about which choice in green chemistry is "safer." It is clear that there is no "one size fits all" solution and multiple data streams need to be weighed in making a decision. Moreover, the overall level of familiarity of the decision-makers and scientists alike with new assessment methodologies, their validity, value and limitations is evolving. Thus, while the "impact" of the new developments in toxicology on the field of green chemistry is great already, it is premature to conclude that the data from new assessment methodologies have been widely accepted yet. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Caenorhabditis elegans as a powerful alternative model organism to promote research in genetic toxicology and biomedicine.

PubMed

Honnen, Sebastian

2017-05-01

In view of increased life expectancy the risk for disturbed integrity of genetic information increases. This inevitably holds the implication for higher incidence of age-related diseases leading to considerable cost increase in health care systems. To develop preventive strategies it is crucial to evaluate external and internal noxae as possible threats to our DNA. Especially the interplay of DNA damage response (DDR) and DNA repair (DR) mechanisms needs further deciphering. Moreover, there is a distinct need for alternative in vivo test systems for basic research and also risk assessment in toxicology. Especially the evaluation of combinational toxicity of environmentally present genotoxins and adverse effects of clinically used DNA damaging anticancer drugs is a major challenge for modern toxicology. This review focuses on the applicability of Caenorhabditis elegans as a model organism to unravel and tackle scientific questions related to the biological consequences of genotoxin exposure and highlights methods for studying DDR and DR. In this regard large-scale in vivo screens of mixtures of chemicals and extensive parallel sequencing are highlighted as unique advantages of C. elegans. In addition, concise information regarding evolutionary conserved molecular mechanisms of the DDR and DR as well as currently available data obtained from the use of prototypical genotoxins and preferential read-outs of genotoxin testing are discussed. The use of established protocols, which are already available in the community, is encouraged to facilitate and further improve the implementation of C. elegans as a powerful genetic model system in genetic toxicology and biomedicine.

The concentration of no toxicologic concern (CoNTC) and airborne mycotoxins.

PubMed

Hardin, Bryan D; Robbins, Coreen A; Fallah, Payam; Kelman, Bruce J

2009-01-01

The threshold of toxicologic concern (TTC) concept was developed as a method to identify a chemical intake level that is predicted to be without adverse human health effects assuming daily intake over the course of a 70-yr life span. The TTC values are based on known structure-activity relationships and do not require chemical-specific toxicity data. This allows safety assessment (or prioritization for testing) of chemicals with known molecular structure but little or no toxicity data. Recently, the TTC concept was extended to inhaled substances by converting a TTC expressed in micrograms per person per day to an airborne concentration (ng/m(3)), making allowance for intake by routes in addition to inhalation and implicitly assuming 100% bioavailability of inhaled toxicants. The resulting concentration of no toxicologic concern (CoNTC), 30 ng/m(3), represents a generic airborne concentration that is expected to pose no hazard to humans exposed continuously throughout a 70-yr lifetime. Published data on the levels of mycotoxins in agricultural dusts or in fungal spores, along with measured levels of airborne mycotoxins, spores, or dust in various environments, were used to identify conditions under which mycotoxin exposures might reach the CoNTC. Data demonstrate that airborne concentrations of dusts and mold spores sometimes encountered in agricultural environments have the potential to produce mycotoxin concentrations greater than the CoNTC. On the other hand, these data suggest that common exposures to mycotoxins from airborne molds in daily life, including in the built indoor environment, are below the concentration of no toxicologic concern.

IRIS Toxicological Review of Benzo[a]pyrene (Interagency ...

EPA Pesticide Factsheets

In January 2017, EPA finalized the IRIS assessment of Benzo[a]pyrene. The Toxicological Review was 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 discussion materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Benzo[a]pyrene are posted on this site. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for benzo[a]pyrene (BaP). The outcome of this project is an updated Toxicological Review and IRIS Summary for BaP that will be entered into the IRIS database.

Research and Development of Energetic Ionic Liquids

DTIC Science & Technology

2012-03-01

Navy/ AF ) – USAF AF - M315E • Propellant uses ionic liquids to yield low vapor toxicity 22 – Sweden/ECAPS LMP-103S • Propellant uses ADN-based formulation...hydrazine replacement monopropellant objectives, relevant monopropellant properties, AF -M1028A monopropellant composition and physical properties...thruster tests of AF -M1028A, ionic liquids as explosives, predictive toxicology, predictive methods expected payoff. AFRL continues efforts in energetic

The toxicology and immunology of detergent enzymes.

PubMed

Basketter, David; Berg, Ninna; Kruszewski, Francis H; Sarlo, Katherine; Concoby, Beth

2012-01-01

Detergent enzymes have a very good safety profile, with almost no capacity to generate adverse acute or chronic responses in humans. The exceptions are the limited ability of some proteases to produce irritating effects at high concentrations, and the intrinsic potential of these bacterial and fungal proteins to act as respiratory sensitizers, demonstrated in humans during the early phase of the industrial use of enzymes during the 1960s and 1970s. How enzymes generate these responses are beginning to become a little clearer, with a developing appreciation of the cell surface mechanism(s) by which the enzymatic activity promotes the T-helper (T(H))-2 cell responses, leading to the generation of IgE. It is a reasonable assumption that the majority of enzyme proteins possess this intrinsic hazard. However, toxicological methods for characterizing further the respiratory sensitization hazard of individual enzymes remains a problematic area, with the consequence that the information feeding into risk assessment/management, although sufficient, is limited. Most of this information was in the past generated in animal models and in vitro immunoassays that assess immunological cross-reactivity. Ultimately, by understanding more fully the mechanisms which drive the IgE response to enzymes, it will be possible to develop better methods for hazard characterization and consequently for risk assessment and management.

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop.

PubMed

Aigner, Achim; Buesen, Roland; Gant, Tim; Gooderham, Nigel; Greim, Helmut; Hackermüller, Jörg; Hubesch, Bruno; Laffont, Madeleine; Marczylo, Emma; Meister, Gunter; Petrick, Jay S; Rasoulpour, Reza J; Sauer, Ursula G; Schmidt, Kerstin; Seitz, Hervé; Slack, Frank; Sukata, Tokuo; van der Vies, Saskia M; Verhaert, Jan; Witwer, Kenneth W; Poole, Alan

2016-12-01

The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that ncRNA expression profiling data requires careful evaluation to determine the utility of specific ncRNAs as biomarkers. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify possibly suitable ncRNAs and areas of toxicology where ncRNA expression profiling could address prevailing scientific deficiencies. (2) Develop consensus on how to conduct ncRNA expression profiling in a toxicological context. (3) Conduct experimental projects, including, e.g., rat (90-day) oral toxicity studies, to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. Thereby, physiological ncRNA expression profiles should be established, including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be dose-dependently linked with substance-induced apical effects. Applying a holistic approach, knowledge on ncRNAs, 'omics and epigenetics technologies should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Development and practical application of a library of CID accurate mass spectra of more than 2,500 toxic compounds for systematic toxicological analysis by LC-QTOF-MS with data-dependent acquisition.

PubMed

Broecker, Sebastian; Herre, Sieglinde; Wüst, Bernhard; Zweigenbaum, Jerry; Pragst, Fritz

2011-04-01

A library of collision-induced dissociation (CID) accurate mass spectra has been developed for efficient use of liquid chromatography in combination with hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) as a tool in systematic toxicological analysis. The mass spectra (Δm < 3 ppm) of more than 2,500 illegal and therapeutic drugs, pesticides, alkaloids, other toxic chemicals and metabolites were measured, by use of an Agilent 6530 instrument, by flow-injection of 1 ng of the pure substances in aqueous ammonium formate-formic acid-methanol, with positive and negative electrospray-ionization (ESI), selection of the protonated or deprotonated molecules [M+H](+) or [M-H](-) by the quadrupole, and collision induced dissociation (CID) with nitrogen as collision gas at CID energies of 10, 20, and 40 eV. The fragment mass spectra were controlled for structural plausibility, corrected by recalculation to the theoretical fragment masses and added to a database of accurate mass data and molecular formulas of more than 7,500 toxicologically relevant substances to form the "database and library of toxic compounds". For practical evaluation, blood and urine samples were spiked with a mixture of 33 drugs at seven concentrations between 0.5 and 500 ng mL(-1), prepared by dichloromethane extraction or protein precipitation, and analyzed by LC-QTOF-MS in data-dependent acquisition mode. Unambiguous identification by library search was possible for typical basic drugs down to 0.5-2 ng mL(-1) and for benzodiazepines down to 2-20 ng mL(-1). The efficiency of the method was also demonstrated by re-analysis of venous blood samples from 50 death cases and comparison with previous results. In conclusion, LC-QTOF-MS in data-dependent acquisition mode combined with an accurate mass database and CID spectra library seemed to be one of the most efficient tools for systematic toxicological analysis.

Application of omics data in regulatory toxicology: report of an international BfR expert workshop.

PubMed

Marx-Stoelting, P; Braeuning, A; Buhrke, T; Lampen, A; Niemann, L; Oelgeschlaeger, M; Rieke, S; Schmidt, F; Heise, T; Pfeil, R; Solecki, R

2015-11-01

Advances in omics techniques and molecular toxicology are necessary to provide new perspectives for regulatory toxicology. By the application of modern molecular techniques, more mechanistic information should be gained to support standard toxicity studies and to contribute to a reduction and refinement of animal experiments required for certain regulatory purposes. The relevance and applicability of data obtained by omics methods to regulatory purposes such as grouping of chemicals, mode of action analysis or classification and labelling needs further improvement, defined validation and cautious expert judgment. Based on the results of an international expert workshop organized 2014 by the Federal Institute for Risk Assessment in Berlin, this paper is aimed to provide a critical overview of the regulatory relevance and reliability of omics methods, basic requirements on data quality and validation, as well as regulatory criteria to decide which effects observed by omics methods should be considered adverse or non-adverse. As a way forward, it was concluded that the inclusion of omics data can facilitate a more flexible approach for regulatory risk assessment and may help to reduce or refine animal testing.

Toxicology and detection methods of the alkaloid neurotoxin produced by cyanobacteria, anatoxin-a.

PubMed

Osswald, Joana; Rellán, Sandra; Gago, Ana; Vasconcelos, Vitor

2007-11-01

Freshwater resources are under stress due to naturally occurring conditions and human impacts. One of the consequences is the proliferation of cyanobacteria, microphytoplankton organisms that are capable to produce toxins called cyanotoxins. Anatoxin-a is one of the main cyanotoxins. It is a very potent neurotoxin that was already responsible for some animal fatalities. In this review we endeavor to divulgate much of the internationally published information about toxicology, occurrence and detection methods of anatoxin-a. Cyanobacteria generalities, anatoxin-a occurrence and production as well as anatoxin-a toxicology and its methods of detection are the aspects focused in this review. Remediation of anatoxin-a occurrence will be addressed with a public health perspective. Final remarks call the attention for some important gaps in the knowledge about this neurotoxin and its implication to public health. Alterations of aquatic ecosystems caused by anatoxin-a is also addressed. Although anatoxin-a is not the more frequent cyanotoxin worldwide, it has to be regarded as a health risk that can be fatal to terrestrial and aquatic organisms because of its high toxicity.

Quantitative analysis of benzodiazepines in vitreous humor by high-performance liquid chromatography

PubMed Central

Bazmi, Elham; Behnoush, Behnam; Akhgari, Maryam; Bahmanabadi, Leila

2016-01-01

Objective: Benzodiazepines are frequently screened drugs in emergency toxicology, drugs of abuse testing, and in forensic cases. As the variations of benzodiazepines concentrations in biological samples during bleeding, postmortem changes, and redistribution could be biasing forensic medicine examinations, hence selecting a suitable sample and a validated accurate method is essential for the quantitative analysis of these main drug categories. The aim of this study was to develop a valid method for the determination of four benzodiazepines (flurazepam, lorazepam, alprazolam, and diazepam) in vitreous humor using liquid–liquid extraction and high-performance liquid chromatography. Methods: Sample preparation was carried out using liquid–liquid extraction with n-hexane: ethyl acetate and subsequent detection by high-performance liquid chromatography method coupled to diode array detector. This method was applied to quantify benzodiazepines in 21 authentic vitreous humor samples. Linear curve for each drug was obtained within the range of 30–3000 ng/mL with coefficient of correlation higher than 0.99. Results: The limit of detection and quantitation were 30 and 100 ng/mL respectively for four drugs. The method showed an appropriate intra- and inter-day precision (coefficient of variation < 10%). Benzodiazepines recoveries were estimated to be over 80%. The method showed high selectivity; no additional peak due to interfering substances in samples was observed. Conclusion: The present method was selective, sensitive, accurate, and precise for the quantitative analysis of benzodiazepines in vitreous humor samples in forensic toxicology laboratory. PMID:27635251

Aggregating Data for Computational Toxicology Applications ...

EPA Pesticide Factsheets

Computational toxicology combines data from high-throughput test methods, chemical structure analyses and other biological domains (e.g., genes, proteins, cells, tissues) with the goals of predicting and understanding the underlying mechanistic causes of chemical toxicity and for predicting toxicity of new chemicals and products. A key feature of such approaches is their reliance on knowledge extracted from large collections of data and data sets in computable formats. The U.S. Environmental Protection Agency (EPA) has developed a large data resource called ACToR (Aggregated Computational Toxicology Resource) to support these data-intensive efforts. ACToR comprises four main repositories: core ACToR (chemical identifiers and structures, and summary data on hazard, exposure, use, and other domains), ToxRefDB (Toxicity Reference Database, a compilation of detailed in vivo toxicity data from guideline studies), ExpoCastDB (detailed human exposure data from observational studies of selected chemicals), and ToxCastDB (data from high-throughput screening programs, including links to underlying biological information related to genes and pathways). The EPA DSSTox (Distributed Structure-Searchable Toxicity) program provides expert-reviewed chemical structures and associated information for these and other high-interest public inventories. Overall, the ACToR system contains information on about 400,000 chemicals from 1100 different sources. The entire system is built usi

Developing an analytical toxicology service: principles and guidance.

PubMed

Flanagan, Robert J

2004-01-01

Many acutely poisoned patients are treated with no laboratory help other than general clinical chemistry and haematology. Emergency toxicological analyses (24-hour availability) that could influence immediate patient management such as iron, lithium and paracetamol (acetaminophen), are relatively few in number and are remarkably similar worldwide. These assays should be provided at hospitals with large accident and emergency departments. More complex, less frequently needed clinical toxicological assays that can often be offered on a less urgent basis are usually provided from regional or national centres because of the need to make best use of resources. Recommendations as to the assays that should be provided locally and at regional centres are available for the UK and US, and are generally applicable. Regional centres normally diversify into specialised therapeutic drug monitoring, urine screening for drugs of abuse, metals analysis and sometimes forensic work in order to widen the repertoire of tests available and to increase funding. Whatever the type and quantity of work undertaken and the instrumentation used, guidelines are now available delineating staff training, method validation, assay operation, quality control/quality assurance, and indeed virtually all other aspects of laboratory operation. These considerations notwithstanding, clinical interpretation of analytical results remains a difficult area and is the responsibility of the reporting laboratory, at least in the first instance.

Enhancing high throughput toxicology - development of putative adverse outcome pathways linking US EPA ToxCast screening targets to relevant apical hazards.

EPA Science Inventory

High throughput toxicology programs, such as ToxCast and Tox21, have provided biological effects data for thousands of chemicals at multiple concentrations. Compared to traditional, whole-organism approaches, high throughput assays are rapid and cost-effective, yet they generall...

75 FR 7477 - Draft Toxicological Review of Inorganic Arsenic: In Support of the Summary Information on the...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-19

... Environmental Assessment (NCEA) within the EPA's Office of Research and Development (ORD). The Toxicological Review of Inorganic Arsenic was submitted to the EPA's Science Advisory Board (SAB) for external peer... IRIS IRIS is a human health assessment program that evaluates quantitative and qualitative risk...

Applications of Computational Toxicology to the Understanding of Risks of Developmental Toxicity

EPA Science Inventory

In response to a request from US EPA, the National Research Council (NRC) developed a long-range vision and strategic plan for the future of toxicity testing in the 21st century. The report, published in 2007, called for a transformation in toxicology that would provide a more r...

The State of the Art of the Zebrafish Model for Toxicology and Toxicologic Pathology Research—Advantages and Current Limitations

PubMed Central

Spitsbergen, Jan M.; Kent, Michael L.

2007-01-01

The zebrafish (Danio rerio) is now the pre-eminent vertebrate model system for clarification of the roles of specific genes and signaling pathways in development. The zebrafish genome will be completely sequenced within the next 1–2 years. Together with the substantial historical database regarding basic developmental biology, toxicology, and gene transfer, the rich foundation of molecular genetic and genomic data makes zebrafish a powerful model system for clarifying mechanisms in toxicity. In contrast to the highly advanced knowledge base on molecular developmental genetics in zebrafish, our database regarding infectious and noninfectious diseases and pathologic lesions in zebrafish lags far behind the information available on most other domestic mammalian and avian species, particularly rodents. Currently, minimal data are available regarding spontaneous neoplasm rates or spontaneous aging lesions in any of the commonly used wild-type or mutant lines of zebrafish. Therefore, to fully utilize the potential of zebrafish as an animal model for understanding human development, disease, and toxicology we must greatly advance our knowledge on zebrafish diseases and pathology. PMID:12597434

SEURAT: Safety Evaluation Ultimately Replacing Animal Testing--recommendations for future research in the field of predictive toxicology.

PubMed

Daston, George; Knight, Derek J; Schwarz, Michael; Gocht, Tilman; Thomas, Russell S; Mahony, Catherine; Whelan, Maurice

2015-01-01

The development of non-animal methodology to evaluate the potential for a chemical to cause systemic toxicity is one of the grand challenges of modern science. The European research programme SEURAT is active in this field and will conclude its first phase, SEURAT-1, in December 2015. Drawing on the experience gained in SEURAT-1 and appreciating international advancement in both basic and regulatory science, we reflect here on how SEURAT should evolve and propose that further research and development should be directed along two complementary and interconnecting work streams. The first work stream would focus on developing new 'paradigm' approaches for regulatory science. The goal here is the identification of 'critical biological targets' relevant for toxicity and to test their suitability to be used as anchors for predicting toxicity. The second work stream would focus on integration and application of new approach methods for hazard (and risk) assessment within the current regulatory 'paradigm', aiming for acceptance of animal-free testing strategies by regulatory authorities (i.e. translating scientific achievements into regulation). Components for both work streams are discussed and may provide a structure for a future research programme in the field of predictive toxicology.

Development of a Fragment-Based in Silico Profiler for Michael Addition Thiol Reactivity.

PubMed

Ebbrell, David J; Madden, Judith C; Cronin, Mark T D; Schultz, Terry W; Enoch, Steven J

2016-06-20

The Adverse Outcome Pathway (AOP) paradigm details the existing knowledge that links the initial interaction between a chemical and a biological system, termed the molecular initiating event (MIE), through a series of intermediate events, to an adverse effect. An important example of a well-defined MIE is the formation of a covalent bond between a biological nucleophile and an electrophilic compound. This particular MIE has been associated with various toxicological end points such as acute aquatic toxicity, skin sensitization, and respiratory sensitization. This study has investigated the calculated parameters that are required to predict the rate of chemical bond formation (reactivity) of a dataset of Michael acceptors. Reactivity of these compounds toward glutathione was predicted using a combination of a calculated activation energy value (Eact, calculated using density functional theory (DFT) calculation at the B3YLP/6-31G+(d) level of theory, and solvent-accessible surface area values (SAS) at the α carbon. To further develop the method, a fragment-based algorithm was developed enabling the reactivity to be predicted for Michael acceptors without the need to perform the time-consuming DFT calculations. Results showed the developed fragment method was successful in predicting the reactivity of the Michael acceptors excluding two sets of chemicals: volatile esters with an extended substituent at the β-carbon and chemicals containing a conjugated benzene ring as part of the polarizing group. Additionally the study also demonstrated the ease with which the approach can be extended to other chemical classes by the calculation of additional fragments and their associated Eact and SAS values. The resulting method is likely to be of use in regulatory toxicology tools where an understanding of covalent bond formation as a potential MIE is important within the AOP paradigm.

Regulatory Forum Opinion Piece*: Use and Utility of Animal Models of Disease for Nonclinical Safety Assessment: A Pharmaceutical Industry Survey.

PubMed

Morgan, Sherry J; Couch, Jessica; Guzzie-Peck, Peggy; Keller, Douglas A; Kemper, Ray; Otieno, Monicah A; Schulingkamp, Robert J; Jones, Thomas W

2017-04-01

An Innovation and Quality (IQ) Consortium focus group conducted a cross-company survey to evaluate current practices and perceptions around the use of animal models of disease (AMDs) in nonclinical safety assessment of molecules in clinical development. The IQ Consortium group is an organization of pharmaceutical and biotechnology companies with the mission of advancing science and technology. The survey queried the utilization of AMDs during drug discovery in which drug candidates are evaluated in efficacy models and limited short-duration non-Good Laboratory Practices (GLP) toxicology testing and during drug development in which drug candidates are evaluated in GLP toxicology studies. The survey determined that the majority of companies used AMDs during drug discovery primarily as a means for proactively assessing potential nonclinical safety issues prior to the conduct of toxicology studies, followed closely by the use of AMDs to better understand toxicities associated with exaggerated pharmacology in traditional toxicology models or to derisk issues when the target is only expressed in the disease state. In contrast, the survey results indicated that the use of AMDs in development is infrequent, being used primarily to investigate nonclinical safety issues associated with targets expressed only in disease states and/or in response to requests from global regulatory authorities.

FutureTox II: in vitro data and in silico models for predictive toxicology.

PubMed

Knudsen, Thomas B; Keller, Douglas A; Sander, Miriam; Carney, Edward W; Doerrer, Nancy G; Eaton, David L; Fitzpatrick, Suzanne Compton; Hastings, Kenneth L; Mendrick, Donna L; Tice, Raymond R; Watkins, Paul B; Whelan, Maurice

2015-02-01

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. © 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.

Assessment of toxicology knowledge in the fourth-year medical students: Three years of data.

PubMed

Buchanan, Jennie; Windels, Daniel; Druck, Jeffrey; Heard, Kennon

2018-01-01

Pharmacology and toxicology are core content knowledge for physicians. Medical students should demonstrate understanding of general pharmacology and basic treatment of poisoning. The objective of this study was to measure the knowledge of the 4th-year medical students (MS4) on these topics over 3 years. A multiple-choice exam (15 questions) was administered to MS4 students in spring of 2010, 2011, and 2012. Questions were developed by medical toxicologists to evaluate basic knowledge in three areas: pharmacologic effects (PE), treatment of poisoning (TOP), and pharmacokinetics (PK). The students were grouped by intended specialties into pharmacologic intense (anesthesia, emergency medicine, internal medicine, pediatrics, and psychiatry), less pharmacologic intense specialties (dermatology, OB/GYN, ophthalmology, pathology, physical medicine and rehabilitation, radiology, and surgery) and by completion of a pharmacology or toxicology elective. Mean group scores were compared using ANOVA. Totally 332 of 401 (83%) students completed the survey. Mean scores were stable over the three years, higher for students completing a toxicology rotation and for students entering a pharmacologically intense specialty. The external validity is limited to a single medical school with incomplete participation and content was limited by the survey length. Consistent results over the three-year period and correlation of performance with completing a toxicology rotation and intent to enter a pharmacology intensive specialty suggest this survey may correlate with toxicology knowledge. Implementation of required core courses focused on toxicology may improve core content knowledge in fourth year medical students.

Toxicological Risks During Human Space Exploration

NASA Technical Reports Server (NTRS)

James, John T.; Limero, T. F.; Lam, C. W.; Billica, Roger (Technical Monitor)

2000-01-01

The goal of toxicological risk assessment of human space flight is to identify and quantify significant risks to astronaut health from air pollution inside the vehicle or habitat, and to develop a strategy for control of those risks. The approach to completing a toxicological risk assessment involves data and experience on the frequency and severity of toxicological incidents that have occurred during space flight. Control of these incidents depends on being able to understand their cause from in-flight and ground-based analysis of air samples, crew reports of air quality, and known failures in containment of toxic chemicals. Toxicological risk assessment in exploration missions must be based on an evaluation of the unique toxic hazards presented by the habitat location. For example, lunar and Martian dust must be toxicologically evaluated to determine the appropriate control measures for exploration missions. Experience with near-earth flights has shown that the toxic products from fires present the highest risk to crew health from air pollution. Systems and payload leaks also present a significant hazard. The health risk from toxicity associated with materials offgassing or accumulation of human metabolites is generally well controlled. Early tests of lunar and Martian dust simulants have shown that each posses the potential to cause fibrosis in the lung in a murine model. Toxicological risks from air pollutants in space habitats originate from many sources. A number of risks have been identified through near-earth operations; however, the evaluation of additional new risks present during exploration missions will be a challenge.

Applicability of predictive toxicology methods for monoclonal antibody therapeutics: status Quo and scope.

PubMed

Kizhedath, Arathi; Wilkinson, Simon; Glassey, Jarka

2017-04-01

Biopharmaceuticals, monoclonal antibody (mAb)-based therapeutics in particular, have positively impacted millions of lives. MAbs and related therapeutics are highly desirable from a biopharmaceutical perspective as they are highly target specific and well tolerated within the human system. Nevertheless, several mAbs have been discontinued or withdrawn based either on their inability to demonstrate efficacy and/or due to adverse effects. Approved monoclonal antibodies and derived therapeutics have been associated with adverse effects such as immunogenicity, cytokine release syndrome, progressive multifocal leukoencephalopathy, intravascular haemolysis, cardiac arrhythmias, abnormal liver function, gastrointestinal perforation, bronchospasm, intraocular inflammation, urticaria, nephritis, neuropathy, birth defects, fever and cough to name a few. The advances made in this field are also impeded by a lack of progress in bioprocess development strategies as well as increasing costs owing to attrition, wherein the lack of efficacy and safety accounts for nearly 60 % of all factors contributing to attrition. This reiterates the need for smarter preclinical development using quality by design-based approaches encompassing carefully designed predictive models during early stages of drug development. Different in vitro and in silico methods are extensively used for predicting biological activity as well as toxicity during small molecule drug development; however, their full potential has not been utilized for biological drug development. The scope of in vitro and in silico tools in early developmental stages of monoclonal antibody-based therapeutics production and how it contributes to lower attrition rates leading to faster development of potential drug candidates has been evaluated. The applicability of computational toxicology approaches in this context as well as the pitfalls and promises of extending such techniques to biopharmaceutical development has been highlighted.

Creation of a digital slide and tissue microarray resource from a multi-institutional predictive toxicology study in the rat: an initial report from the PredTox group.

PubMed

Mulrane, Laoighse; Rexhepaj, Elton; Smart, Valerie; Callanan, John J; Orhan, Diclehan; Eldem, Türkan; Mally, Angela; Schroeder, Susanne; Meyer, Kirstin; Wendt, Maria; O'Shea, Donal; Gallagher, William M

2008-08-01

The widespread use of digital slides has only recently come to the fore with the development of high-throughput scanners and high performance viewing software. This development, along with the optimisation of compression standards and image transfer techniques, has allowed the technology to be used in wide reaching applications including integration of images into hospital information systems and histopathological training, as well as the development of automated image analysis algorithms for prediction of histological aberrations and quantification of immunohistochemical stains. Here, the use of this technology in the creation of a comprehensive library of images of preclinical toxicological relevance is demonstrated. The images, acquired using the Aperio ScanScope CS and XT slide acquisition systems, form part of the ongoing EU FP6 Integrated Project, Innovative Medicines for Europe (InnoMed). In more detail, PredTox (abbreviation for Predictive Toxicology) is a subproject of InnoMed and comprises a consortium of 15 industrial (13 large pharma, 1 technology provider and 1 SME) and three academic partners. The primary aim of this consortium is to assess the value of combining data generated from 'omics technologies (proteomics, transcriptomics, metabolomics) with the results from more conventional toxicology methods, to facilitate further informed decision making in preclinical safety evaluation. A library of 1709 scanned images was created of full-face sections of liver and kidney tissue specimens from male Wistar rats treated with 16 proprietary and reference compounds of known toxicity; additional biological materials from these treated animals were separately used to create 'omics data, that will ultimately be used to populate an integrated toxicological database. In respect to assessment of the digital slides, a web-enabled digital slide management system, Digital SlideServer (DSS), was employed to enable integration of the digital slide content into the 'omics database and to facilitate remote viewing by pathologists connected with the project. DSS also facilitated manual annotation of digital slides by the pathologists, specifically in relation to marking particular lesions of interest. Tissue microarrays (TMAs) were constructed from the specimens for the purpose of creating a repository of tissue from animals used in the study with a view to later-stage biomarker assessment. As the PredTox consortium itself aims to identify new biomarkers of toxicity, these TMAs will be a valuable means of validation. In summary, a large repository of histological images was created enabling the subsequent pathological analysis of samples through remote viewing and, along with the utilisation of TMA technology, will allow the validation of biomarkers identified by the PredTox consortium. The population of the PredTox database with these digitised images represents the creation of the first toxicological database integrating 'omics and preclinical data with histological images.

[Two cases of suspected Munchausen by proxy syndrome: the importance of forensic toxicological analyses in handling suspicions and producing evidence].

PubMed

Musshoff, Frank; Kirschbaum, Katrin M; Madea, Burkhard

2008-01-01

The authors report on two cases of suspected Munchausen by proxy syndrome. In a 3-year-old boy, clinical toxicological analyses produced suspicious clues that an antidepressant had been administered, which could not be verified by forensic toxicological investigations. In a 13-month-old boy, the mother was also suspected of having poisoned the child. Initial clinical toxicological examinations failed to explain the observed symptoms (unclear unconsciousness, narrowed pupils). While in the first case, the incorrect interpretation of findings by a laboratory without forensic experience resulted in suspicions against the mother, the cause for the observed symptoms in the second case could be proved by complex analyses not performed before and the suspicion that the clinical picture had been intentionally brought about could be cleared up (use of an antitussive containing clobutinol). The two reports show that especially in cases with a potential forensic background, adequately qualified forensic laboratories with a broad spectrum of analytical methods should be involved.

Status of characterization techniques for carbon nanotubes and suggestions towards standards suitable for toxicological assessment

NASA Astrophysics Data System (ADS)

Schweinberger, Florian F.; Meyer-Plath, Asmus

2011-07-01

Nanotechnologies promise to contribute significantly to major technological challenges of the upcoming century. Despite profound scientific progress in the last decades, only minor advances have been made in the field of nanomaterial toxicology. The International Team in Nanosafety (TITNT) is an international and multidisciplinary group of scientists, which aims at better understanding the risks of nanomaterials. Carbon nanotubes (CNT) account for one of the most promising nanomaterials and have therefore been chosen as representative material for nanoscaled particles. They are currently investigated by the different platforms of TITNT. As a starting point, the present report summarizes a literature-based study on the physico-chemical properties of CNT, as they are closely linked with toxicological properties. A brief introduction to synthesis, purification and material properties is given. Characterization methods for CNT are discussed with respect to their reliability and the information content on chemical properties. Recommendations for a set of standard characterizations mandatory for toxicological assessment are derived.

Applied Nanotoxicology.

PubMed

Hobson, David W; Roberts, Stephen M; Shvedova, Anna A; Warheit, David B; Hinkley, Georgia K; Guy, Robin C

2016-01-01

Nanomaterials, including nanoparticles and nanoobjects, are being incorporated into everyday products at an increasing rate. These products include consumer products of interest to toxicologists such as pharmaceuticals, cosmetics, food, food packaging, household products, and so on. The manufacturing of products containing or utilizing nanomaterials in their composition may also present potential toxicologic concerns in the workplace. The molecular complexity and composition of these nanomaterials are ever increasing, and the means and methods being applied to characterize and perform useful toxicologic assessments are rapidly advancing. This article includes presentations by experienced toxicologists in the nanotoxicology community who are focused on the applied aspect of the discipline toward supporting state of the art toxicologic assessments for food products and packaging, pharmaceuticals and medical devices, inhaled nanoparticle and gastrointestinal exposures, and addressing occupational safety and health issues and concerns. This symposium overview article summarizes 5 talks that were presented at the 35th Annual meeting of the American College of Toxicology on the subject of "Applied Nanotechnology." © The Author(s) 2016.

Applied Nanotoxicology

PubMed Central

Hobson, David W.; Roberts, Stephen M.; Shvedova, Anna A.; Warheit, David B.; Hinkley, Georgia K.; Guy, Robin C.

2016-01-01

Nanomaterials, including nanoparticles and nanoobjects, are being incorporated into everyday products at an increasing rate. These products include consumer products of interest to toxicologists such as pharmaceuticals, cosmetics, food, food packaging, household products, and so on. The manufacturing of products containing or utilizing nanomaterials in their composition may also present potential toxicologic concerns in the workplace. The molecular complexity and composition of these nanomaterials are ever increasing, and the means and methods being applied to characterize and perform useful toxicologic assessments are rapidly advancing. This article includes presentations by experienced toxicologists in the nanotoxicology community who are focused on the applied aspect of the discipline toward supporting state of the art toxicologic assessments for food products and packaging, pharmaceuticals and medical devices, inhaled nanoparticle and gastrointestinal exposures, and addressing occupational safety and health issues and concerns. This symposium overview article summarizes 5 talks that were presented at the 35th Annual meeting of the American College of Toxicology on the subject of “Applied Nanotechnology.” PMID:26957538

Improving the human hazard characterization of chemicals: a Tox21 update.

PubMed

Tice, Raymond R; Austin, Christopher P; Kavlock, Robert J; Bucher, John R

2013-07-01

In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency's National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on "high throughput screening, toxicity pathway profiling, and biological interpretation of findings." In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21. The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays. Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems. Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology.

Improving the Human Hazard Characterization of Chemicals: A Tox21 Update

PubMed Central

Austin, Christopher P.; Kavlock, Robert J.; Bucher, John R.

2013-01-01

Background: In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency’s National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on “high throughput screening, toxicity pathway profiling, and biological interpretation of findings.” In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21. Objectives: The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays. Discussion: Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems. Conclusion: Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology. PMID:23603828

Determination of Dextromethorphan in Oral Fluid by LC-MS-MS.

PubMed

Amaratunga, Piyadarsha; Clothier, Morgan; Lorenz Lemberg, Bridget; Lemberg, Dave

2016-06-01

Dextromethorphan (DXM) is an antitussive drug found in commonly used nonprescription cold and cough medications. At low doses, DXM is a safe drug that does not produce adverse reactions. However, abuse of DXM has been reported among adolescents and young adults using the drug at higher doses. DXM is not a scheduled drug in the USA, and the primary reason for its abuse is the ease of availability. DXM is available to purchase in the form of over-the-counter cough medications, such as Robitussin(®) and Coricidin(®), or it can be purchased over the Internet in the form of a powder. In this research work, we developed an LC-MS-MS method that can quantify DXM and dextrorphan (DXO) in oral fluid in a high-throughput toxicology laboratory setting. The developed method was validated according to the Scientific Working Group for Forensic Toxicology guidelines. The linear dynamic range was 5-100 ng/mL with a lowest limit of quantitation (LLOQ) of 5.0 ng/mL for DXM and DXO. Overall, the results of the accuracy and the precision values were within the acceptance criteria for both drugs. In addition, selectivity, matrix effect and recovery were calculated for the LC-MS-MS method. Authentic samples (n = 59) were tested to evaluate the applicability of the method. Thirty samples were found to be positive for DXM and DXO and two samples were found to be positive for DXM only. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Supporting evidence-based analysis for modified risk tobacco products through a toxicology data-sharing infrastructure

PubMed Central

Boué, Stéphanie; Exner, Thomas; Ghosh, Samik; Belcastro, Vincenzo; Dokler, Joh; Page, David; Boda, Akash; Bonjour, Filipe; Hardy, Barry; Vanscheeuwijck, Patrick; Hoeng, Julia; Peitsch, Manuel

2017-01-01

The US FDA defines modified risk tobacco products (MRTPs) as products that aim to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products.  Establishing a product’s potential as an MRTP requires scientific substantiation including toxicity studies and measures of disease risk relative to those of cigarette smoking.  Best practices encourage verification of the data from such studies through sharing and open standards. Building on the experience gained from the OpenTox project, a proof-of-concept database and website ( INTERVALS) has been developed to share results from both in vivo inhalation studies and in vitro studies conducted by Philip Morris International R&D to assess candidate MRTPs. As datasets are often generated by diverse methods and standards, they need to be traceable, curated, and the methods used well described so that knowledge can be gained using data science principles and tools. The data-management framework described here accounts for the latest standards of data sharing and research reproducibility. Curated data and methods descriptions have been prepared in ISA-Tab format and stored in a database accessible via a search portal on the INTERVALS website. The portal allows users to browse the data by study or mechanism (e.g., inflammation, oxidative stress) and obtain information relevant to study design, methods, and the most important results. Given the successful development of the initial infrastructure, the goal is to grow this initiative and establish a public repository for 21 st-century preclinical systems toxicology MRTP assessment data and results that supports open data principles. PMID:29123642

Toward sustainable environmental quality: Identifying priority research questions for Latin America.

PubMed

Furley, Tatiana Heid; Brodeur, Julie; Silva de Assis, Helena C; Carriquiriborde, Pedro; Chagas, Katia R; Corrales, Jone; Denadai, Marina; Fuchs, Julio; Mascarenhas, Renata; Miglioranza, Karina Sb; Miguez Caramés, Diana Margarita; Navas, José Maria; Nugegoda, Dayanthi; Planes, Estela; Rodriguez-Jorquera, Ignacio Alejandro; Orozco-Medina, Martha; Boxall, Alistair Ba; Rudd, Murray A; Brooks, Bryan W

2018-05-01

The Global Horizon Scanning Project (GHSP) is an innovative initiative that aims to identify important global environmental quality research needs. Here we report 20 key research questions from Latin America (LA). Members of the Society of Environmental Toxicology and Chemistry (SETAC) LA and other scientists from LA were asked to submit research questions that would represent priority needs to address in the region. One hundred questions were received, then partitioned among categories, examined, and some rearranged during a workshop in Buenos Aires, Argentina. Twenty priority research questions were subsequently identified. These research questions included developing, improving, and harmonizing across LA countries methods for 1) identifying contaminants and degradation products in complex matrices (including biota); 2) advancing prediction of contaminant risks and effects in ecosystems, addressing lab-to-field extrapolation challenges, and understanding complexities of multiple stressors (including chemicals and climate change); and 3) improving management and regulatory tools toward achieving sustainable development. Whereas environmental contaminants frequently identified in these key questions were pesticides, pharmaceuticals, endocrine disruptors or modulators, plastics, and nanomaterials, commonly identified environmental challenges were related to agriculture, urban effluents, solid wastes, pulp and paper mills, and natural extraction activities. Several interesting research topics included assessing and preventing pollution impacts on conservation protected areas, integrating environment and health assessments, and developing strategies for identification, substitution, and design of less hazardous chemicals (e.g., green chemistry). Finally, a recurrent research need included developing an understanding of differential sensitivity of regional species and ecosystems to environmental contaminants and other stressors. Addressing these critical questions will support development of long-term strategic research efforts to advance more sustainable environmental quality and protect public health and the environment in LA. Integr Environ Assess Manag 2018;14:344-357. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Manpower Development in Toxicology. EURO Reports and Studies, No. 9.

ERIC Educational Resources Information Center

World Health Organization, Copenhagen (Denmark). Regional Office for Europe.

This report addresses the widely held view that currently available literature in toxicology is inadequate in that there is a need to identify manpower deficiencies in this field and to suggest means to correct these deficiencies. It contains a list of specific recommendations including the organization of a working group, sponsored by the World…

Could ecological thresholds of toxicological concern (eco-TTCs) be used to support development of ambient water quality criteria?

EPA Science Inventory

The Threshold of Toxicologic Concern (TTC) is an approach used for a decades in human hazard assessment. A TTC establishes an exposure level for a chemical below which no appreciable risk to human health is expected based upon a de minimis value for toxicity identified for many ...

76 FR 68193 - Notice of the Revised Priority List of Hazardous Substances That Will Be the Subject of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-03

... assessments and from site-file data packages used to develop the public health assessments. Since the... toxicological profile subject, as well as a candidate for identification of priority data needs. In addition to... toxicological profile prepared by ATSDR and, subsequently, a candidate for the identification of priority data...

IRIS Toxicological Review of Vanadium Pentoxide ...

EPA Pesticide Factsheets

On September 30, 2011, the draft Toxicological Review of Vanadium Pentoxide and the charge to external peer reviewers were released for external peer review and public comment. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. In the new IRIS process (May 2009), introduced by the EPA Administrator, all written comments on IRIS assessments submitted by other federal agencies and White House Offices will be made publicly available. Accordingly, interagency comments and the interagency science consultation draft of the IRIS Toxicological Review of Vanadium Pentoxide and the charge to external peer reviewers are posted on this site. EPA is reassessing its IRIS toxicological review of vanadium pentoxide (CASRN 1314-62-1). This vanadium pentoxide reassessment consists of an oral reference dose (RfD), an inhalation reference concentration (RfC), an inhalation unit risk (IUR) and a cancer weight of evidence descriptor. This is the first assessment developing an RfC or IUR for this compound. This assessment is intended to provide human health data to support agency regulatory decisions.

FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology

PubMed Central

Knudsen, Thomas B.; Keller, Douglas A.; Sander, Miriam; Carney, Edward W.; Doerrer, Nancy G.; Eaton, David L.; Fitzpatrick, Suzanne Compton; Hastings, Kenneth L.; Mendrick, Donna L.; Tice, Raymond R.; Watkins, Paul B.; Whelan, Maurice

2015-01-01

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. PMID:25628403

Physiological evaluation of men wearing three different toxicological protective systems

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

Levine, L.; Cadarette, B.S.; Sawka, M.N.

1989-08-01

This study examined the physiological responses of seven volunteers exercising in the heat while wearing three different toxicological protective systems. The Toxicological Agent Protective (TAP) suit has been available for use for more than 30 years while the other two protective systems are developmental efforts. The Self-Contained Toxicological Environmental Protection Outfit (STEPO) includes either a backpack-rebreather (with CO{sub 2} scrubber) and ice-cooling vest (STEPO-R), or a tether system which supplies breathing/cooling air inside the suit (STEPO-T). After the volunteers were heat acclimated, the three toxicological protection systems were evaluated utilizing a counter-balanced experimental design initially in a hot and thenmore » in a cool environment while subjects walked at 1.12 m/s, 0% grade for an attempted two hours. There was no statistical advantage of any one system in terms of exercise time in the cool environment. While evaporated sweating rate was greater for the STEPO-T in the cool environment compared to both STEPO-R and TAP. Development efforts to improve the STEPO system designs continue, and physiological evaluation of new developmental models is underway.« less

An investigation of normal urine with a creatinine concentration under the cutoff of 20 mg/dL for specimen validity testing in a toxicology laboratory.

PubMed

Holden, Brad; Guice, Erica A

2014-05-01

In clinical and forensic toxicology laboratories, one commonly used method for urine specimen validity testing is creatinine concentration. In this study, workplace guidelines are examined to determine their relevance to forensic and clinical toxicology samples. Specifically, it investigates the occurrence of urine creatinine concentrations under 20 mg/dL and notes potential issues with factors influencing creatinine concentration by utilizing a simple, novel method consisting of cation-paring high-pressure liquid chromatography in tandem with ultraviolet detection to determine the creatinine concentration in 3019 donors. Of the 4227 sample population in this study, 209 (4.94%) were below the cutoff value of 20 mg/dL for dilute urine. Because there are many factors that can influence the urinary creatinine concentration, samples that have creatinine under the 20 mg/dL cutoff do not always implicate sample adulteration. © 2014 American Academy of Forensic Sciences.

Building on a solid foundation: SAR and QSAR as a fundamental strategy to reduce animal testing.

PubMed

Sullivan, K M; Manuppello, J R; Willett, C E

2014-01-01

The development of more efficient, ethical, and effective means of assessing the effects of chemicals on human health and the environment was a lifetime goal of Gilman Veith. His work has provided the foundation for the use of chemical structure for informing toxicological assessment by regulatory agencies the world over. Veith's scientific work influenced the early development of the SAR models in use today at the US Environmental Protection Agency. He was the driving force behind the Organisation for Economic Co-operation and Development QSAR Toolbox. Veith was one of a few early pioneers whose vision led to the linkage of chemical structure and biological activity as a means of predicting adverse apical outcomes (known as a mode of action, or an adverse outcome pathway approach), and he understood at an early stage the power that could be harnessed when combining computational and mechanistic biological approaches as a means of avoiding animal testing. Through the International QSAR Foundation he organized like-minded experts to develop non-animal methods and frameworks for the assessment of chemical hazard and risk for the benefit of public and environmental health. Avoiding animal testing was Gil's passion, and his work helped to initiate the paradigm shift in toxicology that is now rendering this feasible.

Using zebrafish in systems toxicology for developmental toxicity testing.

PubMed

Nishimura, Yuhei; Inoue, Atsuto; Sasagawa, Shota; Koiwa, Junko; Kawaguchi, Koki; Kawase, Reiko; Maruyama, Toru; Kim, Soonih; Tanaka, Toshio

2016-01-01

With the high cost and the long-term assessment of developmental toxicity testing in mammals, the vertebrate zebrafish has become a useful alternative model organism for high-throughput developmental toxicity testing. Zebrafish is also very favorable for the 3R perspective in toxicology; however, the methodologies used by research groups vary greatly, posing considerable challenges to integrative analysis. In this review, we discuss zebrafish developmental toxicity testing, focusing on the methods of chemical exposure, the assessment of morphological abnormalities, housing conditions and their effects on the production of healthy embryos, and future directions. Zebrafish as a systems toxicology model has the potential to elucidate developmental toxicity pathways, and to provide a sound basis for human health risk assessments. © 2015 Japanese Teratology Society.

Recent advances in materials toxicology

NASA Technical Reports Server (NTRS)

Russo, D. M.

1979-01-01

An overview of the fire toxicology program, its principal objectives and approach, is outlined. The laboratory methods of assessing pyrolysis product toxicity for two experiments are presented. The two experiments are: a comparison of test end points; and an evaluation of operant techniques. A third experiment is outlined for a comparison of full-scale and laboratory toxicity tests, with the purpose of determining animal survivability in full-scale tests. Future research plans are also outlined.

Survey of Methods to Assess the Toxicological Impact of Hazardous Waste Disposal Sites on Aquatic Ecosystems

DTIC Science & Technology

1989-07-01

generalized life cycles of marine invertebrates .................... 6 2. Effect of potassium dichromate (K2CrO,) on the growth of Scenedesmus suhspicatus. 0...agencies, the more commonly used tools will be discussed. TOXICOLOGICAL IMPACTS TO AQUATIC ORGANISMS In the typical life cycle of marine invertebrates ...generalized life cycles of marine invertebrates . 1984). Direct comparisons of bioassay results are limited to examining effects of varying concentrations of

Sequencing CYP2D6 for the detection of poor-metabolizers in post-mortem blood samples with tramadol.

PubMed

Fonseca, Suzana; Amorim, António; Costa, Heloísa Afonso; Franco, João; Porto, Maria João; Santos, Jorge Costa; Dias, Mário

2016-08-01

Tramadol concentrations and analgesic effect are dependent on the CYP2D6 enzymatic activity. It is well known that some genetic polymorphisms are responsible for the variability in the expression of this enzyme and in the individual drug response. The detection of allelic variants described as non-functional can be useful to explain some circumstances of death in the study of post-mortem cases with tramadol. A Sanger sequencing methodology was developed for the detection of genetic variants that cause absent or reduced CYP2D6 activity, such as *3, *4, *6, *8, *10 and *12 alleles. This methodology, as well as the GC/MS method for the detection and quantification of tramadol and its main metabolites in blood samples was fully validated in accordance with international guidelines. Both methodologies were successfully applied to 100 post-mortem blood samples and the relation between toxicological and genetic results evaluated. Tramadol metabolism, expressed as its metabolites concentration ratio (N-desmethyltramadol/O-desmethyltramadol), has been shown to be correlated with the poor-metabolizer phenotype based on genetic characterization. It was also demonstrated the importance of enzyme inhibitors identification in toxicological analysis. According to our knowledge, this is the first study where a CYP2D6 sequencing methodology is validated and applied to post-mortem samples, in Portugal. The developed methodology allows the data collection of post-mortem cases, which is of primordial importance to enhance the application of these genetic tools to forensic toxicology and pathology. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Validation of LC–TOF-MS Screening for Drugs, Metabolites, and Collateral Compounds in Forensic Toxicology Specimens

PubMed Central

Guale, Fessessework; Shahreza, Shahriar; Walterscheid, Jeffrey P.; Chen, Hsin-Hung; Arndt, Crystal; Kelly, Anna T.; Mozayani, Ashraf

2013-01-01

Liquid chromatography time-of-flight mass spectrometry (LC–TOF-MS) analysis provides an expansive technique for identifying many known and unknown analytes. This study developed a screening method that utilizes automated solid-phase extraction to purify a wide array of analytes involving stimulants, benzodiazepines, opiates, muscle relaxants, hypnotics, antihistamines, antidepressants and newer synthetic “Spice/K2” cannabinoids and cathinone “bath salt” designer drugs. The extract was applied to LC–TOF-MS analysis, implementing a 13 min chromatography gradient with mobile phases of ammonium formate and methanol using positive mode electrospray. Several common drugs and metabolites can share the same mass and chemical formula among unrelated compounds, but they are structurally different. In this method, the LC–TOF-MS was able to resolve many isobaric compounds by accurate mass correlation within 15 ppm mass units and a narrow retention time interval of less than 10 s of separation. Drug recovery yields varied among spiked compounds, but resulted in overall robust area counts to deliver an average match score of 86 when compared to the retention time and mass of authentic standards. In summary, this method represents a rapid, enhanced screen for blood and urine specimens in postmortem, driving under the influence, and drug facilitated sexual assault forensic toxicology casework. PMID:23118149

Validation of LC-TOF-MS screening for drugs, metabolites, and collateral compounds in forensic toxicology specimens.

PubMed

Guale, Fessessework; Shahreza, Shahriar; Walterscheid, Jeffrey P; Chen, Hsin-Hung; Arndt, Crystal; Kelly, Anna T; Mozayani, Ashraf

2013-01-01

Liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) analysis provides an expansive technique for identifying many known and unknown analytes. This study developed a screening method that utilizes automated solid-phase extraction to purify a wide array of analytes involving stimulants, benzodiazepines, opiates, muscle relaxants, hypnotics, antihistamines, antidepressants and newer synthetic "Spice/K2" cannabinoids and cathinone "bath salt" designer drugs. The extract was applied to LC-TOF-MS analysis, implementing a 13 min chromatography gradient with mobile phases of ammonium formate and methanol using positive mode electrospray. Several common drugs and metabolites can share the same mass and chemical formula among unrelated compounds, but they are structurally different. In this method, the LC-TOF-MS was able to resolve many isobaric compounds by accurate mass correlation within 15 ppm mass units and a narrow retention time interval of less than 10 s of separation. Drug recovery yields varied among spiked compounds, but resulted in overall robust area counts to deliver an average match score of 86 when compared to the retention time and mass of authentic standards. In summary, this method represents a rapid, enhanced screen for blood and urine specimens in postmortem, driving under the influence, and drug facilitated sexual assault forensic toxicology casework.

Implementing systematic review techniques in chemical risk assessment: challenges, opportunities and recommendations

PubMed Central

Whaley, Paul; Halsall, Crispin; Ågerstrand, Marlene; Benford, Diane; Aiassa, Elisa; Bilotta, Gary; Coggon, David; Dempsey, Ciara; Duarte-Davidson, Raquel; FitzGerald, Rex; Gee, David; Hoffmann, Sebastian; Lam, Juleen; Lassersson, Toby; Levy, Len; Lipworth, Steven; Ross, Sarah Mackenzie; Martin, Olwenn; Meads, Catherine; Meyer-Baron, Monika; Miller, James; Pease, Camilla; Rooney, Andrew; Sapiets, Alison; Stewart, Gavin; Taylor, David

2016-01-01

Systematic review (SR) is a rigorous, protocol-driven approach designed to minimise error and bias when summarising the body of research evidence relevant to a specific scientific question. Taking as a comparator the use of SR in synthesising research in healthcare, we argue that SR methods could also pave the way for a “step change” in the transparency, objectivity and communication of chemical risk assessments (CRA) in Europe and elsewhere. We suggest that current controversies around the safety of certain chemicals are partly due to limitations in current CRA procedures which have contributed to ambiguity about the health risks posed by these substances. We present an overview of how SR methods can be applied to the assessment of risks from chemicals, and indicate how challenges in adapting SR methods from healthcare research to the CRA context might be overcome. Regarding the latter, we report the outcomes from a workshop exploring how to increase uptake of SR methods, attended by experts representing a wide range of fields related to chemical toxicology, risk analysis and SR. Priorities which were identified include: the conduct of CRA-focused prototype SRs; the development of a recognised standard of reporting and conduct for SRs in toxicology and CRA; and establishing a network to facilitate research, communication and training in SR methods. We see this paper as a milestone in the creation of a research climate that fosters communication between experts in CRA and SR and facilitates wider uptake of SR methods into CRA. PMID:26687863

Foundation and progress of Japanese society of toxicologic pathology*.

PubMed

Konishi, Yoichi; Enomoto, Makoto; Hayashi, Yuzo

2011-03-01

The Japanese Society of Toxicologic Pathology (JSTP) has a differing conceptual framework from the Japanese Society of Pathology (JSP) and Japanese Society of Toxicology (JST) and was founded in 1985 by the leadership of late Dr. Yasukazu Nishiyama with the cooperation of several founding members and the support of JSP. The aim of the JSTP is to improve the human and animal health using an interdisciplinary scientific approach based on pathology and toxicology. In its development as a professional society, the JSTP has established society rules and activities. The JSTP has grown in terms of membership and financial aspects and is now recognized not only domestically but also internationally as a well-organized scientific society. To maintain the high professional standard and visibility of JSTP, we here provide the historical background of the society as a basis for current members to contribute to the continued improvement of our scientific organization.

Trouble shooting in toxicopathology

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

Rousseaux, C.G.

2005-09-01

Toxicopathology, also referred to as toxicologic pathology, can be defined as the study of structural and functional changes in cells, tissues, and organs that are induced by toxicants (such as drugs, industrial and agricultural chemicals), toxins (chemicals of biological origin such as mycotoxins and phycotoxins), and physical agents (such as heat and radiation); the investigation of the mechanisms by which these changes are induced; and the development of risk assessment and risk management policies based on such information. Toxicologic pathology primarily deals with the morphologic or structural effects of the toxicant and the mechanism by which this structural effect ismore » induced. This article highlights some of the problems that toxicologic pathologists may encounter in obtaining and interpreting pathology lesions. By alerting toxicologists to some of these issues, it is hoped that a better understanding of the use and limitations of toxicologic pathology data will occur.« less

The NIEHS Predictive-Toxicology Evaluation Project.

PubMed Central

Bristol, D W; Wachsman, J T; Greenwell, A

1996-01-01

The Predictive-Toxicology Evaluation (PTE) project conducts collaborative experiments that subject the performance of predictive-toxicology (PT) methods to rigorous, objective evaluation in a uniquely informative manner. Sponsored by the National Institute of Environmental Health Sciences, it takes advantage of the ongoing testing conducted by the U.S. National Toxicology Program (NTP) to estimate the true error of models that have been applied to make prospective predictions on previously untested, noncongeneric-chemical substances. The PTE project first identifies a group of standardized NTP chemical bioassays either scheduled to be conducted or are ongoing, but not yet complete. The project then announces and advertises the evaluation experiment, disseminates information about the chemical bioassays, and encourages researchers from a wide variety of disciplines to publish their predictions in peer-reviewed journals, using whatever approaches and methods they feel are best. A collection of such papers is published in this Environmental Health Perspectives Supplement, providing readers the opportunity to compare and contrast PT approaches and models, within the context of their prospective application to an actual-use situation. This introduction to this collection of papers on predictive toxicology summarizes the predictions made and the final results obtained for the 44 chemical carcinogenesis bioassays of the first PTE experiment (PTE-1) and presents information that identifies the 30 chemical carcinogenesis bioassays of PTE-2, along with a table of prediction sets that have been published to date. It also provides background about the origin and goals of the PTE project, outlines the special challenge associated with estimating the true error of models that aspire to predict open-system behavior, and summarizes what has been learned to date. PMID:8933048

Alternative Methods for the Detection of Emerging Marine Toxins: Biosensors, Biochemical Assays and Cell-Based Assays

PubMed Central

Reverté, Laia; Soliño, Lucía; Carnicer, Olga; Diogène, Jorge; Campàs, Mònica

2014-01-01

The emergence of marine toxins in water and seafood may have a considerable impact on public health. Although the tendency in Europe is to consolidate, when possible, official reference methods based on instrumental analysis, the development of alternative or complementary methods providing functional or toxicological information may provide advantages in terms of risk identification, but also low cost, simplicity, ease of use and high-throughput analysis. This article gives an overview of the immunoassays, cell-based assays, receptor-binding assays and biosensors that have been developed for the screening and quantification of emerging marine toxins: palytoxins, ciguatoxins, cyclic imines and tetrodotoxins. Their advantages and limitations are discussed, as well as their possible integration in research and monitoring programs. PMID:25431968

High risk of respiratory diseases in children in the fire period in Western Amazon

PubMed Central

Silva, Pãmela Rodrigues de Souza; Ignotti, Eliane; de Oliveira, Beatriz Fátima Alves; Junger, Washington Leite; Morais, Fernando; Artaxo, Paulo; Hacon, Sandra

2016-01-01

ABSTRACT OBJECTIVE To analyze the toxicological risk of exposure to ozone (O3) and fine particulate matter (PM2.5) among schoolchildren.. METHODS Toxicological risk assessment was used to evaluate the risk of exposure to O3 and PM2.5 from biomass burning among schoolchildren aged six to 14 years, residents of Rio Branco, Acre, Southern Amazon, Brazil. We used Monte Carlo simulation to estimate the potential intake dose of both pollutants. RESULTS During the slash-and-burn periods, O3 and PM2.5 concentrations reached 119.4 µg/m3 and 51.1 µg/m3, respectively. The schoolchildren incorporated medium potential doses regarding exposure to O3 (2.83 μg/kg.day, 95%CI 2.72–2.94). For exposure to PM2.5, we did not find toxicological risk (0.93 μg/kg.day, 95%CI 0.86–0.99). The toxicological risk for exposure to O3 was greater than 1 for all children (QR = 2.75; 95%CI 2.64–2.86). CONCLUSIONS Schoolchildren were exposed to high doses of O3 during the dry season of the region. This posed a toxicological risk, especially to those who had previous diseases. PMID:27305405

Using High-Content Imaging to Analyze Toxicological Tipping ...

EPA Pesticide Factsheets

Presentation at International Conference on Toxicological Alternatives & Translational Toxicology (ICTATT) held in China and Discussing the possibility of using High Content Imaging to Analyze Toxicological Tipping Points Slide Presentation at International Conference on Toxicological Alternatives & Translational Toxicology (ICTATT) held in China and Discussing the possibility of using High Content Imaging to Analyze Toxicological Tipping Points

Systematic forensic toxicological analysis by liquid-chromatography-quadrupole-time-of-flight mass spectrometry in serum and comparison to gas chromatography-mass spectrometry.

PubMed

Grapp, Marcel; Kaufmann, Christoph; Streit, Frank; Binder, Lutz

2018-06-01

Comprehensive screening procedures for psychoactive agents in body fluids are an essential task in clinical and forensic toxicology. With the continuous emergence and adaption of new psychoactive substances (NPS) keeping a screening method up to date is challenging. To meet these demands, hyphenated high-resolution mass spectrometry has gained interest as extensive and expandable screening approach. Here we present a comprehensive method for systematic toxicological analysis of serum by liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) with data independent acquisition. The potential of this method was demonstrated by analysis of 247 authentic serum- and 12 post-mortem femoral blood samples. Thus 950 compounds, comprising 185 different drugs and metabolites could be identified. For the detected substances, including pharmaceutical substances, illicit drugs as well as NPS, serum concentrations were confirmed ranging from traces to toxic values indicating the capability for forensic toxicological requirements. Positive identification of drugs was achieved by accurate mass measurement (±5ppm for [M+H] + ; ±10ppm for [M-H] - ), retention time (±0.35min), isotopic pattern match (less than 10 m/z RMS [ppm]), isotope match intensity (less than 20% RMS) and the presence of at least two fragment ions. The LC-QTOF-MS procedure was shown to be superior to serum screening by GC-MS, since 240% (335 versus 141) more drugs were identified in serum samples compared to GC-MS. Copyright © 2018 Elsevier B.V. All rights reserved.

Correlation Between Physicochemical Characteristics and Toxicological Properties of Nanomaterials

DTIC Science & Technology

2012-01-25

gold, Mn, MWCNT , on the targeted surfaces. An in - vivo electrospray system was developed to disperse airborne CNTs and TiO2, QDs with various degrees...Finkelstein, JN, Elder A, Bentley K, Oberdörster G, and Pui DYH. A nanoparticle dispersion method for in vitro and in vivo nanotoxicity study...Pentland, AP, DeLouise, LA. (2008). In vivo skin penetration of quantum dot nanopartiles in the murine model: The effect of UVR. Nano Letters

Engineering Human Neural Tissue by 3D Bioprinting.

PubMed

Gu, Qi; Tomaskovic-Crook, Eva; Wallace, Gordon G; Crook, Jeremy M

2018-01-01

Bioprinting provides an opportunity to produce three-dimensional (3D) tissues for biomedical research and translational drug discovery, toxicology, and tissue replacement. Here we describe a method for fabricating human neural tissue by 3D printing human neural stem cells with a bioink, and subsequent gelation of the bioink for cell encapsulation, support, and differentiation to functional neurons and supporting neuroglia. The bioink uniquely comprises the polysaccharides alginate, water-soluble carboxymethyl-chitosan, and agarose. Importantly, the method could be adapted to fabricate neural and nonneural tissues from other cell types, with the potential to be applied for both research and clinical product development.

Ultra Performance Liquid Chromatography with Tandem Mass Spectrometry for the Quantitation of Seventeen Sedative Hypnotics in Six Common Toxicological Matrices.

PubMed

Mata, Dani C; Davis, John F; Figueroa, Ariana K; Stanford, Mary June

2016-01-01

An ultra performance liquid chromatography triple quadrupole mass spectrometry (LC-MS-MS) method for the quantification of 14 benzodiazepines and three sedative hypnotics is presented. The fast and inexpensive assay was developed for California's Orange County Crime Lab for use in antemortem (AM) and postmortem casework. The drugs were rapidly cleaned up from AM blood, postmortem blood, urine, liver, brain and stomach contents using DPX(®) Weak Anion Exchange (DPX WAX) tips fitted on a pneumatic extractor, which can process up to 48 samples at one time. Assay performance was determined for validation based on recommendations by the Scientific Working Group for Forensic Toxicology for linearity, limit of quantitation, limit of detection, bias, precision (within run and between run), dilution integrity, carry-over, selectivity, recovery, ion suppression and extracted sample stability. Linearity was verified using the therapeutic and toxic ranges of all 17 analytes. Final verification of the method was confirmed by four analysts using 20 blind matrix matched samples. All results were within 20% of each other and the expected value. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Animals and the 3Rs in toxicology research and testing: The way forward.

PubMed

Stokes, W S

2015-12-01

Despite efforts to eliminate the use of animals in testing and the availability of many accepted alternative methods, animals are still widely used for toxicological research and testing. While research using in vitro and computational models has dramatically increased in recent years, such efforts have not yet measurably impacted animal use for regulatory testing and are not likely to do so for many years or even decades. Until regulatory authorities have accepted test methods that can totally replace animals and these are fully implemented, large numbers of animals will continue to be used and many will continue to experience significant pain and distress. In order to positively impact the welfare of these animals, accepted alternatives must be implemented, and efforts must be directed at eliminating pain and distress and reducing animal numbers. Animal pain and distress can be reduced by earlier predictive humane endpoints, pain-relieving medications, and supportive clinical care, while sequential testing and routine use of integrated testing and decision strategies can reduce animal numbers. Applying advances in science and technology to the development of scientifically sound alternative testing models and strategies can improve animal welfare and further reduce and replace animal use. © The Author(s) 2015.

Peer consultation on relationship between PAC profile and toxicity of petroleum substances.

PubMed

Patterson, Jacqueline; Maier, Andrew; Kohrman-Vincent, Melissa; Dourson, Michael L

2013-11-01

An expert peer consultation panel reviewed a report by the PAC Analysis Task Group, which hypothesized that systemic, developmental, and reproductive toxicity observed in repeated-dose dermal toxicity studies was related to polycyclic aromatic compound (PAC) content. Peer consultations seek to solicit scientific and technical input from experts on the scientific basis and merits of the subject report. This peer consultation panel included nine scientists with expertise in petroleum chemistry, biostatistics, toxicology, risk assessment, structure activity, and reproductive and developmental toxicology. The panel evaluated the technical quality of the PAC report and provided recommendations for improving the statistical and biological approaches. The PAC report authors revised their methods and documentation, which are published elsewhere in this supplement. A review of the post peer consultation manuscripts confirmed that many of the key suggestions from expert panel members were considered and incorporated. In cases where the PAC report authors did not fully incorporate panel suggestions from the peer consultation, they have provided an explanation and support for their decision. This peer consultation demonstrates the value of formal engagement of peers in development of new scientific methods and approaches. Copyright © 2012 Elsevier Inc. All rights reserved.

FORUM - FutureTox II: In vitro Data and In Silico Models for ...

EPA Pesticide Factsheets

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. This article reports on the outcome of FutureTox II1,2, the second in a series of Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) Workshops, which was attended by invitees and participants from governmental and regulatory agencies, research institutes, academ

Toxicological Evaluations of Rare Earths and Their Health Impacts to Workers: A Literature Review

PubMed Central

Koo, Kwon Ho; Park, Jung Sun

2013-01-01

In concert with the development of new materials in the last decade, the need for toxicological studies of these materials has been increasing. These new materials include a group of rare earths (RE). The use of RE nanotechnology is being considered in some green applications, to increase their efficiency by using nano-sized RE compounds, and therefore hazard evaluation and risk assessment are highly recommended. This review was conducted through an extensive contemplation of the literatures in toxicology with in vitro and in vivo studies. Major aspects reviewed were the toxicological evaluations of these elements and metallic compounds at the molecular and cellular level, animal and human epidemiological studies and environmental and occupational health impacts on workers. We also discuss the future prospect of industries with appliances using RE together with the significance of preventive efforts for workers' health. To establish a safe and healthy working environment for RE industries, the use of biomarkers is increasing to provide sustainable measure, due to demand for information about the health risks from unfavorable exposures. Given the recent toxicological results on the exposure of cells, animals and workers to RE compounds, it is important to review the toxicological studies to improve the current understanding of the RE compounds in the field of occupational health. This will help to establish a sustainable, safe and healthy working environment for RE industries. PMID:23516020

77 FR 43827 - International Workshop on Alternative Methods for Leptospira

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-26

... DEPARTMENT OF HEALTH AND HUMAN SERVICES International Workshop on Alternative Methods for... NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) announces an ``International Workshop on Alternative Methods for Leptospira Vaccine Potency Testing: State of the Science and...

Adverse outcome pathways: a concise introduction for toxicologists

PubMed Central

Vergauwen, Lucia; Hengstler, Jan G.; Angrish, Michelle; Whelan, Maurice

2018-01-01

Adverse outcome pathways are designed to provide a clear-cut mechanistic representation of critical toxicological effects that propagate over different layers of biological organization from the initial interaction of a chemical with a molecular target to an adverse outcome at the individual or population level. Adverse outcome pathways are currently gaining momentum, especially in view of their many potential applications as pragmatic tools in the fields of human toxicology, ecotoxicology and risk assessment. A number of guidance documents, issued by the Organization for Economic Cooperation and Development, as well as landmark papers, outlining best practices to develop, assess and use adverse outcome pathways, have been published in the last few years. The present paper provides a synopsis of the main principles related to the adverse outcome pathway framework for the toxicologist less familiar with this area, followed by two case studies relevant for human toxicology and ecotoxicology. PMID:28660287

The Lunar Environment: Determining the Health Effects of Exposure to Moon Dusts

NASA Technical Reports Server (NTRS)

Khan-Mayberry, Noreen

2007-01-01

The moon's surface is covered with a thin layer of fine, charged, reactive dust capable of layer of fine, charged, reactive dust capable of capable of entering habitats and vehicle compartments, where it can result in crewmember health problems. NASA formed the Lunar Airborne Dust Toxicity Advisory Group (LADTAG) to study the effects of exposure to Lunar Dust on human health. To date, no scientifically defensible toxicological studies have been performed on lunar dusts, specifically the determination of exposure limits and their affect on human health. The multi-center LADTAG (Lunar Airborne Dust Toxicology center LADTAG (Lunar Airborne Dust Toxicology Advisory Group) was formed in response to the Office of the Chief Health and Medical Office s (OCHMO) request to develop recommendations for defining risk (OCHMO) request to develop recommendations for defining risk defining risk criteria for human lunar dust exposure.

ZEBRAFISH AS AN IN VIVO MODEL FOR SUSTAINABLE CHEMICAL DESIGN.

PubMed

Noyes, Pamela D; Garcia, Gloria R; Tanguay, Robert L

2016-12-21

Heightened public awareness about the many thousands of chemicals in use and present as persistent contaminants in the environment has increased the demand for safer chemicals and more rigorous toxicity testing. There is a growing recognition that the use of traditional test models and empirical approaches is impractical for screening for toxicity the many thousands of chemicals in the environment and the hundreds of new chemistries introduced each year. These realities coupled with the green chemistry movement have prompted efforts to implement more predictive-based approaches to evaluate chemical toxicity early in product development. While used for many years in environmental toxicology and biomedicine, zebrafish use has accelerated more recently in genetic toxicology, high throughput screening (HTS), and behavioral testing. This review describes major advances in these testing methods that have positioned the zebrafish as a highly applicable model in chemical safety evaluations and sustainable chemistry efforts. Many toxic responses have been shown to be shared among fish and mammals owing to their generally well-conserved development, cellular networks, and organ systems. These shared responses have been observed for chemicals that impair endocrine functioning, development, and reproduction, as well as those that elicit cardiotoxicity and carcinogenicity, among other diseases. HTS technologies with zebrafish enable screening large chemical libraries for bioactivity that provide opportunities for testing early in product development. A compelling attribute of the zebrafish centers on being able to characterize toxicity mechanisms across multiple levels of biological organization from the genome to receptor interactions and cellular processes leading to phenotypic changes such as developmental malformations. Finally, there is a growing recognition of the links between human and wildlife health and the need for approaches that allow for assessment of real world multi-chemical exposures. The zebrafish is poised to be an important model in bridging these two conventionally separate areas of toxicology and characterizing the biological effects of chemical mixtures that could augment its role in sustainable chemistry.

ZEBRAFISH AS AN IN VIVO MODEL FOR SUSTAINABLE CHEMICAL DESIGN

PubMed Central

Noyes, Pamela D.; Garcia, Gloria R.; Tanguay, Robert L.

2016-01-01

Heightened public awareness about the many thousands of chemicals in use and present as persistent contaminants in the environment has increased the demand for safer chemicals and more rigorous toxicity testing. There is a growing recognition that the use of traditional test models and empirical approaches is impractical for screening for toxicity the many thousands of chemicals in the environment and the hundreds of new chemistries introduced each year. These realities coupled with the green chemistry movement have prompted efforts to implement more predictive-based approaches to evaluate chemical toxicity early in product development. While used for many years in environmental toxicology and biomedicine, zebrafish use has accelerated more recently in genetic toxicology, high throughput screening (HTS), and behavioral testing. This review describes major advances in these testing methods that have positioned the zebrafish as a highly applicable model in chemical safety evaluations and sustainable chemistry efforts. Many toxic responses have been shown to be shared among fish and mammals owing to their generally well-conserved development, cellular networks, and organ systems. These shared responses have been observed for chemicals that impair endocrine functioning, development, and reproduction, as well as those that elicit cardiotoxicity and carcinogenicity, among other diseases. HTS technologies with zebrafish enable screening large chemical libraries for bioactivity that provide opportunities for testing early in product development. A compelling attribute of the zebrafish centers on being able to characterize toxicity mechanisms across multiple levels of biological organization from the genome to receptor interactions and cellular processes leading to phenotypic changes such as developmental malformations. Finally, there is a growing recognition of the links between human and wildlife health and the need for approaches that allow for assessment of real world multi-chemical exposures. The zebrafish is poised to be an important model in bridging these two conventionally separate areas of toxicology and characterizing the biological effects of chemical mixtures that could augment its role in sustainable chemistry. PMID:28461781

Slit Lamp-Based Ocular Scoring Systems in Toxicology and Drug Development: A Literature Survey.

PubMed

Eaton, Joshua Seth; Miller, Paul E; Bentley, Ellison; Thomasy, Sara M; Murphy, Christopher J

2017-12-01

To present a survey of the features of published slit lamp-based scoring systems and their applicability in the context of modern ocular toxicology and drug development. References describing original or modified slit lamp-based scoring systems for human or veterinary clinical patients or in investigative or toxicologic research were collected following a comprehensive literature review using textbooks and online publication searches. Each system's indications and features were compiled to facilitate comparison. Literature review identified 138 original or modified scoring systems. Most (48%) were published for evaluation of the ocular surface, 34% for the general anterior segment, and 18% for the lens. Most systems were described for assessment of human patients (50%) and small albino laboratory species such as rabbits (19%), rats (12%), and mice (8%). Systems described for pigmented laboratory species and for larger species such as dogs, cats, pigs, and nonhuman primates (NHPs) were comparatively underrepresented. No systems described a lens scoring scheme specific to the dog, cat, pig, or NHP. Scoring schemes for aqueous and vitreous cells were infrequently described for laboratory species. Many slit lamp-based scoring systems have been published, but the features of each differ and complicate translation of findings between different species. Use and interpretation of any scoring system in toxicology and drug development must be done with awareness of the limitations of the system being used.

Military deployment toxicology: a program manager's perspective.

PubMed

Knechtges, P L

2000-02-01

The Persian Gulf War drew attention to the potential hazards of chemicals that personnel may encounter during military operations and deployments overseas. During the War, the oil well fires of Kuwait highlighted the military threat of industrial chemicals in the area of operations. Following the War, the occurrence of Gulf War Illnesses brought home concerns and suspicions regarding "low level" and "mixed" exposures to chemicals. The public's concern and attention resulted in numerous institutional responses to the real and perceived problems of health risks during military deployments. These institutional responses ranged in scope from a Presidential Review Directive to the initiative known as the Deployment Toxicology Research, Development, Testing and Evaluation (RDT&E) Program. Most institutions, however, seem to agree that additional research is needed to assess the health risks from chemical exposures during military deployments. Establishing and managing an effective RDT&E program in risk assessment for deployed forces is a challenging enterprise. The Deployment Toxicology RDT&E Program was conceived utilizing the military's acquisition framework, an effective methodology with a proven record of fielding of new technologies. Based on a series of structured meetings with military representatives that would utilize new risk assessment tools, a hierarchical set of plans was developed to identify and prioritize end products. The challenge ahead for the Deployment Toxicology RDT&E Program is to execute these plans, provide the necessary oversight, and transition the results into successful product development.

The Role of the Food Matrix and Gastrointestinal Tract in the assessment of biological properties of ingested engineered nanomaterials (iENMs): State of the science and knowledge gaps.

PubMed

McClements, David Julian; DeLoid, Glen; Pyrgiotakis, Georgios; Shatkin, Jo Anne; Xiao, Hang; Demokritou, Philip

2016-07-01

Many foods contain appreciable levels of engineered nanomaterials (ENMs) (diameter < 100 nm) that may be either intentionally or unintentionally added. These ENMs vary considerably in their compositions, dimensions, morphologies, physicochemical properties, and biological responses. From a toxicological point of view, it is often convenient to classify ingested ENMs (iENMs) as being either inorganic (such as TiO 2 , SiO 2 , Fe 2 O 3 , or Ag) or organic (such as lipid, protein, or carbohydrate), since the former tend to be indigestible and the latter are generally digestible. At present there is a relatively poor understanding of how different types of iENMs behave within the human gastrointestinal tract (GIT), and how the food matrix and biopolymers transform their physico-chemical properties and influence their gastrointestinal fate. This lack of knowledge confounds an understanding of their potential harmful effects on human health. The purpose of this article is to review our current understanding of the GIT fate of iENMs, and to highlight gaps where further research is urgently needed in assessing potential risks and toxicological implications of iENMs. In particular, a strong emphasis is given to the development of standardized screening methods that can be used to rapidly and accurately assess the toxicological properties of iENMs.

Laboratory for Energy-Related Health Research annual report, fiscal year 1986

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

Abell, D.L.

1989-02-01

This report to the US Department of Energy summarizes research activities for the period from 1 October 1985--30 September 1986 at the Laboratory for Energy-related Health Research (LEHR) which is operated by the University of California, Davis. The laboratory's research objective is to provide new knowledge for an improved understanding of the potential bioenvironmental and occupational health problems associated with energy utilization to contribute to the safe and healthful development of energy resources for the benefit of mankind. This research encompasses several areas of basic investigation that relate to toxicological and biomedical problems associated with potentially toxic chemical and radioactivemore » substances and ionizing radiation, with particular emphasis on carcinogenicity. Studies of systemic injury and nuclear medical diagnostic and therapeutic methods are also involved. This is an interdisciplinary program spanning physics, chemistry, environmental engineering, biophysics and biochemistry, cellular and molecular biology, physiology, immunology, toxicology, both human and veterinary medicine, nuclear medicine, pathology, hematology, radiation biology, reproductive biology, oncology, biomathematics, and computer science. The principal themes of the research at LEHR center around the biology, radiobiology, and health status of the skeleton and its blood-forming constituents; the toxicology and properties of airborne materials; the beagle as an experimental animal model; carcinogenesis; and the scaling of the results from laboratory animal studies to man for appropriate assessment of risk.« less

Efficacy of screens in removing long fibers from an aerosol stream – sample preparation technique for toxicology studies

PubMed Central

Ku, Bon Ki; Deye, Gregory J.; Turkevich, Leonid A.

2015-01-01

Fiber dimension (especially length) and biopersistence are thought to be important variables in determining the pathogenicity of asbestos and other elongate mineral particles. In order to prepare samples of fibers for toxicology studies, it is necessary to develop and evaluate methods for separating fibers by length in the micrometer size range. In this study, we have filtered an aerosol of fibers through nylon screens to investigate whether such screens can efficiently remove the long fibers (L >20 μm, a typical macrophage size) from the aerosol stream. Such a sample, deficient in long fibers, could then be used as the control in a toxicology study to investigate the role of length. A well-dispersed aerosol of glass fibers (a surrogate for asbestos) was generated by vortex shaking a Japan Fibrous Material Research Association (JFMRA) glass fiber powder. Fibers were collected on a mixed cellulose ester (MCE) filter, imaged with phase contrast microscopy (PCM) and lengths were measured. Length distributions of the fibers that penetrated through various screens (10, 20 and 60 μm mesh sizes) were analyzed; additional study was made of fibers that penetrated through double screen and centrally blocked screen configurations. Single screens were not particularly efficient in removing the long fibers; however, the alternative configurations, especially the centrally blocked screen configuration, yielded samples substantially free of the long fibers. PMID:24417374

Best Practices in Stability Indicating Method Development and Validation for Non-clinical Dose Formulations.

PubMed

Henry, Teresa R; Penn, Lara D; Conerty, Jason R; Wright, Francesca E; Gorman, Gregory; Pack, Brian W

2016-11-01

Non-clinical dose formulations (also known as pre-clinical or GLP formulations) play a key role in early drug development. These formulations are used to introduce active pharmaceutical ingredients (APIs) into test organisms for both pharmacokinetic and toxicological studies. Since these studies are ultimately used to support dose and safety ranges in human studies, it is important to understand not only the concentration and PK/PD of the active ingredient but also to generate safety data for likely process impurities and degradation products of the active ingredient. As such, many in the industry have chosen to develop and validate methods which can accurately detect and quantify the active ingredient along with impurities and degradation products. Such methods often provide trendable results which are predictive of stability, thus leading to the name; stability indicating methods. This document provides an overview of best practices for those choosing to include development and validation of such methods as part of their non-clinical drug development program. This document is intended to support teams who are either new to stability indicating method development and validation or who are less familiar with the requirements of validation due to their position within the product development life cycle.

Aviation combustion toxicology: an overview.

PubMed

Chaturvedi, Arvind K

2010-01-01

Aviation combustion toxicology is a subspecialty of the field of aerospace toxicology, which is composed of aerospace and toxicology. The term aerospace, that is, the environment extending above and beyond the surface of the Earth, is also used to represent the combined fields of aeronautics and astronautics. Aviation is another term interchangeably used with aerospace and aeronautics and is explained as the science and art of operating powered aircraft. Toxicology deals with the adverse effects of substances on living organisms. Although toxicology borrows knowledge from biology, chemistry, immunology, pathology, physiology, and public health, the most closely related field to toxicology is pharmacology. Economic toxicology, environmental toxicology, and forensic toxicology, including combustion toxicology, are the three main branches of toxicology. In this overview, a literature search for the period of 1960-2007 was performed and information related to aviation combustion toxicology collected. The overview included introduction; combustion, fire, and smoke; smoke gas toxicity; aircraft material testing; fire gases and their interactive effects; result interpretation; carboxyhemoglobin and blood cyanide ion levels; pyrolytic products of aircraft engine oils, fluids, and lubricants; and references. This review is anticipated to be an informative resource for aviation combustion toxicology and fire-related casualties.

21 CFR 862.3200 - Clinical toxicology calibrator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Clinical toxicology calibrator. 862.3200 Section... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3200 Clinical toxicology calibrator. (a) Identification. A clinical toxicology calibrator is...

21 CFR 862.3200 - Clinical toxicology calibrator.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Clinical toxicology calibrator. 862.3200 Section... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3200 Clinical toxicology calibrator. (a) Identification. A clinical toxicology calibrator is...

21 CFR 862.3200 - Clinical toxicology calibrator.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Clinical toxicology calibrator. 862.3200 Section... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3200 Clinical toxicology calibrator. (a) Identification. A clinical toxicology calibrator is...

21 CFR 862.3200 - Clinical toxicology calibrator.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Clinical toxicology calibrator. 862.3200 Section... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3200 Clinical toxicology calibrator. (a) Identification. A clinical toxicology calibrator is...

Toxicological characterization of the landfill leachate prior/after chemical and electrochemical treatment: a study on human and plant cells.

PubMed

Garaj-Vrhovac, Vera; Oreščanin, Višnja; Gajski, Goran; Gerić, Marko; Ruk, Damir; Kollar, Robert; Radić Brkanac, Sandra; Cvjetko, Petra

2013-10-01

In this research, toxicological safety of two newly developed methods for the treatment of landfill leachate from the Piškornica (Croatia) sanitary landfill was investigated. Chemical treatment procedure combined chemical precipitation with CaO followed by coagulation with ferric chloride and final adsorption by clinoptilolite. Electrochemical treatment approach included pretreatment with ozone followed by electrooxidation/electrocoagulation and final polishing by microwave irradiation. Cell viability of untreated/treated landfill leachate was examined using fluorescence microscopy. Cytotoxic effect of the original leachate was obtained for both exposure periods (4 and 24 h) while treated samples showed no cytotoxic effect even after prolonged exposure time. The potential DNA damage of the untreated/treated landfill leachate was evaluated by the comet assay and cytokinesis-block micronucleus (CBMN) assay using either human or plant cells. The original leachate exhibited significantly higher comet assay parameters compared to negative control after 24 h exposure. On the contrary, there was no significant difference between negative control and chemically/electrochemically treated leachate for any of the parameters tested. There was also no significant increase in either CBMN assay parameter compared to the negative control following the exposure of the lymphocytes to the chemically or electrochemically treated landfill leachate for both exposure periods while the original sample showed significantly higher number of micronuclei, nucleoplasmic bridges and nuclear buds for both exposure times. Results suggest that both methods are suitable for the treatment of such complex waste effluent due to high removal efficiency of all measured parameters and toxicological safety of the treated effluent. Copyright © 2013 Elsevier Ltd. All rights reserved.

Indigofera suffruticosa: An Alternative Anticancer Therapy

PubMed Central

Vieira, Jeymesson Raphael Cardoso; de Souza, Ivone Antônia; do Nascimento, Silene Carneiro

2007-01-01

Indigofera suffruticosa Mill (Fabeceae) occurs in the Northeast countryside and has intensive popular use in the treatment of infectious, inflammatory and other processes. The main aim of the present work was to investigate the cytotoxic and antitumor effects of aqueous extracts of leaves of I. suffruticosa obtained by infusion and maceration as well as to evaluate the toxicological properties. Aqueous extracts did not exhibit cytotoxicity against HEp-2 (human epidermoid cancer cell) cell lines by MTT method. From the aqueous extract by infusion, the toxicological assay showed low order of toxicity. The antitumor effect of aqueous extracts by infusion (64.53%) and maceration (62.62%) against sarcoma 180 in mice at a dose of 50 mg kg−1 (intraperitoneally), based on low order of toxicity was comparable to the control group, which showed 100% development. Considering the low order of toxicity and that it is highly effective in inhibiting growth of solid tumors, the aqueous extracts of leaves of I. suffruticosa may be used as an alternative anticancer agent. PMID:17965767

Neuropsychology and the neurochemical lesion: evolution, applications and extensions.

PubMed

Hartman, D E

1988-01-01

The evolution of neuropsychology into a method for neurotoxic damage detection is reviewed. When neuropsychology is transformed into "neuropsychological toxicology", fundamental philosophical assumptions of the field are altered; the search for brain-behavior relationships must extend from structural damage into the analysis of neurochemical systems. The complementary relationship of human neuropsychology to basic toxicological and animal research is discussed. The great numbers of human "natural experiments" whose employment, medical history or substance abuse subjects them to contact with neurotoxic substances, suggest that there is a great need for expanded human investigations involving neuropsychological testing procedures in the service of research and clinical identification of neurotoxic syndromes. Further, it is argued that neurobehavioral procedures originally developed to detect industrial neurotoxic exposure will prove additionally useful assessing other brain-behavior disruptions mediated by neurochemistry or neurotoxicity rather than structural lesion. These frontiers include physical or emotional illness, substance abuse, effects of abused or prescription drugs as well as little-researched areas deserving of closer study, e.g., allergens or biotoxic exposure.

Toxicodynetics: A new discipline in clinical toxicology.

PubMed

Baud, F J; Houzé, P; Villa, A; Borron, S W; Carli, P

2016-05-01

Regarding the different disciplines that encompass the pharmacology and the toxicology, none is specifically dedicated to the description and analysis of the time-course of relevant toxic effects both in experimental and clinical studies. The lack of a discipline devoted to this major field in toxicology results in misconception and even in errors by clinicians. Review of the basic different disciplines that encompass pharmacology toxicology and comparing with the description of the time-course of effects in conditions in which toxicological analysis was not performed or with limited analytical evidence. Review of the literature clearly shows how misleading is the current extrapolation of toxicokinetic data to the description of the time-course of toxic effects. A new discipline entitled toxicodynetics should be developed aiming at a more systematic description of the time-course of effects in acute human and experimental poisonings. Toxicodynetics might help emergency physicians in risk assessment when facing a poisoning and contribute to a better assessment of quality control of data collected by poison control centres. Toxicodynetics would also allow a quantitative approach to the clinical effects resulting from drug-drug interaction. Copyright © 2016. Published by Elsevier Masson SAS.

21 CFR 862.3280 - Clinical toxicology control material.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Clinical toxicology control material. 862.3280... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3280 Clinical toxicology control material. (a) Identification. A clinical toxicology control...

21 CFR 862.3280 - Clinical toxicology control material.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Clinical toxicology control material. 862.3280... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3280 Clinical toxicology control material. (a) Identification. A clinical toxicology control...

21 CFR 862.3280 - Clinical toxicology control material.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Clinical toxicology control material. 862.3280... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3280 Clinical toxicology control material. (a) Identification. A clinical toxicology control...

21 CFR 862.3280 - Clinical toxicology control material.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Clinical toxicology control material. 862.3280... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3280 Clinical toxicology control material. (a) Identification. A clinical toxicology control...

21 CFR 862.3280 - Clinical toxicology control material.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Clinical toxicology control material. 862.3280... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3280 Clinical toxicology control material. (a) Identification. A clinical toxicology control...

Current assessment of the effects of environmental chemicals on the mammary gland in guideline rodent studies by the U.S. Environmental Protection Agency (U.S. EPA), Organisation for Economic Co-operation and Development (OECD), and National Toxicology Program (NTP).

PubMed

Makris, Susan L

2011-08-01

Evaluation of the structural and/or functional integrity of the mammary gland (MG) across life stages is integral to the assessment of developmental, reproductive, and carcinogenic risk for environmental chemicals. In this commentary I characterize MG assessment recommended in U.S. Environmental Protection Agency, Organisation for Economic Co-operation and Development, and National Toxicology Program guideline toxicology study protocols and identify any information gaps for the evaluation of MG development, structure, and function. Several data gaps, issues, and challenges were identified. Current guidelines that include a lactation phase do not provide specific recommendations to record observations on maternal or offspring lactation or nursing behavior. In guideline studies, the assessment of MG toxicity often relies upon indirect, nonspecific, or surrogate end points, and information that could be useful in the interpretation of these data (e.g., mode of action or toxicokinetics) is often unavailable. Most guideline studies designed to assess general organ toxicity do not expose test animals during sensitive stages of MG development; histopathological evaluation of the developing MG is not routinely conducted; and evaluation of MG tissue for both sexes is inconsistently recommended. I propose the following general recommendations to enhance MG assessment in guideline toxicology studies: a) inclusion of more specific criteria for the evaluation of MG end points in guideline language, b) inclusion of histopathological evaluation of MG development (using whole-mount techniques) in existing or new guideline protocols that include offspring with perinatal and/or pubertal treatment, c) incorporation of perinatal exposures into rodent subchronic and carcinogenicity assays, and d) expansion of the histopathological evaluation of male MG tissue.

Current Assessment of the Effects of Environmental Chemicals on the Mammary Gland in Guideline Rodent Studies by the U.S. Environmental Protection Agency (U.S. EPA), Organisation for Economic Co-operation and Development (OECD), and National Toxicology Program (NTP)

PubMed Central

2010-01-01

Background: Evaluation of the structural and/or functional integrity of the mammary gland (MG) across life stages is integral to the assessment of developmental, reproductive, and carcinogenic risk for environmental chemicals. Objectives: In this commentary I characterize MG assessment recommended in U.S. Environmental Protection Agency, Organisation for Economic Co-operation and Development, and National Toxicology Program guideline toxicology study protocols and identify any information gaps for the evaluation of MG development, structure, and function. Discussion: Several data gaps, issues, and challenges were identified. Current guidelines that include a lactation phase do not provide specific recommendations to record observations on maternal or offspring lactation or nursing behavior. In guideline studies, the assessment of MG toxicity often relies upon indirect, nonspecific, or surrogate end points, and information that could be useful in the interpretation of these data (e.g., mode of action or toxicokinetics) is often unavailable. Most guideline studies designed to assess general organ toxicity do not expose test animals during sensitive stages of MG development; histopathological evaluation of the developing MG is not routinely conducted; and evaluation of MG tissue for both sexes is inconsistently recommended. Conclusions: I propose the following general recommendations to enhance MG assessment in guideline toxicology studies: a) inclusion of more specific criteria for the evaluation of MG end points in guideline language, b) inclusion of histopathological evaluation of MG development (using whole-mount techniques) in existing or new guideline protocols that include offspring with perinatal and/or pubertal treatment, c) incorporation of perinatal exposures into rodent subchronic and carcinogenicity assays, and d) expansion of the histopathological evaluation of male MG tissue. PMID:21118785

How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

PubMed

Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M E Bette; Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M; Whelan, Maurice

2017-02-01

Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

IRIS TOXICOLOGICAL REVIEW AND SUMMARY ...

EPA Pesticide Factsheets

EPA's assessment of the noncancer health effects and carcinogenic potential of Beryllium was added to the IRIS database in 1998. The IRIS program is updating the IRIS assessment for Beryllium. This update will incorporate health effects information published since the last assessment was prepared as well as new risk assessment methods. The IRIS assessment for Beryllium will consist of an updated Toxicological Review and IRIS Summary. The Toxicological Review is a critical review of the physicochemical and toxicokinetic properties of the chemical and its toxicity in humans and experimental systems. The assessment will present reference values for noncancer effects of Beryllium (RfD and RfC) and a cancer assessment. The Toxicological Review and IRIS Summary will be subject to internal peer consultation, Agency and Interagency review, and external scientific peer review. The final products will constitute the Agency's opinion on the toxicity of Beryllium. Beryllium is a light alkaline earth metal used in metal alloys and in high-performance products in the metallurgical, aerospace, and nuclear industries. According to the Superfund database, beryllium is found in over 300 NPL sites

TOXCAST, A TOOL FOR CATEGORIZATION AND ...

EPA Pesticide Factsheets

Across several EPA Program Offices (e.g., OPPTS, OW, OAR), there is a clear need to develop strategies and methods to screen large numbers of chemicals for potential toxicity, and to use the resulting information to prioritize the use of testing resources towards those entities and endpoints that present the greatest likelihood of risk to human health and the environment. This need could be addressed using the experience of the pharmaceutical industry in the use of advanced modern molecular biology and computational chemistry tools for the development of new drugs, with appropriate adjustment to the needs and desires of environmental toxicology. A conceptual approach named ToxCast has been developed to address the needs of EPA Program Offices in the area of prioritization and screening. Modern computational chemistry and molecular biology tools bring enabling technologies forward that can provide information about the physical and biological properties of large numbers of chemicals. The essence of the proposal is to conduct a demonstration project based upon a rich toxicological database (e.g., registered pesticides, or the chemicals tested in the NTP bioassay program), select a fairly large number (50-100 or more chemicals) representative of a number of differing structural classes and phenotypic outcomes (e.g., carcinogens, reproductive toxicants, neurotoxicants), and evaluate them across a broad spectrum of information domains that modern technology has pro

Resource Guide to Careers in Toxicology, 3rd Edition.

ERIC Educational Resources Information Center

Society of Toxicology, Reston, VA.

This resource guide was prepared by the Tox 90's Educational Issues Task Force of the Society of Toxicology. The introduction provides information on the Society of Toxicology and financial support for graduate students in toxicology. Other sections include career opportunities in toxicology, academic and postdoctoral programs in toxicology, and…

Simultaneous determination of nikethamide and lidocaine in human blood and cerebrospinal fluid by high performance liquid chromatography.

PubMed

Chen, Lili; Liao, Linchuan; Zuo, Zhong; Yan, Youyi; Yang, Lin; Fu, Qiang; Chen, Yu; Hou, Junhong

2007-04-11

Nikethamide and lidocaine are often requested to be quantified simultaneously in forensic toxicological analysis. A simple reversed-phase high performance liquid chromatography (RP-HPLC) method has been developed for their simultaneous determination in human blood and cerebrospinal fluid. The method involves simple protein precipitation sample treatment followed by quantification of analytes using HPLC at 263 nm. Analytes were separated on a 5 microm Zorbax Dikema C18 column (150 mm x 4.60 mm, i.d.) with a mobile phase of 22:78 (v/v) mixture of methanol and a diethylamine-acetic acid buffer, pH 4.0. The mean recoveries were between 69.8 and 94.4% for nikethamide and between 78.9 and 97.2% for lidocaine. Limits of detection (LODs) for nikethamide and lidocaine were 0.008 and 0.16 microg/ml in plasma and 0.007 and 0.14 microg/ml in cerebrospinal fluid, respectively. The mean intra-assay and inter-assay coefficients of variation (CVs) for both analytes were less than 9.2 and 10.8%, respectively. The developed method was applied to blood sample analyses in eight forensic cases, where blood concentrations of lidocaine ranged from 0.68 to 34.4 microg/ml and nikethamide ranged from 1.25 to 106.8 microg/ml. In six cases cerebrospinal fluid analysis was requested. The values ranged from 20.3 to 185.6 microg/ml of lidocaine and 8.0 to 72.4 microg/ml of nikethamide. The method is simple and sensitive enough to be used in toxicological analysis for simultaneous determination of nikethamide and lidocaine in blood and cerebrospinal fluid.

CompNanoTox2015: novel perspectives from a European conference on computational nanotoxicology on predictive nanotoxicology.

PubMed

Bañares, Miguel A; Haase, Andrea; Tran, Lang; Lobaskin, Vladimir; Oberdörster, Günter; Rallo, Robert; Leszczynski, Jerzy; Hoet, Peter; Korenstein, Rafi; Hardy, Barry; Puzyn, Tomasz

2017-09-01

A first European Conference on Computational Nanotoxicology, CompNanoTox, was held in November 2015 in Benahavís, Spain with the objectives to disseminate and integrate results from the European modeling and database projects (NanoPUZZLES, ModENPTox, PreNanoTox, MembraneNanoPart, MODERN, eNanoMapper and EU COST TD1204 MODENA) as well as to create synergies within the European NanoSafety Cluster. This conference was supported by the COST Action TD1204 MODENA on developing computational methods for toxicological risk assessment of engineered nanoparticles and provided a unique opportunity for cross fertilization among complementary disciplines. The efforts to develop and validate computational models crucially depend on high quality experimental data and relevant assays which will be the basis to identify relevant descriptors. The ambitious overarching goal of this conference was to promote predictive nanotoxicology, which can only be achieved by a close collaboration between the computational scientists (e.g. database experts, modeling experts for structure, (eco) toxicological effects, performance and interaction of nanomaterials) and experimentalists from different areas (in particular toxicologists, biologists, chemists and material scientists, among others). The main outcome and new perspectives of this conference are summarized here.

Current toxicological aspects on drug and chemical transport and metabolism across the human placental barrier.

PubMed

Giaginis, Constantinos; Theocharis, Stamatios; Tsantili-Kakoulidou, Anna

2012-10-01

Placenta plays an obligatory role in fetal growth and development by performing a multitude of functions, including embryo implantation, transport of nutrients and elimination of metabolic waste products and endocrine activity. Drugs and chemicals can transfer across the placental barrier from mother to fetus either by passive diffusion mechanisms and/or via a network of active transporters, which may lead to potential fetotoxicity effects. Placenta also expresses a wide variety of enzymes, being capable of metabolizing a large diversity of drugs and chemicals to metabolites of lower or even higher toxicity than parent compounds. The present review aims to summarize the current toxicological aspects in the emerging topic of drug transport and metabolism across the human placental barrier. There is an emerging demand for accurate assessment of drug transport and metabolism across the human placental barrier, on the basis of a high throughput screening process in the early stages of drug design, to avoid drug candidates from potential fetotoxicity effects. In this aspect, combined studies, which take into account in vivo and in vitro investigations, as well as the ex vivo perfusion method and the recently developed computer-aided technologies, may significantly contribute to this direction.

CompNanoTox2015: novel perspectives from a European conference on computational nanotoxicology on predictive nanotoxicology

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

Bañares, Miguel A.; Haase, Andrea; Tran, Lang

A first European Conference on Computational Nanotoxicology, CompNanoTox, was held in November 2015 in Benahavís, Spain with the objectives to disseminate and integrate results from the European modeling and database projects (NanoPUZZLES, ModENPTox, PreNanoTox, MembraneNanoPart, MODERN, eNanoMapper and EU COST TD1204 MODENA) as well as to create synergies within the European NanoSafety Cluster. This conference was supported by the COST Action TD1204 MODENA on developing computational methods for toxicological risk assessment of engineered nanoparticles and provided a unique opportunity for crossfertilization among complementary disciplines. The efforts to develop and validate computational models crucially depend on high quality experimental data andmore » relevant assays which will be the basis to identify relevant descriptors. The ambitious overarching goal of this conference was to promote predictive nanotoxicology, which can only be achieved by a close collaboration between the computational scientists (e.g. database experts, modeling experts for structure, (eco) toxicological effects, performance and interaction of nanomaterials) and experimentalists from different areas (in particular toxicologists, biologists, chemists and material scientists, among others). The main outcome and new perspectives of this conference are summarized here.« less

Mouse bioassay for palytoxin. Specific symptoms and dose-response against dose-death time relationships.

PubMed

Riobó, P; Paz, B; Franco, J M; Vázquez, J A; Murado, M A; Cacho, E

2008-08-01

Nowadays, a variety of protocols are applied to quantitate palytoxin. However, there is not desirable agreement among them, the confidence intervals of the basic toxicological parameters are too wide and the formal descriptions lack the necessary generality to establish comparisons. Currently, the mouse bioassay is the most accepted one to categorize marine toxins and it must constitute the reference for other methods. In the present work, the mouse bioassay for palytoxin is deeply analyzed and carefully described showing the initial symptoms of injected mice which are presented here in the first time. These symptoms clearly differ from the more common marine toxins described up to now. Regarding to the toxicological aspects two considerations are taking into account: (i) the empiric models based in the dose-death time relationships cause serious ambiguities and (ii) the traditional moving average method contains in its regular use any inaccuracy elements. Herein is demonstrated that the logistic equation and the accumulative function of Weibull's distribution (with the modifications proposed) generate satisfactory toxicological descriptions in all the respects.

The local lymph node assay in 2014.

PubMed

Basketter, David A; Gerberick, G Frank; Kimber, Ian

2014-01-01

Toxicology endeavors to predict the potential of materials to cause adverse health (and environmental) effects and to assess the risk(s) associated with exposure. For skin sensitizers, the local lymph node assay was the first method to be fully and independently validated, as well as the first to offer an objective end point with a quantitative measure of sensitizing potency (in addition to hazard identification). Fifteen years later, it serves as the primary standard for the development of in vitro/in chemico/in silico alternatives.

[Investigation of the safety of microbial biotechnological products and their hygienic regulation].

PubMed

Omel'ianets', T H; Kovalenko, N K; Holovach, T M

2008-01-01

Peculiarities of influence of microbial preparations based on microorganisms of different taxonomic groups on the warm-blooded organisms are considered, that is necessary to take into account when developing the strategy of toxico-hygienic studying of these preparations and when substanting hygienic standards in industrial objects and in the environment. The possibility to simplify the methodical scheme of the toxicological estimation and the hygienic regulation of microbial preparations on the basis of soil nitrogen-fixing microorganisms is discussed.

Predictive performance of the Vitrigel-eye irritancy test method using 118 chemicals.

PubMed

Yamaguchi, Hiroyuki; Kojima, Hajime; Takezawa, Toshiaki

2016-08-01

We recently developed a novel Vitrigel-eye irritancy test (EIT) method. The Vitrigel-EIT method is composed of two parts, i.e., the construction of a human corneal epithelium (HCE) model in a collagen vitrigel membrane chamber and the prediction of eye irritancy by analyzing the time-dependent profile of transepithelial electrical resistance values for 3 min after exposing a chemical to the HCE model. In this study, we estimated the predictive performance of Vitrigel-EIT method by testing a total of 118 chemicals. The category determined by the Vitrigel-EIT method in comparison to the globally harmonized system classification revealed that the sensitivity, specificity and accuracy were 90.1%, 65.9% and 80.5%, respectively. Here, five of seven false-negative chemicals were acidic chemicals inducing the irregular rising of transepithelial electrical resistance values. In case of eliminating the test chemical solutions showing pH 5 or lower, the sensitivity, specificity and accuracy were improved to 96.8%, 67.4% and 84.4%, respectively. Meanwhile, nine of 16 false-positive chemicals were classified irritant by the US Environmental Protection Agency. In addition, the disappearance of ZO-1, a tight junction-associated protein and MUC1, a cell membrane-spanning mucin was immunohistologically confirmed in the HCE models after exposing not only eye irritant chemicals but also false-positive chemicals, suggesting that such false-positive chemicals have an eye irritant potential. These data demonstrated that the Vitrigel-EIT method could provide excellent predictive performance to judge the widespread eye irritancy, including very mild irritant chemicals. We hope that the Vitrigel-EIT method contributes to the development of safe commodity chemicals. Copyright © 2015 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd. Copyright © 2015 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.

Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028 — For human safety in clinical study

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

Nishizato, Yohei, E-mail: yohei-nishizato@ds-pharma.co.jp; Imai, Satoki; Okahashi, Noriko

2014-05-01

SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect ofmore » this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies. - Highlights: • SMP-028 inhibits neutral CEase more strongly than other steroidogenic enzymes in rats. • Inhibition of neutral CEase in rats by SMP-028 suppresses steroidogenesis in vivo. • SMP-028 does not inhibit neutral CEase in monkeys in vivo. • Steroidogenesis pathway in monkeys treated with SMP-028 was not suppressed. • SMP-028 may not inhibit LIPE in humans in vivo.« less

In vitro toxicological characterization of particulate emissions from residential biomass heating systems based on old and new technologies

NASA Astrophysics Data System (ADS)

Jalava, Pasi I.; Happo, Mikko S.; Kelz, Joachim; Brunner, Thomas; Hakulinen, Pasi; Mäki-Paakkanen, Jorma; Hukkanen, Annika; Jokiniemi, Jorma; Obernberger, Ingwald; Hirvonen, Maija-Riitta

2012-04-01

Residential wood combustion causes major effects on the air quality on a global scale. The ambient particulate levels are known to be responsible for severe adverse health effects that include e.g. cardio-respiratory illnesses and cancer related effects, even mortality. It is known that biomass combustion derived emissions are affected by combustion technology, fuel being used and user-related practices. There are also indications that the health related toxicological effects are influenced by these parameters. This study we evaluated toxicological effects of particulate emissions (PM1) from seven different residential wood combusting furnaces. Two appliances i.e. log wood boiler and stove represented old batch combustion technology, whereas stove and tiled stove were designated as new batch combustion as three modern automated boilers were a log wood boiler, a woodchip boiler and a pellet boiler. The PM1 samples from the furnaces were collected in an experimental setup with a Dekati® gravimetric impactor on PTFE filters with the samples being weighed and extracted from the substrates and prior to toxicological analyses. The toxicological analyses were conducted after a 24-hour exposure of the mouse RAW 264.7 macrophage cell line to four doses of emission particle samples and analysis of levels of the proinflammatory cytokine TNFα, chemokine MIP-2, cytotoxicity with three different methods (MTT, PI, cell cycle analysis) and genotoxicity with the comet assay. In the correlation analysis all the toxicological results were compared with the chemical composition of the samples. All the samples induced dose-dependent increases in the studied parameters. Combustion technology greatly affected the emissions and the concomitant toxicological responses. The modern automated boilers were usually the least potent inducers of most of the parameters while emissions from the old technology log wood boiler were the most potent. In correlation analysis, the PAH and other organic composition and inorganic ash composition affected the toxicological responses differently. In conclusion, combustion technology largely affects the particulate emissions and their toxic potential this being reflected in substantially larger responses in devices with incomplete combustion. These differences become emphasized when the large emission factors from old technology appliances are taken into account.

Advancing environmental toxicology through chemical dosimetry: External exposures versus tissue residues

USGS Publications Warehouse

McCarty, L.S.; Landrum, P.F.; Luoma, S.N.; Meador, J.P.; Merten, A.A.; Shephard, B.K.; van Wezelzz, A.P.

2011-01-01

The tissue residue dose concept has been used, although in a limited manner, in environmental toxicology for more than 100 y. This review outlines the history of this approach and the technical background for organic chemicals and metals. Although the toxicity of both can be explained in tissue residue terms, the relationship between external exposure concentration, body and/or tissues dose surrogates, and the effective internal dose at the sites of toxic action tends to be more complex for metals. Various issues and current limitations related to research and regulatory applications are also examined. It is clear that the tissue residue approach (TRA) should be an integral component in future efforts to enhance the generation, understanding, and utility of toxicity testing data, both in the laboratory and in the field. To accomplish these goals, several key areas need to be addressed: 1) development of a risk-based interpretive framework linking toxicology and ecology at multiple levels of biological organization and incorporating organism-based dose metrics; 2) a broadly applicable, generally accepted classification scheme for modes/mechanisms of toxic action with explicit consideration of residue information to improve both single chemical and mixture toxicity data interpretation and regulatory risk assessment; 3) toxicity testing protocols updated to ensure collection of adequate residue information, along with toxicokinetics and toxicodynamics information, based on explicitly defined toxicological models accompanied by toxicological model validation; 4) continued development of residueeffect databases is needed ensure their ongoing utility; and 5) regulatory guidance incorporating residue-based testing and interpretation approaches, essential in various jurisdictions. ??:2010 SETAC.

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

PubMed Central

Corvi, Raffaella; Ahr, Hans-Jürgen; Albertini, Silvio; Blakey, David H.; Clerici, Libero; Coecke, Sandra; Douglas, George R.; Gribaldo, Laura; Groten, John P.; Haase, Bernd; Hamernik, Karen; Hartung, Thomas; Inoue, Tohru; Indans, Ian; Maurici, Daniela; Orphanides, George; Rembges, Diana; Sansone, Susanna-Assunta; Snape, Jason R.; Toda, Eisaku; Tong, Weida; van Delft, Joost H.; Weis, Brenda; Schechtman, Leonard M.

2006-01-01

This is the report of the first workshop “Validation of Toxicogenomics-Based Test Systems” held 11–12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities. PMID:16507466

Meeting report: Validation of toxicogenomics-based test systems: ECVAM-ICCVAM/NICEATM considerations for regulatory use.

PubMed

Corvi, Raffaella; Ahr, Hans-Jürgen; Albertini, Silvio; Blakey, David H; Clerici, Libero; Coecke, Sandra; Douglas, George R; Gribaldo, Laura; Groten, John P; Haase, Bernd; Hamernik, Karen; Hartung, Thomas; Inoue, Tohru; Indans, Ian; Maurici, Daniela; Orphanides, George; Rembges, Diana; Sansone, Susanna-Assunta; Snape, Jason R; Toda, Eisaku; Tong, Weida; van Delft, Joost H; Weis, Brenda; Schechtman, Leonard M

2006-03-01

This is the report of the first workshop "Validation of Toxicogenomics-Based Test Systems" held 11-12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities.

Environmental Health and Toxicology Resources of the United States National Library of Medicine

PubMed Central

Hochstein, Colette; Arnesen, Stacey; Goshorn, Jeanne

2009-01-01

For over 40 years, the National Library of Medicine’s (NLM) Toxicology and Environmental Health Information Program (TEHIP) has worked to organize and to provide access to an extensive array of environmental health and toxicology resources. During these years, the TEHIP program has evolved from a handful of databases developed primarily for researchers to a broad range of products and services that also serve industry, students, and the general public. TEHIP’s resources include TOXNET® , a collection of databases, including online handbooks, bibliographic references, information on the release of chemicals in the environment, and a chemical dictionary. TEHIP also produces several resources aimed towards the general public, such as the Household Products Database , which helps users explore chemicals often found in common household products, and Tox Town® , an interactive guide to commonly encountered toxic substances, health, and the environment. This paper introduces some of NLM’s environmental health and toxicology resources. PMID:17915629

SERS as a tool for in vitro toxicology.

PubMed

Fisher, Kate M; McLeish, Jennifer A; Jamieson, Lauren E; Jiang, Jing; Hopgood, James R; McLaughlin, Stephen; Donaldson, Ken; Campbell, Colin J

2016-06-23

Measuring markers of stress such as pH and redox potential are important when studying toxicology in in vitro models because they are markers of oxidative stress, apoptosis and viability. While surface enhanced Raman spectroscopy is ideally suited to the measurement of redox potential and pH in live cells, the time-intensive nature and perceived difficulty in signal analysis and interpretation can be a barrier to its broad uptake by the biological community. In this paper we detail the development of signal processing and analysis algorithms that allow SERS spectra to be automatically processed so that the output of the processing is a pH or redox potential value. By automating signal processing we were able to carry out a comparative evaluation of the toxicology of silver and zinc oxide nanoparticles and correlate our findings with qPCR analysis. The combination of these two analytical techniques sheds light on the differences in toxicology between these two materials from the perspective of oxidative stress.

Toxicology profiles of chemical and radiological contaminants at Hanford

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

Harper, B.L.; Strenge, D.L.; Stenner, R.D.

1995-07-01

This document summarizes toxicology information required under Section 3.3 (Toxicity Assessment) of HSRAM, and can also be used to develop the short toxicology profiles required in site assessments (described in HSRAM, Section 3.3.5). Toxicology information is used in the dose-response step of the risk assessment process. The dose-response assessment describes the quantitative relationship between the amount of exposure to a substance and the extent of toxic injury or disease. Data are derived from animal studies or, less frequently, from studies in exposed human populations. The risks of a substance cannot be ascertained with any degree of confidence unless dose-response relationsmore » are quantified. This document summarizes dose-response information available from the US Environmental Protection Agency (EPA). The contaminants selected for inclusion in this document represent most of the contaminants found at Hanford (both radiological and chemical), based on sampling and analysis performed during site investigations, and historical information on waste disposal practices at the Hanford Site.« less

Self-report of illicit substance use versus urine toxicology results from at-risk pregnant women

PubMed Central

YONKERS, KIMBERLY A.; HOWELL, HEATHER B.; GOTMAN, NATHAN; ROUNSAVILLE, BRUCE J.

2013-01-01

Introduction Many factors comprise a patient's decision to disclose use of drugs. Pregnant women may report drug use because they would like help with their addiction but the stigma associated with drug use may dampen their willingness to disclose. Knowledge about the accuracy of self-reported drug use as compared to urine toxicology screens can assist clinicians in the management of substance use in pregnancy. Method We compared the urine toxicology screens and self-reported use of marijuana or cocaine for 168 women enrolled in an integrated obstetrical/substance abuse treatment program. We stratified by various periods of self-reported use and race and utilized Cohen's kappa to measure overall agreement between self-report and toxicology tests. Results Most women with a positive toxicology screen reported use in the past 28 days (78% for marijuana, 86% for cocaine). However, many women reported their most recent use to be outside of the assays’ detection window (14% for marijuana, 57% for cocaine). We did not find differences in self-report for women with positive urine between Whites and non-Whites (p = 1.00). Agreement over the previous month was good (Kappa = 0.74 and 0.70 for marijuana and cocaine, respectively.) Summary A question about use of marijuana or cocaine during the preceding month rather than the prior few days may be a better indicator of use. PMID:23956685

IRIS Toxicological Review and Summary Documents for N ...

EPA Pesticide Factsheets

EPA's assessment of the noncancer health effects and carcinogenic potential of n-hexane was last prepared and added to the IRIS data base in 1990. The IRIS program is updating the IRIS assessment for n-hexane; this update will incorporate health effects information published since the last assessment was prepared as well as new risk assessment methods. The IRIS assessment for n-hexane will consist of a Toxicological Review and IRIS Summary. The Toxicological Review is a critical review of the physicochemical and toxicokinetic properties of the chemical and its toxicity in humans and experimental systems. The assessment will present reference values for noncancer effects of n-hexane (RfD and RfC) and a cancer assessment, where supported by available data. The Toxicological Review and IRIS Summary will be subject to internal peer consultation, Agency review, and external scientific peer review. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for n-hexane. The outcome of this project is an updated Toxicological Review and IRIS Summary for n-Hexane that will be entered into the IRIS database. IRIS is an EPA data base containing Agency scientific positions on potential adverse human health effects that may result from chronic (or lifetime) exposure to chemicals in the environment. IRIS contains chemical-specific summaries of qualitative and quantitative health information in support of two steps of the risk assessment

Collection of biological samples in forensic toxicology.

PubMed

Dinis-Oliveira, R J; Carvalho, F; Duarte, J A; Remião, F; Marques, A; Santos, A; Magalhães, T

2010-09-01

Forensic toxicology is the study and practice of the application of toxicology to the purposes of the law. The relevance of any finding is determined, in the first instance, by the nature and integrity of the specimen(s) submitted for analysis. This means that there are several specific challenges to select and collect specimens for ante-mortem and post-mortem toxicology investigation. Post-mortem specimens may be numerous and can endow some special difficulties compared to clinical specimens, namely those resulting from autolytic and putrefactive changes. Storage stability is also an important issue to be considered during the pre-analytic phase, since its consideration should facilitate the assessment of sample quality and the analytical result obtained from that sample. The knowledge on degradation mechanisms and methods to increase storage stability may enable the forensic toxicologist to circumvent possible difficulties. Therefore, advantages and limitations of specimen preservation procedures are thoroughfully discussed in this review. Presently, harmonized protocols for sampling in suspected intoxications would have obvious utility. In the present article an overview is given on sampling procedures for routinely collected specimens as well as on alternative specimens that may provide additional information on the route and timing of exposure to a specific xenobiotic. Last, but not least, a discussion on possible bias that can influence the interpretation of toxicological results is provided. This comprehensive review article is intented as a significant help for forensic toxicologists to accomplish their frequently overwhelming mission.

Implementing systematic review techniques in chemical risk assessment: Challenges, opportunities and recommendations.

PubMed

Whaley, Paul; Halsall, Crispin; Ågerstrand, Marlene; Aiassa, Elisa; Benford, Diane; Bilotta, Gary; Coggon, David; Collins, Chris; Dempsey, Ciara; Duarte-Davidson, Raquel; FitzGerald, Rex; Galay-Burgos, Malyka; Gee, David; Hoffmann, Sebastian; Lam, Juleen; Lasserson, Toby; Levy, Len; Lipworth, Steven; Ross, Sarah Mackenzie; Martin, Olwenn; Meads, Catherine; Meyer-Baron, Monika; Miller, James; Pease, Camilla; Rooney, Andrew; Sapiets, Alison; Stewart, Gavin; Taylor, David

2016-01-01

Systematic review (SR) is a rigorous, protocol-driven approach designed to minimise error and bias when summarising the body of research evidence relevant to a specific scientific question. Taking as a comparator the use of SR in synthesising research in healthcare, we argue that SR methods could also pave the way for a "step change" in the transparency, objectivity and communication of chemical risk assessments (CRA) in Europe and elsewhere. We suggest that current controversies around the safety of certain chemicals are partly due to limitations in current CRA procedures which have contributed to ambiguity about the health risks posed by these substances. We present an overview of how SR methods can be applied to the assessment of risks from chemicals, and indicate how challenges in adapting SR methods from healthcare research to the CRA context might be overcome. Regarding the latter, we report the outcomes from a workshop exploring how to increase uptake of SR methods, attended by experts representing a wide range of fields related to chemical toxicology, risk analysis and SR. Priorities which were identified include: the conduct of CRA-focused prototype SRs; the development of a recognised standard of reporting and conduct for SRs in toxicology and CRA; and establishing a network to facilitate research, communication and training in SR methods. We see this paper as a milestone in the creation of a research climate that fosters communication between experts in CRA and SR and facilitates wider uptake of SR methods into CRA. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Mixtures, Metabolites, and Mechanisms: Understanding Toxicology Using Zebrafish.

PubMed

Gamse, Joshua T; Gorelick, Daniel A

2016-10-01

For more than 60 years, zebrafish have been used in toxicological studies. Due to their transparency, genetic tractability, and compatibility with high-throughput screens, zebrafish embryos are uniquely suited to study the effects of pharmaceuticals and environmental insults on embryonic development, organ formation and function, and reproductive success. This special issue of Zebrafish highlights the ways zebrafish are used to investigate the toxic effects of endocrine disruptors, pesticides, and heavy metals.

Toxicologic and Analytical Studies with T-2 and Related Trichothecene Mycotoxins

DTIC Science & Technology

1984-09-01

SUPPORTED BY U. S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND Fort Detrick, Frederick, Maryland 21701 Contract No. DAMV 17-82-C-2179 College of...Paula M. Bratich, Researcher Robert H. Poppenga, Researcher Richard A. Corley, Researcher "SUBMITTED SEPTEMBER 4, 1984 SUPPORTED BY’ U. S. ARMY MEDICAL ... Medical Records Technician Technical Reports ,7V Toxicology Department of Vet Biosciences Walter E. Hoffmann Associate Professor of Clinical

The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology.

PubMed

Eaton, Joshua Seth; Miller, Paul E; Bentley, Ellison; Thomasy, Sara M; Murphy, Christopher J

2017-12-01

To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development. Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett-McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations. This semiquantitative preclinical ocular toxicology scoring (SPOTS) system was driven by limitations of previously published systems identified by our group's recent review of slit lamp-based scoring systems in clinical ophthalmology, toxicology, and vision science. The SPOTS system provides scoring criteria for the anterior segment, posterior segment, and characterization of intravitreal test articles. Key elements include: standardized slit lamp settings; expansion of criteria to enhance applicability to nonrabbit species; refinement and disambiguation of scoring criteria for corneal opacity, fluorescein staining severity, and aqueous flare; introduction of novel criteria for scoring of aqueous and anterior vitreous cell; and introduction of criteria for findings observed with drugs/devices targeting the posterior segment. A modified Standardization of Uveitis Nomenclature (SUN) system is also introduced to facilitate accurate use of SUN's criteria in laboratory species. The SPOTS systems provide criteria that stand to enhance the applicability of semiquantitative scoring criteria to the full range of laboratory species, in the context of modern approaches to ocular therapeutics and drug delivery and drug and device development.

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

Kienhuis, Anne S., E-mail: anne.kienhuis@rivm.nl; RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen; Netherlands Toxicogenomics Centre

Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as a model compound to discuss the application of toxicogenomics in hepatic systems toxicology for its potential role in the risk assessment process, to progress from hazard identification towards hazard characterization. The toxicogenomics-based parallelogram is usedmore » to identify current achievements and limitations of acetaminophen toxicogenomic in vivo and in vitro studies for in vitro-to-in vivo and interspecies comparisons, with the ultimate aim to extrapolate animal studies to humans in vivo. This article provides a model for comparison of more species and more in vitro models enhancing the robustness of common toxicogenomic responses and their relevance to human risk assessment. To progress to quantitative dose-response analysis needed for hazard characterization, in hepatic systems toxicology studies, generation of toxicogenomic data of multiple doses/concentrations and time points is required. Newly developed bioinformatics tools for quantitative analysis of toxicogenomic data can aid in the elucidation of dose-responsive effects. The challenge herein is to assess which toxicogenomic responses are relevant for induction of the apical effect and whether perturbations are sufficient for the induction of downstream events, eventually causing toxicity.« less

[Interest of toxicological analysis for poisonings].

PubMed

Mégarbane, Bruno; Baud, Frédéric J

2008-04-30

The clinical approach of the poisoned patients is mainly based on the analysis of the circumstances of intoxication and the search for toxidromes. Toxicological analysis aims to detect the toxicants or measure their concentrations, in order to confirm the hypothesis of poisoning, to evaluate its severity and to help the follow-up regarding the treatment efficiency. Emergent toxicological analysis appears only useful if the method is specific and the results rapidly obtained. Therefore, systematic screening using immunochesmistry-based tests is not recommended in the situation of emergency. Measurement of blood concentrations of the toxicants is only indicated if it may influence the patient management. However, in the perspective of research, the study of toxicokinetic/toxicodynamic relationships, i.e. the relationships between the toxicant effects and its blood concentrations, may be helpful to understand the inter-individual variability of the response to a toxicant.

Poison control centers in developing countries and Asia's need for toxicology education

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

Makalinao, Irma R.; Awang, Rahmat

2005-09-01

Poison control centers (PCCs) in developing countries have been set up in response to the challenge of decreasing mortality and morbidity from poisoning. The services range from poison information to actual clinical treatment mostly of acute cases. Lately, PCCs have expanded from their traditional role to one that actively engages in community health studies, toxicovigilance along with treatment of chronic poisoning. Recognizing that types of poisoning and specific needs may vary from country to country, toxicology education that addresses these unique regional issues has become more necessary. Toxicology education, both formal and informal, exists in various stages of development inmore » Asia. Clearly, there are gaps that need to be addressed especially in areas where there are no poison centers or where strengthening is necessary. Collaboration between PCCs in developing countries can help augment available resources including human, analytical and technical expertise. The critical mass of trained toxicologists will fill in the demand for clinical and regulatory specialists and educators as well. This paper highlights the experiences and resources available to the Philippine and Malaysian poison centers and the strengths generated by networking and collaboration. The role of Asia Pacific Association of Medical Toxicology (APAMT) as the Science NGO representative to the Intergovernmental Forum on Chemical Safety (IFCS) forum standing committee in promoting chemical safety at the regional level will be discussed. The 'Clearinghouse on the Sound Management of Chemicals', a platform for engaging multi-stakeholder and interdisciplinary partnerships, will be described as a possible model for capacity building to advance chemical safety through education and training not only in developing countries in Asia but globally as well.« less

The Evolution of Toxicology and Chemical Regulation ...

EPA Pesticide Factsheets

Presentation for lecture for the 17th Annual Sitlington Lecture in Toxicology at Oklahoma State University Interdisciplinary Toxicology Symposium Presentation for lecture for the 17th Annual Sitlington Lecture in Toxicology at Oklahoma State University Interdisciplinary Toxicology Symposium

Ensuring the Quality of Stem Cell-Derived In Vitro Models for Toxicity Testing.

PubMed

Stacey, Glyn N; Coecke, Sandra; Price, Anna-Bal; Healy, Lyn; Jennings, Paul; Wilmes, Anja; Pinset, Christian; Ingelman-Sundberg, Magnus; Louisse, Jochem; Haupt, Simone; Kidd, Darren; Robitski, Andrea; Jahnke, Heinz-Georg; Lemaitre, Gilles; Myatt, Glenn

Quality control of cell cultures used in new in vitro toxicology assays is crucial to the provision of reliable, reproducible and accurate toxicity data on new drugs or constituents of new consumer products. This chapter explores the key scientific and ethical criteria that must be addressed at the earliest stages of developing toxicology assays based on human pluripotent stem cell (hPSC) lines. It also identifies key considerations for such assays to be acceptable for regulatory, laboratory safety and commercial purposes. Also addressed is the development of hPSC-based assays for the tissue and cell types of greatest interest in drug toxicology. The chapter draws on a range of expert opinion within the European Commission/Cosmetics Europe-funded alternative testing cluster SEURAT-1 and consensus from international groups delivering this guidance such as the International Stem Cell Banking Initiative. Accordingly, the chapter summarizes the most up-date best practices in the use and quality control of human Pluripotent Stem Cell lines in the development of in vitro toxicity assays from leading experts in the field.

Rubber (Hevea brasiliensis) seed oil toxicity effect and Linamarin compound analysis.

PubMed

Salimon, Jumat; Abdullah, Bashar Mudhaffar; Salih, Nadia

2012-06-13

The lipid fraction of rubber (Hevea brasiliensis (kunth. Muell)) seed was extracted and analyzed for toxicological effect. The toxicological compound such as linamarin in rubber seed oil (RSO) extracted using different solvents, such as hexane (RSOh), mixture of chloroform + methanol (RSOchl+mth) and ethanol (RSOeth) were also studied. Various methods analysis such as Fourier transforms infrared spectroscopy (FTIR) and colorimetric methods were carried out to determine the present of such compounds. FTIR spectrum of RSO did not show any presence of cyanide peak. The determination of cyanide by using colorimetric method was demonstrated no response of the cyanide in RSO and didn't show any colored comparing with commercial cyanide which observed blue color. The results showed that no functional groups such as cyanide (C ≡ N) associated with linamarin were observed. Toxicological test using rats was also conducted to further confirm the absence of such compounds. RSO did not show any toxic potential to the rats. Bioassay experiments using shrimps had been used as test organisms to evaluate the toxicity of linamarin extract from RSO(h,) RSO(chl+mth) and RSO(eth) and LC50 were found to be (211.70 %, 139.40 %, and 117.41 %, respectively). This can be attributed no hazardous linamarin were found in RSO.

Rubber (Hevea brasiliensis) seed oil toxicity effect and Linamarin compound analysis

PubMed Central

2012-01-01

Background The lipid fraction of rubber (Hevea brasiliensis (kunth. Muell)) seed was extracted and analyzed for toxicological effect. The toxicological compound such as linamarin in rubber seed oil (RSO) extracted using different solvents, such as hexane (RSOh), mixture of chloroform + methanol (RSOchl+mth) and ethanol (RSOeth) were also studied. Various methods analysis such as Fourier transforms infrared spectroscopy (FTIR) and colorimetric methods were carried out to determine the present of such compounds. Results FTIR spectrum of RSO did not show any presence of cyanide peak. The determination of cyanide by using colorimetric method was demonstrated no response of the cyanide in RSO and didn’t show any colored comparing with commercial cyanide which observed blue color. The results showed that no functional groups such as cyanide (C ≡ N) associated with linamarin were observed. Toxicological test using rats was also conducted to further confirm the absence of such compounds. RSO did not show any toxic potential to the rats. Bioassay experiments using shrimps had been used as test organisms to evaluate the toxicity of linamarin extract from RSOh, RSOchl+mth and RSOeth and LC50 were found to be (211.70 %, 139.40 %, and 117.41 %, respectively). Conclusions This can be attributed no hazardous linamarin were found in RSO. PMID:22694753

Evidence-based causation in toxicology: A 10-year retrospective.

PubMed

James, R C; Britt, J K; Halmes, N C; Guzelian, P S

2015-12-01

We introduced Evidence-based Toxicology (EBT) in 2005 to address the disparities that exist between the various Weight-of-Evidence (WOE) methods typically applied in the regulatory hazard decision-making arena and urged toxicologists to adopt the evidence-based guidelines long-utilized in medicine (i.e., Evidence-Based Medicine or EBM). This review of the activities leading to the adoption of evidence-based methods and EBT during the last decade demonstrates how fundamental concepts that form EBT, such as the use of systematic reviews to capture and consider all available information, are improving toxicological evaluations performed by various groups and agencies. We reiterate how the EBT framework, a process that provides a method for performing human chemical causation analyses in an objective, transparent and reproducible manner, differs significantly from past and current regulatory WOE approaches. We also discuss why the uncertainties associated with regulatory WOE schemes lead to a definition of the term "risk" that contains unquantifiable uncertainties not present in this term as it is used in epidemiology and medicine. We believe this distinctly different meaning of "risk" should be clearly conveyed to those not familiar with this difference (e.g., the lay public), when theoretical/nomologic risks associated with chemical-induced toxicities are presented outside of regulatory and related scientific parlance. © The Author(s) 2015.