78 FR 30951 - SBIR/STTR Phase I to Phase II Transition Benchmarks

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-23

... (NIST) 0.25 5 DOC (NOAA) 0.25 5 NASA 0.25 5 DHS 0.25 5 DOE 0.25 5 EPA 0.25 5 DoD 0.25 5 NSF 0.25 5 DOT 0... for the Environmental Protection Agency (EPA) and the Department of Education (ED) from the current... used by EPA and ED for this benchmark calculation is currently 10 years. EPA and ED have concluded that...

Aquatic Life Benchmarks and Ecological Risk Assessments for Registered Pesticides

EPA Pesticide Factsheets

Each Aquatic Life Benchmark is based on the most sensitive, scientifically acceptable toxicity endpoint available to EPA for a given taxon (for example, freshwater fish) of all scientifically acceptable toxicity data available to EPA.

U.S. EPA'S ACUTE REFERENCE EXPOSURE METHODOLOGY FOR ACUTE INHALATION EXPOSURES

EPA Science Inventory

The US EPA National Center for Environmental Assessment has developed a methodology to derive acute inhalation toxicity benchmarks, called acute reference exposures (AREs), for noncancer effects. The methodology provides guidance for the derivation of chemical-specific benchmark...

The U. S. Environmental Protection Agency's inhalation RfD methodology: Risk assessment for air toxics

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

Jarabek, A.M.; Menache, M.G.; Overton, J.H. Jr.

1990-10-01

The U.S. Environmental Protection Agency (U.S. EPA) has advocated the establishment of general and scientific guidelines for the evaluation of toxicological data and their use in deriving benchmark values to protect exposed populations from adverse health effects. The Agency's reference dose (RfD) methodology for deriving benchmark values for noncancer toxicity originally addressed risk assessment of oral exposures. This paper presents a brief background on the development of the inhalation reference dose (RfDi) methodology, including concepts and issues related to addressing the dynamics of the respiratory system as the portal of entry. Different dosimetric adjustments are described that were incorporated intomore » the methodology to account for the nature of the inhaled agent (particle or gas) and the site of the observed toxic effects (respiratory or extra-respiratory). Impacts of these adjustments on the extrapolation of toxicity data of inhaled agents for human health risk assessment and future research directions are also discussed.« less

U. S. Environmental Protection Agency's inhalation RFD methodology: Risk assessment for air toxics

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

Jarabek, A.M.; Menache, M.G.; Overton, J.H.

1989-01-01

The U.S. Environmental Protection Agency (U.S. EPA) has advocated the establishment of general and scientific guidelines for the evaluation of toxicological data and their use in deriving benchmark values to protect exposed populations from adverse health effects. The Agency's reference dose (RfD) methodology for deriving benchmark values for noncancer toxicity originally addressed risk assessment of oral exposures. The paper presents a brief background on the development of the inhalation reference dose (RFDi) methodology, including concepts and issues related to addressing the dynamics of the respiratory system as the portal of entry. Different dosimetric adjustments are described that were incorporated intomore » the methodology to account for the nature of the inhaled agent (particle or gas) and the site of the observed toxic effects (respiratory or extrarespiratory). Impacts of these adjustments on the extrapolation of toxicity data of inhaled agents for human health risk assessment and future research directions are also discussed.« less

Human health risk assessment database, "the NHSRC toxicity value database": supporting the risk assessment process at US EPA's National Homeland Security Research Center.

PubMed

Moudgal, Chandrika J; Garrahan, Kevin; Brady-Roberts, Eletha; Gavrelis, Naida; Arbogast, Michelle; Dun, Sarah

2008-11-15

The toxicity value database of the United States Environmental Protection Agency's (EPA) National Homeland Security Research Center has been in development since 2004. The toxicity value database includes a compilation of agent property, toxicity, dose-response, and health effects data for 96 agents: 84 chemical and radiological agents and 12 biotoxins. The database is populated with multiple toxicity benchmark values and agent property information from secondary sources, with web links to the secondary sources, where available. A selected set of primary literature citations and associated dose-response data are also included. The toxicity value database offers a powerful means to quickly and efficiently gather pertinent toxicity and dose-response data for a number of agents that are of concern to the nation's security. This database, in conjunction with other tools, will play an important role in understanding human health risks, and will provide a means for risk assessors and managers to make quick and informed decisions on the potential health risks and determine appropriate responses (e.g., cleanup) to agent release. A final, stand alone MS ACESSS working version of the toxicity value database was completed in November, 2007.

EPA Presentation Regarding the Advanced Light-Duty Powertrain and Hybrid Analysis (ALPHA) Tool

EPA Pesticide Factsheets

This page contains a selection of the presentations that EPA has publicly presented about our work on the Midterm Evaluation (MTE). It highlights EPA's benchmarking and modeling activities relating to light duty greenhouse gas (GHG) emissions.

75 FR 60112 - SFIREG Full Committee; Notice of Public Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-29

... to pesticides, and insight into EPA's decision-making process. You are invited and encouraged to... benchmarks. 2. EPA use of monitoring data vs. use of modeling outputs in registration review process. 3... ENVIRONMENTAL PROTECTION AGENCY [EPA-HQ-OPP-2010-0001; FRL-8847-2] SFIREG Full Committee; Notice...

EPA Corporate GHG Goal Evaluation Model

EPA Pesticide Factsheets

The EPA Corporate GHG Goal Evaluation Model provides companies with a transparent and publicly available benchmarking resource to help evaluate and establish new or existing GHG goals that go beyond business as usual for their individual sectors.

[Benchmarking in ambulatory care practices--The European Practice Assessment (EPA)].

PubMed

Szecsenyi, Joachim; Broge, Björn; Willms, Sara; Brodowski, Marc; Götz, Katja

2011-01-01

The European Practice Assessment (EPA) is a comprehensive quality management which consists of 220 indicators covering 5 domains (infrastructure, people, information, finance, and quality and safety). The aim of the project presented was to evaluate EPA as an instrument for benchmarking in ambulatory care practices. A before-and-after design with a comparison group was chosen. One hundred and two practices conducted EPA at baseline (t1) and at the 3-year follow-up (t2). A further 209 practices began EPA at t2 (comparison group). Since both practice groups differed in several variables (age of GP, location and size of practice), a matched-pair design based on propensity scores was applied leading to a subgroup of 102 comparable practices (out of the 209 practices). Data analysis was carried out using Z scores of the EPA domains. The results showed significant improvements in all domains between t1 and t2 as well as between the comparison group and t2. Furthermore, the results demonstrate that the implementation of total quality management and the re-assessment of the EPA procedure can lead to significant improvements in almost all domains. Copyright © 2011. Published by Elsevier GmbH.

BENCHMARK DOSE TECHNICAL GUIDANCE DOCUMENT ...

EPA Pesticide Factsheets

The purpose of this document is to provide guidance for the Agency on the application of the benchmark dose approach in determining the point of departure (POD) for health effects data, whether a linear or nonlinear low dose extrapolation is used. The guidance includes discussion on computation of benchmark doses and benchmark concentrations (BMDs and BMCs) and their lower confidence limits, data requirements, dose-response analysis, and reporting requirements. This guidance is based on today's knowledge and understanding, and on experience gained in using this approach.

Benchmarking and Hardware-In-The-Loop Operation of a ...

EPA Pesticide Factsheets

Engine Performance evaluation in support of LD MTE. EPA used elements of its ALPHA model to apply hardware-in-the-loop (HIL) controls to the SKYACTIV engine test setup to better understand how the engine would operate in a chassis test after combined with future leading edge technologies, advanced high-efficiency transmission, reduced mass, and reduced roadload. Predict future vehicle performance with Atkinson engine. As part of its technology assessment for the upcoming midterm evaluation of the 2017-2025 LD vehicle GHG emissions regulation, EPA has been benchmarking engines and transmissions to generate inputs for use in its ALPHA model

CRYPTOSPORIDIUM OOCYST RECOVERY IN WATER BY EPA METHOD 1623: EVALUATION OF A MODIFIED IMS DISSOCIATION

EPA Science Inventory

EPA Methods 1622 and 1623 are the benchmarks for detection of Cryptosporidium spp. oocysts in water. These methods consist of filtration, elution, purification by immunomagnetic separation (IMS), and microscopic analysis after staining with a fluorescein isothiocyanate conjugate...

A Field-Based Aquatic Life Benchmark for Conductivity in Central Appalachian Streams (Final Report)

EPA Science Inventory

EPA announced the availability of the final report, A Field-Based Aquatic Life Benchmark for Conductivity in Central Appalachian Streams. This report describes a method to characterize the relationship between the extirpation (the effective extinction) of invertebrate g...

Source-term development for a contaminant plume for use by multimedia risk assessment models

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

Whelan, Gene; McDonald, John P.; Taira, Randal Y.

1999-12-01

Multimedia modelers from the U.S. Environmental Protection Agency (EPA) and the U.S. Department of Energy (DOE) are collaborating to conduct a comprehensive and quantitative benchmarking analysis of four intermedia models: DOE's Multimedia Environmental Pollutant Assessment System (MEPAS), EPA's MMSOILS, EPA's PRESTO, and DOE's RESidual RADioactivity (RESRAD). These models represent typical analytically, semi-analytically, and empirically based tools that are utilized in human risk and endangerment assessments for use at installations containing radioactive and/or hazardous contaminants. Although the benchmarking exercise traditionally emphasizes the application and comparison of these models, the establishment of a Conceptual Site Model (CSM) should be viewed with equalmore » importance. This paper reviews an approach for developing a CSM of an existing, real-world, Sr-90 plume at DOE's Hanford installation in Richland, Washington, for use in a multimedia-based benchmarking exercise bet ween MEPAS, MMSOILS, PRESTO, and RESRAD. In an unconventional move for analytically based modeling, the benchmarking exercise will begin with the plume as the source of contamination. The source and release mechanism are developed and described within the context of performing a preliminary risk assessment utilizing these analytical models. By beginning with the plume as the source term, this paper reviews a typical process and procedure an analyst would follow in developing a CSM for use in a preliminary assessment using this class of analytical tool.« less

75 FR 29339 - Science Advisory Board Staff Office; Notification of a Public Meeting of the SAB Panel for the...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-25

... ENVIRONMENTAL PROTECTION AGENCY [FRL-9154-7] Science Advisory Board Staff Office; Notification of... Aquatic Ecosystems and Aquatic Life Benchmark for Conductivity AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: The EPA Science Advisory Board (SAB) Staff Office announces a public...

Supporting Documentation Used in the Derivation of Selected Freshwater Tier 2 ESBs

EPA Science Inventory

Compilation of toxicity data used to derive secondary chronic values (SCVs) and tier 2 equilibrium partitioning sediment benchmarks (ESBs) for a selection of nonionic organic chemicals. The values are used in the following U.S. EPA document: U.S. EPA. 2008. Procedures for th...

EVALUATION OF CRYPTOSPORIDIUM OOCYST RECOVERY IN WATER BY EPA METHOD 1623 WITH A MODIFIED IMS DISSOCIATION PROCEDURE.

EPA Science Inventory

EPA Methods 1622 and 1623 are the benchmarks for detection of Cryptosporidium spp. oocysts in water. 5-7 These methods consist of filtration, elution, purification by immunomagnetic separation (IMS), and microscopic analysis after staining with a fluorescein isothiocyanate conju...

A Field-Based Aquatic Life Benchmark for Conductivity in ...

EPA Pesticide Factsheets

EPA announced the availability of the final report, A Field-Based Aquatic Life Benchmark for Conductivity in Central Appalachian Streams. This report describes a method to characterize the relationship between the extirpation (the effective extinction) of invertebrate genera and salinity (measured as conductivity) and from that relationship derives a freshwater aquatic life benchmark. This benchmark of 300 µS/cm may be applied to waters in Appalachian streams that are dominated by calcium and magnesium salts of sulfate and bicarbonate at circum-neutral to mildly alkaline pH. This report provides scientific evidence for a conductivity benchmark in a specific region rather than for the entire United States.

A Field-Based Aquatic Life Benchmark for Conductivity in Central Appalachian Streams (2010) (External Review Draft)

EPA Science Inventory

This report adapts the standard U.S. EPA methodology for deriving ambient water quality criteria. Rather than use toxicity test results, the adaptation uses field data to determine the loss of 5% of genera from streams. The method is applied to derive effect benchmarks for disso...

BENCHMARK DOSES FOR CHEMICAL MIXTURES: EVALUATION OF A MIXTURE OF 18 PHAHS.

EPA Science Inventory

Benchmark doses (BMDs), defined as doses of a substance that are expected to result in a pre-specified level of "benchmark" response (BMR), have been used for quantifying the risk associated with exposure to environmental hazards. The lower confidence limit of the BMD is used as...

USE OF CATEGORICAL REGRESSION IN THE DEFINITION OF THE DURATION/CONCENTRATION CURVE IN THE U.S. EPA'S ACUTE REFEFENCE EXPOSURE (ARE) METHODOLOGY

EPA Science Inventory

The U.S. EPA's current draft ARE methodology offers three different approaches for derivation of health effects values for various chemicals and agents under inhalation exposure scenarios of < 24 hrs. These approaches, the NOAEL, benchmark concentration (BMC), and categorical ...

Estimating human-equivalent no observed adverse-effect levels for VOCs (volatile organic compounds) based on minimal knowledge of physiological parameters. Technical paper

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

Overton, J.H.; Jarabek, A.M.

1989-01-01

The U.S. EPA advocates the assessment of health-effects data and calculation of inhaled reference doses as benchmark values for gauging systemic toxicity to inhaled gases. The assessment often requires an inter- or intra-species dose extrapolation from no observed adverse effect level (NOAEL) exposure concentrations in animals to human equivalent NOAEL exposure concentrations. To achieve this, a dosimetric extrapolation procedure was developed based on the form or type of equations that describe the uptake and disposition of inhaled volatile organic compounds (VOCs) in physiologically-based pharmacokinetic (PB-PK) models. The procedure assumes allometric scaling of most physiological parameters and that the value ofmore » the time-integrated human arterial-blood concentration must be limited to no more than to that of experimental animals. The scaling assumption replaces the need for most parameter values and allows the derivation of a simple formula for dose extrapolation of VOCs that gives equivalent or more-conservative exposure concentrations values than those that would be obtained using a PB-PK model in which scaling was assumed.« less

Children's Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making.

PubMed

Zartarian, Valerie; Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-09-12

Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)'s National Drinking Water Advisory Council (NDWAC) recommended establishment of a "health-based, household action level" for lead in drinking water based on children's exposure. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine what drinking water lead concentrations keep children's blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. A modeling approach using the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Modeled BLLs compared well with nationally representative BLLs (0-23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605.

75 FR 51058 - The Effects of Mountaintop Mines and Valley Fills on Aquatic Ecosystems of the Central...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

... the public additional time to evaluate the data used to derive a benchmark for conductivity. The... FR 18499). By following the link below, reviewers may download the initial data and EPA's derivative data sets that were used to calculate the conductivity benchmark. These reports were developed by the...

A Field-Based Aquatic Life Benchmark for Conductivity in ...

EPA Pesticide Factsheets

This report adapts the standard U.S. EPA methodology for deriving ambient water quality criteria. Rather than use toxicity test results, the adaptation uses field data to determine the loss of 5% of genera from streams. The method is applied to derive effect benchmarks for dissolved salts as measured by conductivity in Central Appalachian streams using data from West Virginia and Kentucky. This report provides scientific evidence for a conductivity benchmark in a specific region rather than for the entire United States.

Nonparametric estimation of benchmark doses in environmental risk assessment

PubMed Central

Piegorsch, Walter W.; Xiong, Hui; Bhattacharya, Rabi N.; Lin, Lizhen

2013-01-01

Summary An important statistical objective in environmental risk analysis is estimation of minimum exposure levels, called benchmark doses (BMDs), that induce a pre-specified benchmark response in a dose-response experiment. In such settings, representations of the risk are traditionally based on a parametric dose-response model. It is a well-known concern, however, that if the chosen parametric form is misspecified, inaccurate and possibly unsafe low-dose inferences can result. We apply a nonparametric approach for calculating benchmark doses, based on an isotonic regression method for dose-response estimation with quantal-response data (Bhattacharya and Kong, 2007). We determine the large-sample properties of the estimator, develop bootstrap-based confidence limits on the BMDs, and explore the confidence limits’ small-sample properties via a short simulation study. An example from cancer risk assessment illustrates the calculations. PMID:23914133

75 FR 30393 - The Effects of Mountaintop Mines and Valley Fills on Aquatic Ecosystems of the Central...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-01

... opportunity to evaluate the data used to derive a benchmark for conductivity. By following the link below, reviewers may download the initial data and EPA's derivative data sets that were used to calculate the... surface coal mining projects, in coordination with Federal and State regulatory agencies ( http://www.epa...

A MULTIMODEL APPROACH FOR CALCULATING BENCHMARK DOSE

EPA Science Inventory

A Multimodel Approach for Calculating Benchmark Dose
Ramon I. Garcia and R. Woodrow Setzer

In the assessment of dose response, a number of plausible dose- response models may give fits that are consistent with the data. If no dose response formulation had been speci...

Cumulative organophosphate pesticide exposure and risk assessment among pregnant women living in an agricultural community: a case study from the CHAMACOS cohort.

PubMed Central

Castorina, Rosemary; Bradman, Asa; McKone, Thomas E; Barr, Dana B; Harnly, Martha E; Eskenazi, Brenda

2003-01-01

Approximately 230,000 kg of organophosphate (OP) pesticides are applied annually in California's Salinas Valley. These activities have raised concerns about exposures to area residents. We collected three spot urine samples from pregnant women (between 1999 and 2001) enrolled in CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas), a longitudinal birth cohort study, and analyzed them for six dialkyl phosphate metabolites. We used urine from 446 pregnant women to estimate OP pesticide doses with two deterministic steady-state modeling methods: method 1, which assumed the metabolites were attributable entirely to a single diethyl or dimethyl OP pesticide; and method 2, which adapted U.S. Environmental Protection Agency (U.S. EPA) draft guidelines for cumulative risk assessment to estimate dose from a mixture of OP pesticides that share a common mechanism of toxicity. We used pesticide use reporting data for the Salinas Valley to approximate the mixture to which the women were exposed. Based on average OP pesticide dose estimates that assumed exposure to a single OP pesticide (method 1), between 0% and 36.1% of study participants' doses failed to attain a margin of exposure (MOE) of 100 relative to the U.S. EPA oral benchmark dose(10) (BMD(10)), depending on the assumption made about the parent compound. These BMD(10) values are doses expected to produce a 10% reduction in brain cholinesterase activity compared with background response in rats. Given the participants' average cumulative OP pesticide dose estimates (method 2) and regardless of the index chemical selected, we found that 14.8% of the doses failed to attain an MOE of 100 relative to the BMD(10) of the selected index. An uncertainty analysis of the pesticide mixture parameter, which is extrapolated from pesticide application data for the study area and not directly quantified for each individual, suggests that this point estimate could range from 1 to 34%. In future analyses, we will use pesticide-specific urinary metabolites, when available, to evaluate cumulative OP pesticide exposures. PMID:14527844

Development of biomonitoring equivalents for barium in urine and plasma for interpreting human biomonitoring data.

PubMed

Poddalgoda, Devika; Macey, Kristin; Assad, Henry; Krishnan, Kannan

2017-06-01

The objectives of the present work were: (1) to assemble population-level biomonitoring data to identify the concentrations of urinary and plasma barium across the general population; and (2) to derive biomonitoring equivalents (BEs) for barium in urine and plasma in order to facilitate the interpretation of barium concentrations in the biological matrices. In population level biomonitoring studies, barium has been measured in urine in the U.S. (NHANES study), but no such data on plasma barium levels were identified. The BE values for plasma and urine were derived from U.S. EPA's reference dose (RfD) of 0.2 mg/kg bw/d, based on a lower confidence limit on the benchmark dose (BMDL 05 ) of 63 mg/kg bw/d. The plasma BE (9 μg Ba/L) was derived by regression analysis of the near-steady-state plasma concentrations associated with the administered doses in animals exposed to barium chloride dihydrate in drinking water for 2-years in a NTP study. Using a human urinary excretion fraction of 0.023, a BE for urinary barium (0.19 mg/L or 0.25 mg/g creatinine) was derived for US EPA's RfD. The median and the 95 th percentile barium urine concentrations of the general population in U.S. are below the BE determined in this study, indicating that the population exposure to inorganic barium is expected to be below the exposure guidance value of 0.2 mg/kg bw/d. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies.

PubMed

Bays, Harold E; Ballantyne, Christie M; Doyle, Ralph T; Juliano, Rebecca A; Philip, Sephy

2016-09-01

Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved at a dose of 4g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500mg/dL) hypertriglyceridemia. This post-hoc exploratory analysis examined the relationship of icosapent ethyl dose with EPA concentrations in plasma and red blood cells (RBCs) across 3 clinical studies-a phase 1 pharmacokinetic study in healthy adult volunteers and 2 pivotal phase 3 studies (MARINE and ANCHOR) in adult patients with hypertriglyceridemia-and examined the relationship between EPA levels and TG-lowering effects in MARINE and ANCHOR. In all 3 studies, icosapent ethyl produced dose-dependent increases in the concentrations of EPA in plasma and RBCs. In both MARINE and ANCHOR, these dose-dependent EPA increases correlated with the degree of TG level lowering (all P<0.01). In patients with high TG levels (≥200mg/dL) and treated with icosapent ethyl 4g/day, the end-of-treatment plasma and RBC EPA concentrations were >170μg/mL and>70μg/mL, respectively. These studies support icosapent ethyl as producing predictable dose-dependent pharmacokinetics/pharmacodynamics, with TG level lowering dependent upon icosapent ethyl dose and EPA concentrations in plasma and RBCs. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Role of the standard deviation in the estimation of benchmark doses with continuous data.

PubMed

Gaylor, David W; Slikker, William

2004-12-01

For continuous data, risk is defined here as the proportion of animals with values above a large percentile, e.g., the 99th percentile or below the 1st percentile, for the distribution of values among control animals. It is known that reducing the standard deviation of measurements through improved experimental techniques will result in less stringent (higher) doses for the lower confidence limit on the benchmark dose that is estimated to produce a specified risk of animals with abnormal levels for a biological effect. Thus, a somewhat larger (less stringent) lower confidence limit is obtained that may be used as a point of departure for low-dose risk assessment. It is shown in this article that it is important for the benchmark dose to be based primarily on the standard deviation among animals, s(a), apart from the standard deviation of measurement errors, s(m), within animals. If the benchmark dose is incorrectly based on the overall standard deviation among average values for animals, which includes measurement error variation, the benchmark dose will be overestimated and the risk will be underestimated. The bias increases as s(m) increases relative to s(a). The bias is relatively small if s(m) is less than one-third of s(a), a condition achieved in most experimental designs.

Health Physics Society Comments to U.S. Environmental Protection Agency Regulatory Reform Task Force.

PubMed

Ring, Joseph; Tupin, Edward; Elder, Deirdre; Hiatt, Jerry; Sheetz, Michael; Kirner, Nancy; Little, Craig

2018-05-01

The Health Physics Society (HPS) provided comment to the U.S. Environmental Protection Agency (EPA) on options to consider when developing an action plan for President Trump's Executive Order to evaluate regulations for repeal, replacement, or modification. The HPS recommended that the EPA reconsider their adherence to the linear no-threshold (LNT) model for radiation risk calculations and improve several documents by better addressing uncertainties in low-dose, low dose-rate (LDDR) radiation exposure environments. The authors point out that use of the LNT model near background levels cannot provide reliable risk projections, use of the LNT model and collective-dose calculations in some EPA documents is inconsistent with the recommendations of international organizations, and some EPA documents have not been exposed to the public comment rule-making process. To assist in establishing a better scientific basis for the risks of low dose rate and low dose radiation exposure, the EPA should continue to support the "Million Worker Study," led by the National Council on Radiation Protection and Measurement.

Model Uncertainty and Bayesian Model Averaged Benchmark Dose Estimation for Continuous Data

EPA Science Inventory

The benchmark dose (BMD) approach has gained acceptance as a valuable risk assessment tool, but risk assessors still face significant challenges associated with selecting an appropriate BMD/BMDL estimate from the results of a set of acceptable dose-response models. Current approa...

Peer Review for EPA’s Biologically Based Dose-Response (BBDR) Model for Perchlorate

EPA Science Inventory

EPA is developing a regulation for perchlorate in drinking water. As part the regulatory process EPA must develop a Maximum Contaminant Level Goal (MCLG). FDA and EPA scientists developed a biologically based dose-response (BBDR) model to assist in deriving the MCLG. This mode...

WOULD YOU BELIEVE A 20% EXCESS RISK OF CARDIOVASCULAR MORTALITY FOR A 10UG/M3 INCREASE IN FINE PM (FOR PEOPLE 65-99 YEARS OLD) IN PHOENIX, AZ 1995-1997? IF SO, WHAT IS SPECIAL ABOUT PHOENIX? IF NOT, FIND THE ERROR!

EPA Science Inventory

The US EPA National Center for Environmental Assessment has developed a methodology to derive acute inhalation toxicity benchmarks, called acute reference exposures (AREs), for noncancer effects. The methodology provides guidance for the derivation of chemical-specific benchmark...

Safety assessment of EPA-rich triglyceride oil produced from yeast: genotoxicity and 28-day oral toxicity in rats.

PubMed

Belcher, Leigh A; MacKenzie, Susan A; Donner, Maria; Sykes, Greg P; Frame, Steven R; Gillies, Peter J

2011-02-01

The 28-day repeat-dose oral and genetic toxicity of eicosapentaenoic acid triglyceride oil (EPA oil) produced from genetically modified Yarrowia lipolytica yeast were assessed. Groups of rats received 0 (olive oil), 940, 1880, or 2820 mg EPA oil/kg/day, or fish oil (sardine/anchovy source) by oral gavage. Lower total serum cholesterol was seen in all EPA and fish oil groups. Liver weights were increased in the medium and high-dose EPA (male only), and fish oil groups but were considered non-adverse physiologically adaptive responses. Increased thyroid follicular cell hypertrophy was observed in male high-dose EPA and fish oil groups, and was considered to be an adaptive response to high levels of polyunsaturated fatty acids. No adverse test substance-related effects were observed on body weight, nutritional, or other clinical or anatomic pathology parameters. The oil was not mutagenic in the in vitro Ames or mouse lymphoma assay, and was not clastogenic in the in vivo mouse micronucleus test. In conclusion, exposure for 28 days to EPA oil derived from yeast did not produce adverse effects at doses up to 2820 mg/kg/day and was not genotoxic. The safety profile of the EPA oil in these tests was comparable to a commercial fish oil. Copyright © 2010 Elsevier Inc. All rights reserved.

OVERVIEW OF EPA'S HUMAN EXPOSURE AND SOURCE-TO-DOSE MODELING PROGRAM: HEADSUP

EPA Science Inventory

EPA's human exposure and source-to-dose modeling program is designed to provide a scientifically sound approach to understanding how people are actually exposed to pollutants and the magnitude of predicted exposures and dose. The objective of this research project is to develo...

NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

EPA Science Inventory

Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

Dose-response estimation is a critical feature of risk assessment. It can be...

Correlation of Noncancer Benchmark Doses in Short- and Long-Term Rodent Bioassays.

PubMed

Kratchman, Jessica; Wang, Bing; Fox, John; Gray, George

2018-05-01

This study investigated whether, in the absence of chronic noncancer toxicity data, short-term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose-response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best-fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012. Models were then developed at the chemical level using orthogonal regression techniques to predict chronic (two years) noncancer health effect levels using the results of the short-term (three months) toxicity data. The findings indicate that short-term animal studies may reasonably provide a quantitative estimate of a chronic BMD or BMDL. This can allow for faster development of human health toxicity values for risk assessment for chemicals that lack chronic toxicity data. © 2017 Society for Risk Analysis.

APPLICATION OF BENCHMARK DOSE METHODOLOGY TO DATA FROM PRENATAL DEVELOPMENTAL TOXICITY STUDIES

EPA Science Inventory

The benchmark dose (BMD) concept was applied to 246 conventional developmental toxicity datasets from government, industry and commercial laboratories. Five modeling approaches were used, two generic and three specific to developmental toxicity (DT models). BMDs for both quantal ...

Properties of model-averaged BMDLs: a study of model averaging in dichotomous response risk estimation.

PubMed

Wheeler, Matthew W; Bailer, A John

2007-06-01

Model averaging (MA) has been proposed as a method of accounting for model uncertainty in benchmark dose (BMD) estimation. The technique has been used to average BMD dose estimates derived from dichotomous dose-response experiments, microbial dose-response experiments, as well as observational epidemiological studies. While MA is a promising tool for the risk assessor, a previous study suggested that the simple strategy of averaging individual models' BMD lower limits did not yield interval estimators that met nominal coverage levels in certain situations, and this performance was very sensitive to the underlying model space chosen. We present a different, more computationally intensive, approach in which the BMD is estimated using the average dose-response model and the corresponding benchmark dose lower bound (BMDL) is computed by bootstrapping. This method is illustrated with TiO(2) dose-response rat lung cancer data, and then systematically studied through an extensive Monte Carlo simulation. The results of this study suggest that the MA-BMD, estimated using this technique, performs better, in terms of bias and coverage, than the previous MA methodology. Further, the MA-BMDL achieves nominal coverage in most cases, and is superior to picking the "best fitting model" when estimating the benchmark dose. Although these results show utility of MA for benchmark dose risk estimation, they continue to highlight the importance of choosing an adequate model space as well as proper model fit diagnostics.

Alternative Fuels Data Center

Science.gov Websites

technologies and operational practices which increase fuel efficiency and reduce emissions from goods movement . EPA provides partners with performance benchmarking tools, fleet management best practices, technology is working with partners to test and verify advanced technologies and operational practices that save

Modeling Respiratory Toxicity of Authentic Lunar Dust

NASA Technical Reports Server (NTRS)

Santana, Patricia A.; James, John T.; Lam, Chiu-Wing

2010-01-01

The lunar expeditions of the Apollo operations from the 60 s and early 70 s have generated awareness about lunar dust exposures and their implication towards future lunar explorations. Critical analyses on the reports from the Apollo crew members suggest that lunar dust is a mild respiratory and ocular irritant. Currently, NASA s space toxicology group is functioning with the Lunar Airborne Dust Toxicity Assessment Group (LADTAG) and the National Institute for Occupational Safety and Health (NIOSH) to investigate and examine toxic effects to the respiratory system of rats in order to establish permissible exposure levels (PELs) for human exposure to lunar dust. In collaboration with the space toxicology group, LADTAG and NIOSH the goal of the present research is to analyze dose-response curves from rat exposures seven and twenty-eight days after intrapharyngeal instillations, and model the response using BenchMark Dose Software (BMDS) from the Environmental Protection Agency (EPA). Via this analysis, the relative toxicities of three types of Apollo 14 lunar dust samples and two control dust samples, titanium dioxide (TiO2) and quartz will be determined. This will be executed for several toxicity endpoints such as cell counts and biochemical markers in bronchoaveolar lavage fluid (BALF) harvested from the rats.

A novel self-micro-emulsifying delivery system (SMEDS) formulation significantly improves the fasting absorption of EPA and DHA from a single dose of an omega-3 ethyl ester concentrate.

PubMed

Qin, Yan; Nyheim, Hilde; Haram, Else Marie; Moritz, Joseph M; Hustvedt, Svein Olaf

2017-10-16

Absorption of EPA and DHA from Omega-3-acid ethyl ester (EE) concentrate supplements occurs most efficiently when taken in context of a fatty meal; adequate fat intake is required to release bile salts that emulsify and pancreatic enzymes that digest omega-3-containing lipids in the intestine. Current guidelines recommend reduction in fat intake and therefore there is a need to optimize the absorption of Omega-3 in those consuming low-fat or no-fat meals. To this end, BASF has developed an Absorption Acceleration Technology, a novel self-micro-emulsifying delivery system (SMEDS) formulation of highly concentrated Omega-3-acid EE which enables rapid emulsification and microdroplet formation upon entering the aqueous environment of the gut therefore enhances the absorption. Two separate single dose, crossover studies were conducted to determine the relative bioavailability of omega-3-acid EE concentrate, either as a novel SMEDS formulation (PRF-021) or as control, in healthy fasted male and female adults at two dose levels (Study 1 "low dose": 630 mg EPA + DHA in PRF-021 vs. 840 mg EPA + DHA in control; Study 2 "high dose": 1680 mg EPA + DHA in PRF-021 vs. 3360 mg EPA + DHA in control). Blood samples were collected immediately before supplementation and at defined time intervals for 48 h. Plasma concentration of total EPA and DHA were determined for pharmacokinetic analysis, area under the curve (AUC) and maximum observed concentration (C max ) was determined. Total EPA plus DHA absorption from SMEDS formulation PRF-021 were 6.4 and 11.5 times higher compared to control in low- and high-dose studies respectively, determined as the ratio of baseline corrected, dose normalized AUC 0-24h of PRF-021 over that of control. EPA and DHA individually showed differing levels of enhancement: the AUC 0-24h ratio for EPA was 23.8 and 25.7 in low and high dose studies, respectively, and the AUC 0-24h ratio for DHA was 3.6 and 5.6 in low and high dose studies, respectively. C max was also increased for both EPA and DHA 2.7- to 9.2-fold. PRF-021 is a novel SMEDS formulation of Omega-3-acid EE demonstrating a marked improvement in absorption of a single dose of EPA and DHA EE under fasted conditions. This allows adequate absorption of Omega-3 from the supplement without the requirement of a high-fat meal.

Human Health Benchmarks for Pesticides

EPA Pesticide Factsheets

Advanced testing methods now allow pesticides to be detected in water at very low levels. These small amounts of pesticides detected in drinking water or source water for drinking water do not necessarily indicate a health risk. The EPA has developed human health benchmarks for 363 pesticides to enable our partners to better determine whether the detection of a pesticide in drinking water or source waters for drinking water may indicate a potential health risk and to help them prioritize monitoring efforts.The table below includes benchmarks for acute (one-day) and chronic (lifetime) exposures for the most sensitive populations from exposure to pesticides that may be found in surface or ground water sources of drinking water. The table also includes benchmarks for 40 pesticides in drinking water that have the potential for cancer risk. The HHBP table includes pesticide active ingredients for which Health Advisories or enforceable National Primary Drinking Water Regulations (e.g., maximum contaminant levels) have not been developed.

Experimental benchmarking of a Monte Carlo dose simulation code for pediatric CT

NASA Astrophysics Data System (ADS)

Li, Xiang; Samei, Ehsan; Yoshizumi, Terry; Colsher, James G.; Jones, Robert P.; Frush, Donald P.

2007-03-01

In recent years, there has been a desire to reduce CT radiation dose to children because of their susceptibility and prolonged risk for cancer induction. Concerns arise, however, as to the impact of dose reduction on image quality and thus potentially on diagnostic accuracy. To study the dose and image quality relationship, we are developing a simulation code to calculate organ dose in pediatric CT patients. To benchmark this code, a cylindrical phantom was built to represent a pediatric torso, which allows measurements of dose distributions from its center to its periphery. Dose distributions for axial CT scans were measured on a 64-slice multidetector CT (MDCT) scanner (GE Healthcare, Chalfont St. Giles, UK). The same measurements were simulated using a Monte Carlo code (PENELOPE, Universitat de Barcelona) with the applicable CT geometry including bowtie filter. The deviations between simulated and measured dose values were generally within 5%. To our knowledge, this work is one of the first attempts to compare measured radial dose distributions on a cylindrical phantom with Monte Carlo simulated results. It provides a simple and effective method for benchmarking organ dose simulation codes and demonstrates the potential of Monte Carlo simulation for investigating the relationship between dose and image quality for pediatric CT patients.

A Four-step Approach for Evaluation of Dose Additivity

EPA Science Inventory

A four step approach was developed for evaluating toxicity data on a chemical mixture for consistency with dose addition. Following the concepts in the U.S. EPA mixture guidance (EPA 2000), toxicologic interaction for a defined mixture (all components known) is departure from a c...

A Four Step Approach to Evaluate Mixtures for Consistency with Dose Addition

EPA Science Inventory

We developed a four step approach for evaluating chemical mixture data for consistency with dose addition for use in environmental health risk assessment. Following the concepts in the U.S. EPA mixture risk guidance (EPA 2000a,b), toxicological interaction for a defined mixture (...

Revisions to US EPA Superfund Risk and Dose Assessment Models and Guidance - 13403

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

Walker, Stuart A.

2013-07-01

The U.S. Environmental Protection Agency (EPA) Superfund program's six Preliminary Remediation Goal (PRG) and Dose Compliance Concentration (DCC) internet based calculators for risk and dose assessment at Superfund sites are being revised to reflect better science, revisions to existing exposure scenarios and new scenarios, and changes to match up more closely with the EPA chemical regional screening level calculator. A revised version of the 1999 guidance document that provides an overview for the Superfund risk assessment process at radioactively contaminated sites, 'Radiation Risk Assessment At CERCLA Sites: Q and A', is being completed that will reflect Superfund recommended guidance andmore » other technical documents issued over the past 13 years. EPA is also issuing a series of fact sheets in the document 'Superfund Radiation Risk Assessment: A Community Tool-kit'. This presentation would go over those changes that are expected to be finished by this spring. (authors)« less

Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish.

PubMed

Browning, Lucy M; Walker, Celia G; Mander, Adrian P; West, Annette L; Madden, Jackie; Gambell, Joanna M; Young, Stephen; Wang, Laura; Jebb, Susan A; Calder, Philip C

2012-10-01

Estimation of the intake of oily fish at a population level is difficult. The measurement of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in biological samples may provide a useful biomarker of intake. We identified the most appropriate biomarkers for the assessment of habitual oily fish intake and changes in intake by elucidating the dose- and time-dependent response of EPA and DHA incorporation into various biological samples that represent roles in fatty acid transport, function, and storage. This was a double-blind, randomized, controlled intervention trial in 204 men and women that lasted 12 mo. EPA and DHA capsules were provided in a manner to reflect sporadic consumption of oily fish (ie, 1, 2, or 4 times/wk). EPA and DHA were assessed at 9 time points over 12 mo in 9 sample types (red blood cells, mononuclear cells, platelets, buccal cells, adipose tissue, plasma phosphatidylcholine, triglycerides, cholesteryl esters, and nonesterified fatty acids). A dose response (P < 0.05) was observed for EPA and DHA in all pools except for red blood cell EPA (P = 0.057). EPA and DHA measures in plasma phosphatidylcholine and platelets were best for the discrimination between different intakes (P < 0.0001). The rate of incorporation varied between sample types, with the time to maximal incorporation ranging from days (plasma phosphatidylcholine) to months (mononuclear cells) to >12 mo (adipose tissue). Plasma phosphatidylcholine EPA plus DHA was identified as the most suitable biomarker of acute changes in EPA and DHA intake, and platelet and mononuclear cell EPA plus DHA were the most suitable biomarkers of habitual intake.

Benchmarking pediatric cranial CT protocols using a dose tracking software system: a multicenter study.

PubMed

De Bondt, Timo; Mulkens, Tom; Zanca, Federica; Pyfferoen, Lotte; Casselman, Jan W; Parizel, Paul M

2017-02-01

To benchmark regional standard practice for paediatric cranial CT-procedures in terms of radiation dose and acquisition parameters. Paediatric cranial CT-data were retrospectively collected during a 1-year period, in 3 different hospitals of the same country. A dose tracking system was used to automatically gather information. Dose (CTDI and DLP), scan length, amount of retakes and demographic data were stratified by age and clinical indication; appropriate use of child-specific protocols was assessed. In total, 296 paediatric cranial CT-procedures were collected. Although the median dose of each hospital was below national and international diagnostic reference level (DRL) for all age categories, statistically significant (p-value < 0.001) dose differences among hospitals were observed. The hospital with lowest dose levels showed smallest dose variability and used age-stratified protocols for standardizing paediatric head exams. Erroneous selection of adult protocols for children still occurred, mostly in the oldest age-group. Even though all hospitals complied with national and international DRLs, dose tracking and benchmarking showed that further dose optimization and standardization is possible by using age-stratified protocols for paediatric cranial CT. Moreover, having a dose tracking system revealed that adult protocols are still applied for paediatric CT, a practice that must be avoided. • Significant differences were observed in the delivered dose between age-groups and hospitals. • Using age-adapted scanning protocols gives a nearly linear dose increase. • Sharing dose-data can be a trigger for hospitals to reduce dose levels.

Dose specification for hippocampal sparing whole brain radiotherapy (HS WBRT): considerations from the UK HIPPO trial QA programme.

PubMed

Megias, Daniel; Phillips, Mark; Clifton-Hadley, Laura; Harron, Elizabeth; Eaton, David J; Sanghera, Paul; Whitfield, Gillian

2017-03-01

The HIPPO trial is a UK randomized Phase II trial of hippocampal sparing (HS) vs conventional whole-brain radiotherapy after surgical resection or radiosurgery in patients with favourable prognosis with 1-4 brain metastases. Each participating centre completed a planning benchmark case as part of the dedicated radiotherapy trials quality assurance programme (RTQA), promoting the safe and effective delivery of HS intensity-modulated radiotherapy (IMRT) in a multicentre trial setting. Submitted planning benchmark cases were reviewed using visualization for radiotherapy software (VODCA) evaluating plan quality and compliance in relation to the HIPPO radiotherapy planning and delivery guidelines. Comparison of the planning benchmark data highlighted a plan specified using dose to medium as an outlier by comparison with those specified using dose to water. Further evaluation identified that the reported plan statistics for dose to medium were lower as a result of the dose calculated at regions of PTV inclusive of bony cranium being lower relative to brain. Specification of dose to water or medium remains a source of potential ambiguity and it is essential that as part of a multicentre trial, consideration is given to reported differences, particularly in the presence of bone. Evaluation of planning benchmark data as part of an RTQA programme has highlighted an important feature of HS IMRT dosimetry dependent on dose being specified to water or medium, informing the development and undertaking of HS IMRT as part of the HIPPO trial. Advances in knowledge: The potential clinical impact of differences between dose to medium and dose to water are demonstrated for the first time, in the setting of HS whole-brain radiotherapy.

EVALUATION OF A CRYPTOSPORIDIUM INTERNAL STANDARD FOR DETERMINING RECOVERY WITH ENVIRONMENTAL PROTECTION AGENCY METHOD 1623

EPA Science Inventory

The current benchmark method for detecting Cryptosporidium oocysts in water is the U.S. Environmental Protection Agency (U.S. EPA) Method 1623. Studies evaluating this method report that recoveries are highly variable and dependent upon laboratory, water sample, and analyst. Ther...

Benchmarking and Modeling of a Conventional Mid-Size Car Using ALPHA (SAE Paper 2015-01-1140)

EPA Science Inventory

The Advanced Light-Duty Powertrain and Hybrid Analysis (ALPHA) modeling tool was created by EPA to estimate greenhouse gas (GHG) emissions of light-duty vehicles. ALPHA is a physics-based, forward-looking, full vehicle computer simulation capable of analyzing various vehicle type...

Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database.

PubMed

Zargar, Atanaz; Ito, Matthew K

2011-08-01

Dietary fish oil supplements are increasingly used as an alternative to prescription-grade omega-3 fatty acids (P-OM3) for the treatment of hypertriglyceridemia. The content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in these supplement products varies widely and may result in a suboptimal response. The aim of this study was to review marketed fish oil supplements and to develop a reference for clinicians to compare products. The National Library of Medicine Herbal Supplement Database was systematically searched using fish oil, EPA, DHA, and omega-3 fatty acid as search terms. Daily doses needed to achieve the Food and Drug Administration (FDA)-approved dose (RxDose) (3,360 mg of combined EPA and DHA) were calculated from the milligrams of EPA and DHA per serving, and suggested retail prices were used to calculate monthly cost of each product. A "usage criteria" was set to highlight products at the RxDose with a monthly cost of <$50, daily servings <8, daily amount of vitamins A and D less than or equal to the U.S. Dietary Reference Intake upper limit defined as 10,000 and 4,000 IU, respectively, and if the product was U.S. Pharmacopeia verified. A total of 163 products were identified, and 102 nonliquid and liquid products met our entry criteria. The median amount of EPA and DHA per serving in the nonliquid products was 216 mg and 200 mg, respectively, and the median number of servings at the RxDose was 11.2 at a median monthly cost of $63.49. The median amount of EPA (460 mg) and DHA (400 mg) per serving in the liquid products was higher than the nonliquid products. Thus, the median number of servings at the RxDose was only 3.6 teaspoons and the median monthly cost of $13.60. Only 22% of products met our "usage criteria." The amount of EPA and DHA per recommended serving in these products was highly variable. Clinicians should heighten their scrutiny in terms of selection of the appropriate product.

Meeting The Joint Commission's Dose Incident Identification and External Benchmarking Requirements Using the ACR's Dose Index Registry.

PubMed

Bohl, Michael A; Goswami, Roopa; Strassner, Brett; Stanger, Paula

2016-08-01

The purpose of this investigation was to evaluate the potential of using the ACR's Dose Index Registry(®) to meet The Joint Commission's requirements to identify incidents in which the radiation dose index from diagnostic CT examinations exceeded the protocol's expected dose index range. In total, 10,970 records in the Dose Index Registry were statistically analyzed to establish both an upper and lower expected dose index for each protocol. All 2015 studies to date were then retrospectively reviewed to identify examinations whose total examination dose index exceeded the protocol's defined upper threshold. Each dose incident was then logged and reviewed per the new Joint Commission requirements. Facilities may leverage their participation in the ACR's Dose Index Registry to fully meet The Joint Commission's dose incident identification review and external benchmarking requirements. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

A Novel ω-3 Acid Ethyl Ester Formulation Incorporating Advanced Lipid TechnologiesTM (ALT®) Improves Docosahexaenoic Acid and Eicosapentaenoic Acid Bioavailability Compared with Lovaza®.

PubMed

Lopez-Toledano, Miguel A; Thorsteinsson, Thorsteinn; Daak, Ahmed; Maki, Kevin C; Johns, Colleen; Rabinowicz, Adrian L; Sancilio, Frederick D

2017-03-01

The US Food and Drug Administration has approved several highly purified ω-3 fatty acid prescription drugs for the treatment of severe hypertriglyceridemia. These differ in the amounts and forms of docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). This study compared the bioavailability of SC401 (1530 mg EPA-ethyl esters [EEs] and DHA-EEs plus Advanced Lipid Technologies ⁎ [ALT † ], a proprietary lipid-delivery platform to improve absorption), with. Lovaza ‡ (3600 mg ω-3, primarily EPA-EEs and DHA-EEs) under low-fat feeding conditions. This was a Phase I, randomized, open-label, single-dose, 2-way crossover study in healthy participants housed from day -3 to day 2 in each treatment period. Blood samples for pharmacokinetic measurements were collected before and after dosing, and safety profile and tolerability were assessed. In unadjusted analyses, SC401 had 5% lower C max and approximately the same AUC 0-last of EPA + DHA total lipids compared with Lovaza. When adjusted for baseline, SC401 had ~6% higher C max and 18% higher AUC 0-last for EPA + DHA total lipids, and dose- and baseline-adjusted analyses found that SC401 had ~149% higher C max and 178% higher AUC 0-last than Lovaza for EPA + DHA total lipids. The T max was also substantially longer with Lovaza (~10 hours) than with SC401 (~6 hours). These results indicate that SC401, an ω-3 acid EE formulation containing ALT † achieved high bioavailability of EPA and DHA, at a lower dose (1530 mg) than Lovaza (3600 mg), under low-fat feeding conditions. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

ORANGE: a Monte Carlo dose engine for radiotherapy.

PubMed

van der Zee, W; Hogenbirk, A; van der Marck, S C

2005-02-21

This study presents data for the verification of ORANGE, a fast MCNP-based dose engine for radiotherapy treatment planning. In order to verify the new algorithm, it has been benchmarked against DOSXYZ and against measurements. For the benchmarking, first calculations have been done using the ICCR-XIII benchmark. Next, calculations have been done with DOSXYZ and ORANGE in five different phantoms (one homogeneous, two with bone equivalent inserts and two with lung equivalent inserts). The calculations have been done with two mono-energetic photon beams (2 MeV and 6 MeV) and two mono-energetic electron beams (10 MeV and 20 MeV). Comparison of the calculated data (from DOSXYZ and ORANGE) against measurements was possible for a realistic 10 MV photon beam and a realistic 15 MeV electron beam in a homogeneous phantom only. For the comparison of the calculated dose distributions and dose distributions against measurements, the concept of the confidence limit (CL) has been used. This concept reduces the difference between two data sets to a single number, which gives the deviation for 90% of the dose distributions. Using this concept, it was found that ORANGE was always within the statistical bandwidth with DOSXYZ and the measurements. The ICCR-XIII benchmark showed that ORANGE is seven times faster than DOSXYZ, a result comparable with other accelerated Monte Carlo dose systems when no variance reduction is used. As shown for XVMC, using variance reduction techniques has the potential for further acceleration. Using modern computer hardware, this brings the total calculation time for a dose distribution with 1.5% (statistical) accuracy within the clinical range (less then 10 min). This means that ORANGE can be a candidate for a dose engine in radiotherapy treatment planning.

Combination of n-3 polyunsaturated fatty acids reduces atherogenesis in apolipoprotein E-deficient mice by inhibiting macrophage activation.

PubMed

Takashima, Akira; Fukuda, Daiju; Tanaka, Kimie; Higashikuni, Yasutomi; Hirata, Yoichiro; Nishimoto, Sachiko; Yagi, Shusuke; Yamada, Hirotsugu; Soeki, Takeshi; Wakatsuki, Tetsuzo; Taketani, Yutaka; Shimabukuro, Michio; Sata, Masataka

2016-11-01

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are major components of n-3 polyunsaturated fatty acids (n-3 PUFAs) which inhibit atherogenesis, although few studies have examined the effects of the combination of EPA and DHA on atherogenesis. The aim of this study was to investigate whether DHA has additional anti-atherosclerotic effects when combined with EPA. Male 8-week-old apolipoprotein E-deficient (Apoe -/- ) mice were fed a western-type diet supplemented with different amounts of EPA and DHA; EPA (2.5%, w/w), low-dose EPA + DHA (2.5%, w/w), or high-dose EPA + DHA (5%, w/w) for 20 weeks. The control group was fed a western-type diet containing no n-3 PUFA. Histological and gene expression analysis were performed in atherosclerotic lesions in the aorta. To address the mechanisms, RAW264.7 cells were used. All n-3 PUFA treatments significantly attenuated the development and destabilization of atherosclerotic plaques compared with the control. The anti-atherosclerotic effects were enhanced in the high-dose EPA + DHA group (p < 0.001), whereas the pure EPA group and low-dose EPA + DHA group showed similar results. EPA and DHA additively attenuated the expression of inflammatory molecules in RAW264.7 cells stimulated with LPS. DHA or EPA + DHA suppressed LPS-induced toll-like receptor 4 (TLR4) expression in lipid rafts on RAW264.7 cells (p < 0.05). Lipid raft disruption by methyl-β-cyclodextrin suppressed mRNA expression of inflammatory molecules in LPS-stimulated macrophages. n-3 PUFAs suppressed atherogenesis. DHA combined with EPA had additional anti-inflammatory effects and inhibited atherogenesis in Apoe -/- mice. The reduction of TLR4 expression in lipid rafts in macrophages by DHA might be involved in this mechanism, at least partially. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Development of water quality criteria and screening benchmarks for 2,4,6 trinitrotoluene

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

Talmage, S.S.; Opresko, D.M.

1995-12-31

Munitions compounds and their degradation products are present at many Army Ammunition Plant Superfund sites. Neither Water Quality Criteria (WQC) for aquatic organisms nor safe soil levels for terrestrial plants and animals have been developed for munitions compounds including trinitrotoluene (TNT). Data are available for the calculation of an acute WQC for TNT according to US EPA guidelines but are insufficient to calculate a chronic criterion. However, available data can be used to determine a Secondary Chronic Value (SCV) and to determine lowest chronic values for fish and daphnids (used by EPA in the absence of criteria). Based on datamore » from eight genera of aquatic organisms, an acute WOC of 0.566 mg/L was calculated. Using available data, a SCV of 0.137 mg/L was calculated. Lowest chronic values for fish and for daphnids are 0.04 mg/L and 1.03 mg/L, respectively. The lowest concentration that affected the growth of aquatic plants was 1.0 mg/L. For terrestrial animals, data from studies of laboratory animals can be extrapolated to derive screening benchmarks in the same way in which human toxicity values are derived from laboratory animal data. For terrestrial animals, a no-observed-adverse-effect-level (NOAEL) for reproductive effects of 1.60 mg/kg/day was determined from a subchronic laboratory feeding study with rats. By scaling the test NOAEL on the basis of differences in body size, screening benchmarks were calculated for oral intake for selected mammalian wildlife species. Screening benchmarks were also derived for protection of benthic organisms in sediment, for soil invertebrates, and for terrestrial plants.« less

Peer Review for EPA's Biologically Based Dose-Response ...

EPA Pesticide Factsheets

EPA is developing a regulation for perchlorate in drinking water. As part the regulatory process EPA must develop a Maximum Contaminant Level Goal (MCLG). FDA and EPA scientists developed a biologically based dose-response (BBDR) model to assist in deriving the MCLG. This model is designed to determine under what conditions of iodine nutrition and exposure to perchlorate across sensitive lifestages would result in low serum free and total thyroxine (hypothyroxinemia). EPA is undertaking a peer review to provide a focused, objective independent peer evaluation of the draft model and its model results report. EPA is undertaking a peer review to provide a focused, objective independent peer evaluation of the draft model and its model results report. Peer review is an important component of the scientific process. The criticism, suggestions, and new ideas provided by the peer reviewers stimulate creative thought, strengthen the interpretation of the reviewed material, and confer credibility on the product. The peer review objective is to provide advice to EPA on steps that will yield a highly credible scientific product that is supported by the scientific community and a defensible perchlorate MCLG.

Fisk-based criteria to support validation of detection methods for drinking water and air.

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

MacDonell, M.; Bhattacharyya, M.; Finster, M.

2009-02-18

This report was prepared to support the validation of analytical methods for threat contaminants under the U.S. Environmental Protection Agency (EPA) National Homeland Security Research Center (NHSRC) program. It is designed to serve as a resource for certain applications of benchmark and fate information for homeland security threat contaminants. The report identifies risk-based criteria from existing health benchmarks for drinking water and air for potential use as validation targets. The focus is on benchmarks for chronic public exposures. The priority sources are standard EPA concentration limits for drinking water and air, along with oral and inhalation toxicity values. Many contaminantsmore » identified as homeland security threats to drinking water or air would convert to other chemicals within minutes to hours of being released. For this reason, a fate analysis has been performed to identify potential transformation products and removal half-lives in air and water so appropriate forms can be targeted for detection over time. The risk-based criteria presented in this report to frame method validation are expected to be lower than actual operational targets based on realistic exposures following a release. Note that many target criteria provided in this report are taken from available benchmarks without assessing the underlying toxicological details. That is, although the relevance of the chemical form and analogues are evaluated, the toxicological interpretations and extrapolations conducted by the authoring organizations are not. It is also important to emphasize that such targets in the current analysis are not health-based advisory levels to guide homeland security responses. This integrated evaluation of chronic public benchmarks and contaminant fate has identified more than 200 risk-based criteria as method validation targets across numerous contaminants and fate products in drinking water and air combined. The gap in directly applicable values is considerable across the full set of threat contaminants, so preliminary indicators were developed from other well-documented benchmarks to serve as a starting point for validation efforts. By this approach, at least preliminary context is available for water or air, and sometimes both, for all chemicals on the NHSRC list that was provided for this evaluation. This means that a number of concentrations presented in this report represent indirect measures derived from related benchmarks or surrogate chemicals, as described within the many results tables provided in this report.« less

75 FR 47482 - National Oil and Hazardous Substance Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-06

..., groundwater, and soil gas. The PRPs, through their consultants, Benchmark Environmental Engineering and... November 2000 to December 2003 and the final RI report was submitted to EPA in February 2005. The chemicals... boundary located more that 500 feet across the wetland. Site-related chemicals in the overburden...

75 FR 39934 - The Effects of Mountaintop Mines and Valley Fills on Aquatic Ecosystems of the Central...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-13

... additional time to evaluate the data used to derive a benchmark for conductivity. The original Federal... below, reviewers may download the initial data and EPA's derivative data sets that were used to... and other surface coal mining projects, in coordination with federal and state regulatory agencies...

High-energy neutron depth-dose distribution experiment.

PubMed

Ferenci, M S; Hertel, N E

2003-01-01

A unique set of high-energy neutron depth-dose benchmark experiments were performed at the Los Alamos Neutron Science Center/Weapons Neutron Research (LANSCE/WNR) complex. The experiments consisted of filtered neutron beams with energies up to 800 MeV impinging on a 30 x 30 x 30 cm3 liquid, tissue-equivalent phantom. The absorbed dose was measured in the phantom at various depths with tissue-equivalent ion chambers. This experiment is intended to serve as a benchmark experiment for the testing of high-energy radiation transport codes for the international radiation protection community.

Soil ingestion: a concern for acute toxicity in children.

PubMed Central

Calabrese, E J; Stanek, E J; James, R C; Roberts, S M

1997-01-01

Several soil ingestion studies have indicated that some children ingest substantial amounts of soil on given days. Although the EPA has assumed that 95% of children ingest 200 mg soil/day or less for exposure assessment purposes, some children have been observed to ingest up to 25-60 g soil during a single day. In light of the potential for children to ingest such large amounts of soil, an assessment was made of the possibility for soil pica episodes to result in acute intoxication from contaminant concentrations the EPA regards as representing conservative screening values (i.e., EPA soil screening levels and EPA Region III risk-based concentrations for residential soils). For a set of 13 chemicals included in the analysis, contaminant doses resulting from a one-time soil pica episode (5-50 g of soil ingested) were compared with acute dosages shown to produce toxicity in humans in clinical studies or case reports. For four of these chemicals, a soil pica episode was found to result in a contaminant dose approximating or exceeding the acute human lethal dose. For five of the remaining chemicals, the contaminant dose from a soil pica episode was well within the reported dose range in humans for toxicity other than lethality. Because both the exposure episodes and the toxicological response information are derived from observations in humans, these findings are regarded as particularly relevant for human health risk assessment. They suggest that, for some chemicals, ostensibly conservative soil criteria based on chronic exposure using current EPA methodology may not be protective of children during acute soil pica episodes. PMID:9405323

Supplementation with high-dose docosahexaenoic acid increases the Omega-3 Index more than high-dose eicosapentaenoic acid.

PubMed

Allaire, Janie; Harris, William S; Vors, Cécile; Charest, Amélie; Marin, Johanne; Jackson, Kristina Harris; Tchernof, André; Couture, Patrick; Lamarche, Benoît

2017-05-01

Recent studies suggest that eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids have distinct effects on cardiometabolic risk factors. The Omega-3 Index (O3I), which is calculated as the proportion of EPA and DHA in red blood cell (RBC) membranes, has been inversely associated with the risk of coronary heart diseases and coronary mortality. The objective of this study was to compare the effects of EPA and DHA supplementation on the O3I in men and women with abdominal obesity and subclinical inflammation. In a double-blind controlled crossover study, 48 men and 106 women with abdominal obesity and subclinical inflammation were randomized to a sequence of three treatment phases: 1-2.7g/d of EPA, 2-2.7g/d of DHA, and 3-3g/d of corn oil (0g of EPA+DHA). All supplements were provided as 3×1g capsules for a total of 3g/d. The 10-week treatment phases were separated by nine-week washouts. RBC membrane fatty acid composition and O3I were assessed at baseline and the end of each phase. Differences in O3I between treatments were assessed using mixed models for repeated measures. The increase in the O3I after supplementation with DHA (+5.6% compared with control, P<0.0001) was significantly greater than after EPA (+3.3% compared with control, P<0.0001; DHA vs. EPA, P<0.0001). Compared to control, DHA supplementation decreased (-0.8%, P<0.0001) while EPA increased (+2.5%, P<0.0001) proportion of docosapentaenoic acid (DPA) in RBCs (DHA vs. EPA, P<0.0001). The baseline O3I was higher in women than in men (6.3% vs. 5.8%, P=0.011). The difference between DHA and EPA in increasing the O3I tended to be higher in men than in women (+2.6% vs. +2.2% respectively, P for the treatment by sex interaction=0.0537). The increase in the O3I is greater with high dose DHA supplementation than with high dose EPA, which is consistent with the greater potency of DHA to modulate cardiometabolic risk factors. The extent to which such differences between EPA and DHA in increasing the O3I relates to long-term cardiovascular risk needs to be investigated in the future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Optimizing Radiation Doses for Computed Tomography Across Institutions: Dose Auditing and Best Practices.

PubMed

Demb, Joshua; Chu, Philip; Nelson, Thomas; Hall, David; Seibert, Anthony; Lamba, Ramit; Boone, John; Krishnam, Mayil; Cagnon, Christopher; Bostani, Maryam; Gould, Robert; Miglioretti, Diana; Smith-Bindman, Rebecca

2017-06-01

Radiation doses for computed tomography (CT) vary substantially across institutions. To assess the impact of institutional-level audit and collaborative efforts to share best practices on CT radiation doses across 5 University of California (UC) medical centers. In this before/after interventional study, we prospectively collected radiation dose metrics on all diagnostic CT examinations performed between October 1, 2013, and December 31, 2014, at 5 medical centers. Using data from January to March (baseline), we created audit reports detailing the distribution of radiation dose metrics for chest, abdomen, and head CT scans. In April, we shared reports with the medical centers and invited radiology professionals from the centers to a 1.5-day in-person meeting to review reports and share best practices. We calculated changes in mean effective dose 12 weeks before and after the audits and meeting, excluding a 12-week implementation period when medical centers could make changes. We compared proportions of examinations exceeding previously published benchmarks at baseline and following the audit and meeting, and calculated changes in proportion of examinations exceeding benchmarks. Of 158 274 diagnostic CT scans performed in the study period, 29 594 CT scans were performed in the 3 months before and 32 839 CT scans were performed 12 to 24 weeks after the audit and meeting. Reductions in mean effective dose were considerable for chest and abdomen. Mean effective dose for chest CT decreased from 13.2 to 10.7 mSv (18.9% reduction; 95% CI, 18.0%-19.8%). Reductions at individual medical centers ranged from 3.8% to 23.5%. The mean effective dose for abdominal CT decreased from 20.0 to 15.0 mSv (25.0% reduction; 95% CI, 24.3%-25.8%). Reductions at individual medical centers ranged from 10.8% to 34.7%. The number of CT scans that had an effective dose measurement that exceeded benchmarks was reduced considerably by 48% and 54% for chest and abdomen, respectively. After the audit and meeting, head CT doses varied less, although some institutions increased and some decreased mean head CT doses and the proportion above benchmarks. Reviewing institutional doses and sharing dose-optimization best practices resulted in lower radiation doses for chest and abdominal CT and more consistent doses for head CT.

The Pattern of Fatty Acids Displaced by EPA and DHA Following 12 Months Supplementation Varies between Blood Cell and Plasma Fractions.

PubMed

Walker, Celia G; West, Annette L; Browning, Lucy M; Madden, Jackie; Gambell, Joanna M; Jebb, Susan A; Calder, Philip C

2015-08-03

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are increased in plasma lipids and blood cell membranes in response to supplementation. Whilst arachidonic acid (AA) is correspondingly decreased, the effect on other fatty acids (FA) is less well described and there may be site-specific differences. In response to 12 months EPA + DHA supplementation in doses equivalent to 0-4 portions of oily fish/week (1 portion: 3.27 g EPA+DHA) multinomial regression analysis was used to identify important FA changes for plasma phosphatidylcholine (PC), cholesteryl ester (CE) and triglyceride (TAG) and for blood mononuclear cells (MNC), red blood cells (RBC) and platelets (PLAT). Dose-dependent increases in EPA + DHA were matched by decreases in several n-6 polyunsaturated fatty acids (PUFA) in PC, CE, RBC and PLAT, but were predominantly compensated for by oleic acid in TAG. Changes were observed for all FA classes in MNC. Consequently the n-6:n-3 PUFA ratio was reduced in a dose-dependent manner in all pools after 12 months (37%-64% of placebo in the four portions group). We conclude that the profile of the FA decreased in exchange for the increase in EPA + DHA following supplementation differs by FA pool with implications for understanding the impact of n-3 PUFA on blood lipid and blood cell biology.

The Pattern of Fatty Acids Displaced by EPA and DHA Following 12 Months Supplementation Varies between Blood Cell and Plasma Fractions

PubMed Central

Walker, Celia G.; West, Annette L.; Browning, Lucy M.; Madden, Jackie; Gambell, Joanna M.; Jebb, Susan A.; Calder, Philip C.

2015-01-01

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are increased in plasma lipids and blood cell membranes in response to supplementation. Whilst arachidonic acid (AA) is correspondingly decreased, the effect on other fatty acids (FA) is less well described and there may be site-specific differences. In response to 12 months EPA + DHA supplementation in doses equivalent to 0–4 portions of oily fish/week (1 portion: 3.27 g EPA+DHA) multinomial regression analysis was used to identify important FA changes for plasma phosphatidylcholine (PC), cholesteryl ester (CE) and triglyceride (TAG) and for blood mononuclear cells (MNC), red blood cells (RBC) and platelets (PLAT). Dose-dependent increases in EPA + DHA were matched by decreases in several n-6 polyunsaturated fatty acids (PUFA) in PC, CE, RBC and PLAT, but were predominantly compensated for by oleic acid in TAG. Changes were observed for all FA classes in MNC. Consequently the n-6:n-3 PUFA ratio was reduced in a dose-dependent manner in all pools after 12 months (37%–64% of placebo in the four portions group). We conclude that the profile of the FA decreased in exchange for the increase in EPA + DHA following supplementation differs by FA pool with implications for understanding the impact of n-3 PUFA on blood lipid and blood cell biology. PMID:26247960

IRIS Toxicological Review of Ethylene Glycol Mono-Butyl ...

EPA Pesticide Factsheets

EPA has conducted a peer review of the scientific basis supporting the human health hazard and dose-response assessment of ethylene glycol monobutyl ether that will appear on the Integrated Risk Information System (IRIS) database. EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of propionaldehyde that will appear on the Integrated Risk Information System (IRIS) database.

Vehicle Component Benchmarking Using a Chassis Dynamometer: Using a 2013 Chevrolet Malibu and a 2013 Mercedes E350 (SAE Paper 2015-01-0589)

EPA Science Inventory

Light-duty vehicle greenhouse gas (GHG) and fuel economy (FE) standards for MYs 2012 -2025 are requiring vehicle powertrains to become much more efficient. The EPA is using a full vehicle simulation model, called the Advanced Light-duty Powertrain and Hybrid Analysis (ALPHA), to ...

QUANTIFICATION AND INTERPRETATION OF TOTAL PETROLEUM HYDROCARBONS IN SEDIMENT SAMPLES BY A GC/MS METHOD AND COMPARISON WITH EPA 418.1 AND A RAPID FIELD METHOD

EPA Science Inventory

ABSTRACT: Total Petroleum hydrocarbons (TPH) as a lumped parameter can be easily and rapidly measured or monitored. Despite interpretational problems, it has become an accepted regulatory benchmark used widely to evaluate the extent of petroleum product contamination. Three cu...

Benchmarking and Hardware-In-The-Loop Operation of a 2014 MAZDA SkyActiv (SAE 2016-01-1007)

EPA Science Inventory

Engine Performance evaluation in support of LD MTE. EPA used elements of its ALPHA model to apply hardware-in-the-loop (HIL) controls to the SKYACTIV engine test setup to better understand how the engine would operate in a chassis test after combined with future leading edge tech...

Increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long-chain omega-3 PUFA.

PubMed

Schuchardt, Jan Philipp; Schneider, Inga; Willenberg, Ina; Yang, Jun; Hammock, Bruce D; Hahn, Andreas; Schebb, Nils Helge

2014-06-01

Several supplementation studies with long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) describe an increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acids in blood, while changes in levels of other LC n-3 and n-6 PUFA-derived oxylipins were minor. In order to investigate the kinetics of changes in oxylipin levels in response to LC n-3 PUFA ingestion, we conducted a single dose treatment study with healthy subjects. In the present kinetic study, we compared patterns of hydroxy, epoxy and dihydroxy fatty acids in plasma of 6 healthy men before and after 6, 8, 24, and 48h of fish oil (1008mg EPA and 672mg DHA) ingestion. Levels of EPA- as well as other LC PUFA-derived hydroxy, epoxy and dihydroxy fatty acids were analyzed in plasma by LC-MS. Additionally, levels of these oxylipins were compared with their parent PUFA levels in plasma phospholipids. All EPA-derived oxylipin levels were significantly increased 6h after LC n-3 PUFA ingestion and gradually drop thereafter reaching the baseline levels about 48h after treatment. The relative increase in EPA plasma phospholipid levels highly correlated with the increase of plasma EPA-derived oxylipin levels at different time points. In contrast, plasma levels of arachidonic acid- and DHA-derived oxylipins as well as parent PUFA levels in plasma phospholipids were hardly changed. Our findings demonstrate that a single dose of LC n-3 PUFAs can rapidly induce a shift in the EPA oxylipin profile of healthy subjects within a few hours. Taking the high biological activity of the EPA-derived epoxy fatty acids into account, even short-term treatment with LC n-3 PUFAs may cause systemic effects, which warrant further investigation. Copyright © 2014 Elsevier Inc. All rights reserved.

APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION

EPA Science Inventory

APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION.
Evans, M.V1., Power, F.W2., Dary, C.C2., Tornero-Velez, R2., and Blancato, J.N2.
1 NHEERL, US EPA, ORD, ETD, RTP, NC; 2 NERL, US EPA, ORD, EDRB, LV, NV
Re...

Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat

EPA Science Inventory

Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat M.F. Hughes1, D.G. Ross1, J.M. Starr1, E.J. Scollon1,2, M.J. Wolansky1,3, K.M. Crofton1, M.J. DeVito1,4 1U.S. EPA, ORD, Research Triangle Park, NC, 2U.S. EPA,...

Benchmarking B-Cell Epitope Prediction with Quantitative Dose-Response Data on Antipeptide Antibodies: Towards Novel Pharmaceutical Product Development

PubMed Central

Caoili, Salvador Eugenio C.

2014-01-01

B-cell epitope prediction can enable novel pharmaceutical product development. However, a mechanistically framed consensus has yet to emerge on benchmarking such prediction, thus presenting an opportunity to establish standards of practice that circumvent epistemic inconsistencies of casting the epitope prediction task as a binary-classification problem. As an alternative to conventional dichotomous qualitative benchmark data, quantitative dose-response data on antibody-mediated biological effects are more meaningful from an information-theoretic perspective in the sense that such effects may be expressed as probabilities (e.g., of functional inhibition by antibody) for which the Shannon information entropy (SIE) can be evaluated as a measure of informativeness. Accordingly, half-maximal biological effects (e.g., at median inhibitory concentrations of antibody) correspond to maximally informative data while undetectable and maximal biological effects correspond to minimally informative data. This applies to benchmarking B-cell epitope prediction for the design of peptide-based immunogens that elicit antipeptide antibodies with functionally relevant cross-reactivity. Presently, the Immune Epitope Database (IEDB) contains relatively few quantitative dose-response data on such cross-reactivity. Only a small fraction of these IEDB data is maximally informative, and many more of them are minimally informative (i.e., with zero SIE). Nevertheless, the numerous qualitative data in IEDB suggest how to overcome the paucity of informative benchmark data. PMID:24949474

Report on the technical review workshop on the reference dose for Aroclor 1016. Held in Washington, DC on May 24-25, 1994

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

NONE

1994-11-01

The report includes information and material from a technical review workshop organized by the U.S. Environmental Protection Agency`s (EPA`s) Risk Assessment Forum for EPA`s Reference Dose/Reference Concentration (RfD/RfC) Work Group. The meeting was held in Washington, DC, at the Barcelo Washington Hotel on May 24-25, 1994. The subject of the technical review was the Integrated Risk Information System (IRIS) RfD entry for Aroclor 1016, a polychlorinated biphenyl (PCB). The expert technical review panel was convened to independently evaluate whether the RfD for Aroclor 1016 is based on a scientifically responsible analysis that represents full consideration of the available data andmore » clean articulation of that analysis in the IRIS RfD entry. EPA also requested panel members to consider four broad options for the Aroclor 1016 RfD as potential recommendations to the RfD/RfC Work Group.« less

SU-E-T-466: Implementation of An Extension Module for Dose Response Models in the TOPAS Monte Carlo Toolkit

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

Ramos-Mendez, J; Faddegon, B; Perl, J

2015-06-15

Purpose: To develop and verify an extension to TOPAS for calculation of dose response models (TCP/NTCP). TOPAS wraps and extends Geant4. Methods: The TOPAS DICOM interface was extended to include structure contours, for subsequent calculation of DVH’s and TCP/NTCP. The following dose response models were implemented: Lyman-Kutcher-Burman (LKB), critical element (CE), population based critical volume (CV), parallel-serials, a sigmoid-based model of Niemierko for NTCP and TCP, and a Poisson-based model for TCP. For verification, results for the parallel-serial and Poisson models, with 6 MV x-ray dose distributions calculated with TOPAS and Pinnacle v9.2, were compared to data from the benchmarkmore » configuration of the AAPM Task Group 166 (TG166). We provide a benchmark configuration suitable for proton therapy along with results for the implementation of the Niemierko, CV and CE models. Results: The maximum difference in DVH calculated with Pinnacle and TOPAS was 2%. Differences between TG166 data and Monte Carlo calculations of up to 4.2%±6.1% were found for the parallel-serial model and up to 1.0%±0.7% for the Poisson model (including the uncertainty due to lack of knowledge of the point spacing in TG166). For CE, CV and Niemierko models, the discrepancies between the Pinnacle and TOPAS results are 74.5%, 34.8% and 52.1% when using 29.7 cGy point spacing, the differences being highly sensitive to dose spacing. On the other hand, with our proposed benchmark configuration, the largest differences were 12.05%±0.38%, 3.74%±1.6%, 1.57%±4.9% and 1.97%±4.6% for the CE, CV, Niemierko and LKB models, respectively. Conclusion: Several dose response models were successfully implemented with the extension module. Reference data was calculated for future benchmarking. Dose response calculated for the different models varied much more widely for the TG166 benchmark than for the proposed benchmark, which had much lower sensitivity to the choice of DVH dose points. This work was supported by National Cancer Institute Grant R01CA140735.« less

Benchmark Credentialing Results for NRG-BR001: The First National Cancer Institute-Sponsored Trial of Stereotactic Body Radiation Therapy for Multiple Metastases

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

Al-Hallaq, Hania A., E-mail: halhallaq@radonc.uchicago.edu; Chmura, Steven J.; Salama, Joseph K.

Purpose: The NRG-BR001 trial is the first National Cancer Institute–sponsored trial to treat multiple (range 2-4) extracranial metastases with stereotactic body radiation therapy. Benchmark credentialing is required to ensure adherence to this complex protocol, in particular, for metastases in close proximity. The present report summarizes the dosimetric results and approval rates. Methods and Materials: The benchmark used anonymized data from a patient with bilateral adrenal metastases, separated by <5 cm of normal tissue. Because the planning target volume (PTV) overlaps with organs at risk (OARs), institutions must use the planning priority guidelines to balance PTV coverage (45 Gy in 3 fractions) againstmore » OAR sparing. Submitted plans were processed by the Imaging and Radiation Oncology Core and assessed by the protocol co-chairs by comparing the doses to targets, OARs, and conformity metrics using nonparametric tests. Results: Of 63 benchmarks submitted through October 2015, 94% were approved, with 51% approved at the first attempt. Most used volumetric arc therapy (VMAT) (78%), a single plan for both PTVs (90%), and prioritized the PTV over the stomach (75%). The median dose to 95% of the volume was 44.8 ± 1.0 Gy and 44.9 ± 1.0 Gy for the right and left PTV, respectively. The median dose to 0.03 cm{sup 3} was 14.2 ± 2.2 Gy to the spinal cord and 46.5 ± 3.1 Gy to the stomach. Plans that spared the stomach significantly reduced the dose to the left PTV and stomach. Conformity metrics were significantly better for single plans that simultaneously treated both PTVs with VMAT, intensity modulated radiation therapy, or 3-dimensional conformal radiation therapy compared with separate plans. No significant differences existed in the dose at 2 cm from the PTVs. Conclusions: Although most plans used VMAT, the range of conformity and dose falloff was large. The decision to prioritize either OARs or PTV coverage varied considerably, suggesting that the toxicity outcomes in the trial could be affected. Several benchmarks met the dose-volume histogram metrics but produced unacceptable plans owing to low conformity. Dissemination of a frequently-asked-questions document improved the approval rate at the first attempt. Benchmark credentialing was found to be a valuable tool for educating institutions about the protocol requirements.« less

Benchmark Credentialing Results for NRG-BR001: The First National Cancer Institute-Sponsored Trial of Stereotactic Body Radiation Therapy for Multiple Metastases.

PubMed

Al-Hallaq, Hania A; Chmura, Steven J; Salama, Joseph K; Lowenstein, Jessica R; McNulty, Susan; Galvin, James M; Followill, David S; Robinson, Clifford G; Pisansky, Thomas M; Winter, Kathryn A; White, Julia R; Xiao, Ying; Matuszak, Martha M

2017-01-01

The NRG-BR001 trial is the first National Cancer Institute-sponsored trial to treat multiple (range 2-4) extracranial metastases with stereotactic body radiation therapy. Benchmark credentialing is required to ensure adherence to this complex protocol, in particular, for metastases in close proximity. The present report summarizes the dosimetric results and approval rates. The benchmark used anonymized data from a patient with bilateral adrenal metastases, separated by <5 cm of normal tissue. Because the planning target volume (PTV) overlaps with organs at risk (OARs), institutions must use the planning priority guidelines to balance PTV coverage (45 Gy in 3 fractions) against OAR sparing. Submitted plans were processed by the Imaging and Radiation Oncology Core and assessed by the protocol co-chairs by comparing the doses to targets, OARs, and conformity metrics using nonparametric tests. Of 63 benchmarks submitted through October 2015, 94% were approved, with 51% approved at the first attempt. Most used volumetric arc therapy (VMAT) (78%), a single plan for both PTVs (90%), and prioritized the PTV over the stomach (75%). The median dose to 95% of the volume was 44.8 ± 1.0 Gy and 44.9 ± 1.0 Gy for the right and left PTV, respectively. The median dose to 0.03 cm 3 was 14.2 ± 2.2 Gy to the spinal cord and 46.5 ± 3.1 Gy to the stomach. Plans that spared the stomach significantly reduced the dose to the left PTV and stomach. Conformity metrics were significantly better for single plans that simultaneously treated both PTVs with VMAT, intensity modulated radiation therapy, or 3-dimensional conformal radiation therapy compared with separate plans. No significant differences existed in the dose at 2 cm from the PTVs. Although most plans used VMAT, the range of conformity and dose falloff was large. The decision to prioritize either OARs or PTV coverage varied considerably, suggesting that the toxicity outcomes in the trial could be affected. Several benchmarks met the dose-volume histogram metrics but produced unacceptable plans owing to low conformity. Dissemination of a frequently-asked-questions document improved the approval rate at the first attempt. Benchmark credentialing was found to be a valuable tool for educating institutions about the protocol requirements. Copyright © 2016 Elsevier Inc. All rights reserved.

Dose Comparisons for a Site-specific Representative Person Using the Age-dependent Dose Coefficients in CAP88-PC Version 4.

PubMed

Stagich, Brooke H; Moore, Kelsey R; Newton, Joseph R; Dixon, Kenneth L; Jannik, G Timothy

2017-04-01

Most U.S. Department of Energy (DOE) facilities with radiological airborne releases use the U.S. Environmental Protection Agency's (EPA) environmental dosimetry code CAP88-PC to demonstrate compliance with regulations in 40CFR61, subpart H [National Emission Standards for Hazardous Air Pollutants: Radiological (NESHAP)]. In 2015, EPA released Version 4 of CAP88-PC, which included significant modifications that improved usability and age-dependent dose coefficients and usage factors for six age groups (infant, 1 y, 5 y, 10 y, 15 y, and adult). However, EPA has not yet provided specific guidance on how to use these age-dependent factors. For demonstrating compliance with DOE public dose regulations, the Savannah River Site (SRS) recently changed from using the maximally exposed individual (MEI) concept (adult male) to the representative person concept (age- and gender-averaged reference person). In this study, dose comparisons are provided between the MEI and a SRS-specific representative person using the age-specific dose coefficients and usage factors in CAP88-PC V.4. Dose comparisons also are provided for each of the six age groups using five radionuclides of interest at SRS (tritium oxide, Cs, Sr, Pu, and I). In general, the total effective dose increases about 11% for the representative person as compared to the current NESHAP MEI because of the inclusion of the more radiosensitive age groups.

Reevaluation of health risk benchmark for sustainable water practice through risk analysis of rooftop-harvested rainwater.

PubMed

Lim, Keah-Ying; Jiang, Sunny C

2013-12-15

Health risk concerns associated with household use of rooftop-harvested rainwater (HRW) constitute one of the main impediments to exploit the benefits of rainwater harvesting in the United States. However, the benchmark based on the U.S. EPA acceptable annual infection risk level of ≤1 case per 10,000 persons per year (≤10(-4) pppy) developed to aid drinking water regulations may be unnecessarily stringent for sustainable water practice. In this study, we challenge the current risk benchmark by quantifying the potential microbial risk associated with consumption of HRW-irrigated home produce and comparing it against the current risk benchmark. Microbial pathogen data for HRW and exposure rates reported in literature are applied to assess the potential microbial risk posed to household consumers of their homegrown produce. A Quantitative Microbial Risk Assessment (QMRA) model based on worst-case scenario (e.g. overhead irrigation, no pathogen inactivation) is applied to three crops that are most popular among home gardeners (lettuce, cucumbers, and tomatoes) and commonly consumed raw. The infection risks of household consumers attributed to consumption of these home produce vary with the type of produce. The lettuce presents the highest risk, which is followed by tomato and cucumber, respectively. Results show that the 95th percentile values of infection risk per intake event of home produce are one to three orders of magnitude (10(-7) to 10(-5)) lower than U.S. EPA risk benchmark (≤10(-4) pppy). However, annual infection risks under the same scenario (multiple intake events in a year) are very likely to exceed the risk benchmark by one order of magnitude in some cases. Estimated 95th percentile values of the annual risk are in the 10(-4) to 10(-3) pppy range, which are still lower than the 10(-3) to 10(-1) pppy risk range of reclaimed water irrigated produce estimated in comparable studies. We further discuss the desirability of HRW for irrigating home produce based on the relative risk of HRW to reclaimed wastewater for irrigation of food crops. The appropriateness of the ≤10(-4) pppy risk benchmark for assessing safety level of HRW-irrigated fresh produce is questioned by considering the assumptions made for the QMRA model. Consequently, the need of an updated approach to assess appropriateness of sustainable water practice for making guidelines and policies is proposed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Benchmark dose analysis via nonparametric regression modeling

PubMed Central

Piegorsch, Walter W.; Xiong, Hui; Bhattacharya, Rabi N.; Lin, Lizhen

2013-01-01

Estimation of benchmark doses (BMDs) in quantitative risk assessment traditionally is based upon parametric dose-response modeling. It is a well-known concern, however, that if the chosen parametric model is uncertain and/or misspecified, inaccurate and possibly unsafe low-dose inferences can result. We describe a nonparametric approach for estimating BMDs with quantal-response data based on an isotonic regression method, and also study use of corresponding, nonparametric, bootstrap-based confidence limits for the BMD. We explore the confidence limits’ small-sample properties via a simulation study, and illustrate the calculations with an example from cancer risk assessment. It is seen that this nonparametric approach can provide a useful alternative for BMD estimation when faced with the problem of parametric model uncertainty. PMID:23683057

[Benchmark experiment to verify radiation transport calculations for dosimetry in radiation therapy].

PubMed

Renner, Franziska

2016-09-01

Monte Carlo simulations are regarded as the most accurate method of solving complex problems in the field of dosimetry and radiation transport. In (external) radiation therapy they are increasingly used for the calculation of dose distributions during treatment planning. In comparison to other algorithms for the calculation of dose distributions, Monte Carlo methods have the capability of improving the accuracy of dose calculations - especially under complex circumstances (e.g. consideration of inhomogeneities). However, there is a lack of knowledge of how accurate the results of Monte Carlo calculations are on an absolute basis. A practical verification of the calculations can be performed by direct comparison with the results of a benchmark experiment. This work presents such a benchmark experiment and compares its results (with detailed consideration of measurement uncertainty) with the results of Monte Carlo calculations using the well-established Monte Carlo code EGSnrc. The experiment was designed to have parallels to external beam radiation therapy with respect to the type and energy of the radiation, the materials used and the kind of dose measurement. Because the properties of the beam have to be well known in order to compare the results of the experiment and the simulation on an absolute basis, the benchmark experiment was performed using the research electron accelerator of the Physikalisch-Technische Bundesanstalt (PTB), whose beam was accurately characterized in advance. The benchmark experiment and the corresponding Monte Carlo simulations were carried out for two different types of ionization chambers and the results were compared. Considering the uncertainty, which is about 0.7 % for the experimental values and about 1.0 % for the Monte Carlo simulation, the results of the simulation and the experiment coincide. Copyright © 2015. Published by Elsevier GmbH.

40 CFR 26.1603 - EPA review of proposed human research.

Code of Federal Regulations, 2014 CFR

2014-07-01

... important scientific or policy question that cannot be resolved on the basis of animal data or human... National Academy of Sciences (NAS), entitled “Intentional Human Dosing Studies for EPA Regulatory Purposes...

40 CFR 26.1603 - EPA review of proposed human research.

Code of Federal Regulations, 2013 CFR

2013-07-01

... important scientific or policy question that cannot be resolved on the basis of animal data or human... National Academy of Sciences (NAS), entitled “Intentional Human Dosing Studies for EPA Regulatory Purposes...

IRIS Toxicological Review of Methanol (Non-Cancer) ...

EPA Pesticide Factsheets

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of methanol (non-cancer) that when finalized will appear on the Integrated Risk Information System (IRIS) database. EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of methanol (non-cancer) that will appear in the Integrated Risk Information System (IRIS) database.

Comparative Benchmark Dose Modeling as a Tool to Make the First Estimate of Safe Human Exposure Levels to Lunar Dust

NASA Technical Reports Server (NTRS)

James, John T.; Lam, Chiu-wing; Scully, Robert R.

2013-01-01

Brief exposures of Apollo Astronauts to lunar dust occasionally elicited upper respiratory irritation; however, no limits were ever set for prolonged exposure ot lunar dust. Habitats for exploration, whether mobile of fixed must be designed to limit human exposure to lunar dust to safe levels. We have used a new technique we call Comparative Benchmark Dose Modeling to estimate safe exposure limits for lunar dust collected during the Apollo 14 mission.

Rapid Chemical Exposure and Dose Research

EPA Pesticide Factsheets

EPA evaluates the potential risks of the manufacture and use of thousands of chemicals. To assist with this evaluation, EPA scientists developed a rapid, automated model using off the shelf technology that predicts exposures for thousands of chemicals.

Blue Book: EPA Radiogenic Cancer Risk Models and Projections for the U.S. Population

EPA Pesticide Factsheets

This document presents EPA estimates of cancer incidence and mortality risk coefficients pertaining to low dose exposures to ionizing radiation for the U.S. population, as well as their scientific basis.

A Study of the Differential Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Gene Expression Profiles of Stimulated Thp-1 Macrophages.

PubMed

Allam-Ndoul, Bénédicte; Guénard, Frédéric; Barbier, Olivier; Vohl, Marie-Claude

2017-04-25

Background: An appropriate intake of omega-3 ( n -3) fatty acids (FAs) such as eicosapentaenoic and docosahexaenoic acid (EPA/DHA) from marine sources is known to have anti-inflammatory effects. However, molecular mechanisms underlying their beneficial effects on health are not fully understood. The aim of the present study was to characterize gene expression profiles of THP-1 macrophages, incubated in either EPA or DHA and stimulated with lipopolysaccharide (LPS), a pro-inflammatory agent. Methods: THP-1 macrophages were incubated into 10, 50 and 75 µM of EPA or DHA for 24 h, and 100 nM of LPS was added to the culture media for 18 h. Total mRNA was extracted and gene expression examined by microarray analysis using Illumina Human HT-12 expression beadchips (Illumina). Results: Pathway analysis revealed that EPA and DHA regulate genes involved in cell cycle regulation, apoptosis, immune response and inflammation, oxidative stress and cancer pathways in a differential and dose-dependent manner. Conclusions: EPA and DHA appear to exert differential effects on gene expression in THP-1 macrophages. Specific effects of n -3 FAs on gene expression levels are also dose-dependent.

Using the benchmark dose (BMD) methodology to determine an appropriate reduction of certain ingredients in food products.

PubMed

Bi, Jian

2010-01-01

As the desire to promote health increases, reductions of certain ingredients, for example, sodium, sugar, and fat in food products, are widely requested. However, the reduction is not risk free in sensory and marketing aspects. Over reduction may change the taste and influence the flavor of a product and lead to a decrease in consumer's overall liking or purchase intent for the product. This article uses the benchmark dose (BMD) methodology to determine an appropriate reduction. Calculations of BMD and one-sided lower confidence limit of BMD are illustrated. The article also discusses how to calculate BMD and BMDL for over dispersed binary data in replicated testing based on a corrected beta-binomial model. USEPA Benchmark Dose Software (BMDS) were used and S-Plus programs were developed. The method discussed in the article is originally used to determine an appropriate reduction of certain ingredients, for example, sodium, sugar, and fat in food products, considering both health reason and sensory or marketing risk.

Multiscale benchmarking of drug delivery vectors.

PubMed

Summers, Huw D; Ware, Matthew J; Majithia, Ravish; Meissner, Kenith E; Godin, Biana; Rees, Paul

2016-10-01

Cross-system comparisons of drug delivery vectors are essential to ensure optimal design. An in-vitro experimental protocol is presented that separates the role of the delivery vector from that of its cargo in determining the cell response, thus allowing quantitative comparison of different systems. The technique is validated through benchmarking of the dose-response of human fibroblast cells exposed to the cationic molecule, polyethylene imine (PEI); delivered as a free molecule and as a cargo on the surface of CdSe nanoparticles and Silica microparticles. The exposure metrics are converted to a delivered dose with the transport properties of the different scale systems characterized by a delivery time, τ. The benchmarking highlights an agglomeration of the free PEI molecules into micron sized clusters and identifies the metric determining cell death as the total number of PEI molecules presented to cells, determined by the delivery vector dose and the surface density of the cargo. Copyright © 2016 Elsevier Inc. All rights reserved.

Benchmarking analysis of three multimedia models: RESRAD, MMSOILS, and MEPAS

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

Cheng, J.J.; Faillace, E.R.; Gnanapragasam, E.K.

1995-11-01

Multimedia modelers from the United States Environmental Protection Agency (EPA) and the United States Department of Energy (DOE) collaborated to conduct a comprehensive and quantitative benchmarking analysis of three multimedia models. The three models-RESRAD (DOE), MMSOILS (EPA), and MEPAS (DOE)-represent analytically based tools that are used by the respective agencies for performing human exposure and health risk assessments. The study is performed by individuals who participate directly in the ongoing design, development, and application of the models. A list of physical/chemical/biological processes related to multimedia-based exposure and risk assessment is first presented as a basis for comparing the overall capabilitiesmore » of RESRAD, MMSOILS, and MEPAS. Model design, formulation, and function are then examined by applying the models to a series of hypothetical problems. Major components of the models (e.g., atmospheric, surface water, groundwater) are evaluated separately and then studied as part of an integrated system for the assessment of a multimedia release scenario to determine effects due to linking components of the models. Seven modeling scenarios are used in the conduct of this benchmarking study: (1) direct biosphere exposure, (2) direct release to the air, (3) direct release to the vadose zone, (4) direct release to the saturated zone, (5) direct release to surface water, (6) surface water hydrology, and (7) multimedia release. Study results show that the models differ with respect to (1) environmental processes included (i.e., model features) and (2) the mathematical formulation and assumptions related to the implementation of solutions (i.e., parameterization).« less

Fish oil supplemental dose needed to reach 1g% DHA+EPA in mature milk.

PubMed

Stoutjesdijk, E; Schaafsma, A; Dijck-Brouwer, D A J; Muskiet, F A J

2018-01-01

Erythrocyte (RBC) DHA+EPA is considered optimal at 8g%. Mothers with lifetime high fish intakes exhibiting this status produce milk with about 1g% DHA+EPA. We established DHA+EPA supplemental dosages needed to augment RBC DHA+EPA to 8g% and milk DHA+EPA to 1g%. Pregnant women were randomly allocated to DHA+EPA dosages of: 225+90 (n=9), 450+180 (n=9), 675+270 (n=11) and 900+360 (n=7) mg/day. Samples were collected at 20 and 36 gestational weeks and 4 weeks postpartum. Linear regression revealed needed dosages rounded at 750mg/day to reach 8g% RBC DHA+EPA and 1000mg/day for 1g% milk DHA+EPA. RBC DHA+EPA increment depended on baseline values. There was no effect on milk AA, but milk EPA/AA ratio increased. Women with an RBC DHA+EPA status of 5.5g% need 750 and 1000mg DHA+EPA/day to reach 8g% RBC DHA+EPA at the pregnancy end and 1g% mature milk DHA+EPA, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

Benchmark studies of induced radioactivity produced in LHC materials, Part II: Remanent dose rates.

PubMed

Brugger, M; Khater, H; Mayer, S; Prinz, A; Roesler, S; Ulrici, L; Vincke, H

2005-01-01

A new method to estimate remanent dose rates, to be used with the Monte Carlo code FLUKA, was benchmarked against measurements from an experiment that was performed at the CERN-EU high-energy reference field facility. An extensive collection of samples of different materials were placed downstream of, and laterally to, a copper target, intercepting a positively charged mixed hadron beam with a momentum of 120 GeV c(-1). Emphasis was put on the reduction of uncertainties by taking measures such as careful monitoring of the irradiation parameters, using different instruments to measure dose rates, adopting detailed elemental analyses of the irradiated materials and making detailed simulations of the irradiation experiment. The measured and calculated dose rates are in good agreement.

SU-E-T-148: Benchmarks and Pre-Treatment Reviews: A Study of Quality Assurance Effectiveness

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

Lowenstein, J; Nguyen, H; Roll, J

Purpose: To determine the impact benchmarks and pre-treatment reviews have on improving the quality of submitted clinical trial data. Methods: Benchmarks are used to evaluate a site’s ability to develop a treatment that meets a specific protocol’s treatment guidelines prior to placing their first patient on the protocol. A pre-treatment review is an actual patient placed on the protocol in which the dosimetry and contour volumes are evaluated to be per protocol guidelines prior to allowing the beginning of the treatment. A key component of these QA mechanisms is that sites are provided timely feedback to educate them on howmore » to plan per the protocol and prevent protocol deviations on patients accrued to a protocol. For both benchmarks and pre-treatment reviews a dose volume analysis (DVA) was performed using MIM softwareTM. For pre-treatment reviews a volume contour evaluation was also performed. Results: IROC Houston performed a QA effectiveness analysis of a protocol which required both benchmarks and pre-treatment reviews. In 70 percent of the patient cases submitted, the benchmark played an effective role in assuring that the pre-treatment review of the cases met protocol requirements. The 35 percent of sites failing the benchmark subsequently modified there planning technique to pass the benchmark before being allowed to submit a patient for pre-treatment review. However, in 30 percent of the submitted cases the pre-treatment review failed where the majority (71 percent) failed the DVA. 20 percent of sites submitting patients failed to correct their dose volume discrepancies indicated by the benchmark case. Conclusion: Benchmark cases and pre-treatment reviews can be an effective QA tool to educate sites on protocol guidelines and to minimize deviations. Without the benchmark cases it is possible that 65 percent of the cases undergoing a pre-treatment review would have failed to meet the protocols requirements.Support: U24-CA-180803.« less

Metabolism of uniformly labeled 13C-eicosapentaenoic acid and 13C-arachidonic acid in young and old men.

PubMed

Léveillé, Pauline; Chouinard-Watkins, Raphaël; Windust, Anthony; Lawrence, Peter; Cunnane, Stephen C; Brenna, J Thomas; Plourde, Mélanie

2017-08-01

Background: Plasma eicosapentaenoic acid (EPA) and arachidonic acid (AA) concentrations increase with age. Objective: The aim of this study was to evaluate EPA and AA metabolism in young and old men by using uniformly labeled carbon-13 ( 13 C) fatty acids. Design: Six young (∼25 y old) and 6 old (∼75 y old) healthy men were recruited. Each participant consumed a single oral dose of 35 mg 13 C-EPA and its metabolism was followed in the course of 14 d in the plasma and 28 d in the breath. After the washout period of ≥28 d, the same participants consumed a single oral dose of 50 mg 13 C-AA and its metabolism was followed for 28 d in plasma and breath. Results: There was a time × age interaction for 13 C-EPA ( P time × age = 0.008), and the shape of the postprandial curves was different between young and old men. The 13 C-EPA plasma half-life was ∼2 d for both young and old men ( P = 0.485). The percentage dose recovered of 13 C-EPA per hour as 13 CO 2 and the cumulative β-oxidation of 13 C-EPA did not differ between young and old men. At 7 d, however, old men had a >2.2-fold higher plasma 13 C-DHA concentration synthesized from 13 C-EPA compared with young men ( P age = 0.03). 13 C-AA metabolism was not different between young and old men. The 13 C-AA plasma half-life was ∼4.4 d in both young and old participants ( P = 0.589). Conclusions: The metabolism of 13 C-AA was not modified by age, whereas 13 C-EPA metabolism was slightly but significantly different in old compared with young men. The higher plasma 13 C-DHA seen in old men may be a result of slower plasma DHA clearance with age. This trial was registered at clinicaltrials.gov as NCT02957188. © 2017 American Society for Nutrition.

APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)

EPA Science Inventory

Route-to-route extrapolations are a crucial step in many risk assessments. Often the doses which result In toxicological end points in one route must be compared with doses resulting from typical environmental exposures by another route. In this case we used EPA's Dose Estimati...

Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Fetal Pulmonary Circulation: An Experimental Study in Fetal Lambs

PubMed Central

Sharma, Dyuti; Aubry, Estelle; Ouk, Thavarak; Houeijeh, Ali; Houfflin-Debarge, Véronique; Besson, Rémi; Deruelle, Philippe; Storme, Laurent

2017-01-01

Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n-3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep and in fetal pulmonary arterial rings. Methods: At 128 days of gestation, catheters were placed surgically in fetal systemic and pulmonary circulation, and a Doppler probe around the left pulmonary artery (LPA). Pulmonary arterial pressure and LPA flow were measured while infusing EPA or DHA for 120 min to the fetus, to compute pulmonary vascular resistance (PVR). The dose effects of EPA or DHA were studied in vascular rings pre-constricted with serotonin. Rings treated with EPA were separated into three groups: E+ (intact endothelium), E− (endothelium stripped) and LNA E+ (pretreatment of E+ rings with l-nitro-arginine). Results: EPA, but not DHA, induced a significant and prolonged 25% drop in PVR (n = 8, p < 0.001). Incubation of vascular rings with EPA (100 µM) caused a maximum relaxation of 60% in the E+ (n = 6), whereas vessel tone did not change in the E− (n = 6, p < 0.001). The vascular effects of EPA were significantly decreased in LNA E+ (n = 6). Incubation with DHA resulted in only a mild relaxation at the highest concentration of DHA (300 µM) compared to E+. Conclusions: EPA induces a sustained pulmonary vasodilatation in fetal lambs. This effect is endothelium- and dose-dependent and involves nitric oxide (NO) production. We speculate that EPA supplementation may improve pulmonary circulation in clinical conditions with PPHN. PMID:28714905

Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Fetal Pulmonary Circulation: An Experimental Study in Fetal Lambs.

PubMed

Sharma, Dyuti; Aubry, Estelle; Ouk, Thavarak; Houeijeh, Ali; Houfflin-Debarge, Véronique; Besson, Rémi; Deruelle, Philippe; Storme, Laurent

2017-07-16

Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n -3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep and in fetal pulmonary arterial rings. Methods: At 128 days of gestation, catheters were placed surgically in fetal systemic and pulmonary circulation, and a Doppler probe around the left pulmonary artery (LPA). Pulmonary arterial pressure and LPA flow were measured while infusing EPA or DHA for 120 min to the fetus, to compute pulmonary vascular resistance (PVR). The dose effects of EPA or DHA were studied in vascular rings pre-constricted with serotonin. Rings treated with EPA were separated into three groups: E+ (intact endothelium), E- (endothelium stripped) and LNA E+ (pretreatment of E+ rings with l-nitro-arginine). Results: EPA, but not DHA, induced a significant and prolonged 25% drop in PVR ( n = 8, p < 0.001). Incubation of vascular rings with EPA (100 µM) caused a maximum relaxation of 60% in the E+ ( n = 6), whereas vessel tone did not change in the E- ( n = 6, p < 0.001). The vascular effects of EPA were significantly decreased in LNA E+ ( n = 6). Incubation with DHA resulted in only a mild relaxation at the highest concentration of DHA (300 µM) compared to E+. Conclusions: EPA induces a sustained pulmonary vasodilatation in fetal lambs. This effect is endothelium- and dose-dependent and involves nitric oxide (NO) production. We speculate that EPA supplementation may improve pulmonary circulation in clinical conditions with PPHN.

Diagnostic reference levels of paediatric computed tomography examinations performed at a dedicated Australian paediatric hospital.

PubMed

Bibbo, Giovanni; Brown, Scott; Linke, Rebecca

2016-08-01

Diagnostic Reference Levels (DRL) of procedures involving ionizing radiation are important tools to optimizing radiation doses delivered to patients and in identifying cases where the levels of doses are unusually high. This is particularly important for paediatric patients undergoing computed tomography (CT) examinations as these examinations are associated with relatively high-dose. Paediatric CT studies, performed at our institution from January 2010 to March 2014, have been retrospectively analysed to determine the 75th and 95th percentiles of both the volume computed tomography dose index (CTDIvol ) and dose-length product (DLP) for the most commonly performed studies to: establish local diagnostic reference levels for paediatric computed tomography examinations performed at our institution, benchmark our DRL with national and international published paediatric values, and determine the compliance of CT radiographer with established protocols. The derived local 75th percentile DRL have been found to be acceptable when compared with those published by the Australian National Radiation Dose Register and two national children's hospitals, and at the international level with the National Reference Doses for the UK. The 95th percentiles of CTDIvol for the various CT examinations have been found to be acceptable values for the CT scanner Dose-Check Notification. Benchmarking CT radiographers shows that they follow the set protocols for the various examinations without significant variations in the machine setting factors. The derivation of DRL has given us the tool to evaluate and improve the performance of our CT service by improved compliance and a reduction in radiation dose to our paediatric patients. We have also been able to benchmark our performance with similar national and international institutions. © 2016 The Royal Australian and New Zealand College of Radiologists.

IRIS Toxicological Review of Ammonia (External Review Draft ...

EPA Pesticide Factsheets

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of ammonia that will appear in the Integrated Risk Information System (IRIS) database. EPA is undertaking an Integrated Risk Information System (IRIS) health assessment for ammonia. IRIS is an EPA database 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 paradigm, i.e., hazard identification and dose-response evaluation. IRIS assessments are used in combination with specific situational exposure assessment information to evaluate potential public health risk associated with environmental contaminants.

IRIS Toxicological Review of n-Butanol (External Review Draft ...

EPA Pesticide Factsheets

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of n-butanol that will appear in the Integrated Risk Information System (IRIS) database. EPA is undertaking an Integrated Risk Information System (IRIS) health assessment for n-butanol. IRIS is an EPA database 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 paradigm, i.e., hazard identification and dose-response evaluation. IRIS assessments are used in combination with specific situational exposure assessment information to evaluate potential public health risk associated with environmental contaminants.

Barium and Compounds

Integrated Risk Information System (IRIS)

EPA / 635 / R - 05 / 001 www.epa.gov / iris TOXICOLOGICAL REVIEW OF BARIUM AND COMPOUNDS ( CAS No . 7440 - 39 - 3 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) March 1998 Minor revisions January 1999 Reference dose revised June 2005 U.S . Environmental Protec

PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

EPA Science Inventory

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
Dose-response analysis requires quantitatively linking infor...

EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and ...

EPA Pesticide Factsheets

EPA is releasing the draft report, EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments (Volume 1), 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 objective of this report is to respond to the NAS coments on dose-response modeling conducted in the EPA Reassessment of the health effects associated with dioxin exposure.

A Study of the Differential Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Gene Expression Profiles of Stimulated Thp-1 Macrophages

PubMed Central

Allam-Ndoul, Bénédicte; Guénard, Frédéric; Barbier, Olivier; Vohl, Marie-Claude

2017-01-01

Background: An appropriate intake of omega-3 (n-3) fatty acids (FAs) such as eicosapentaenoic and docosahexaenoic acid (EPA/DHA) from marine sources is known to have anti-inflammatory effects. However, molecular mechanisms underlying their beneficial effects on health are not fully understood. The aim of the present study was to characterize gene expression profiles of THP-1 macrophages, incubated in either EPA or DHA and stimulated with lipopolysaccharide (LPS), a pro-inflammatory agent. Methods: THP-1 macrophages were incubated into 10, 50 and 75 µM of EPA or DHA for 24 h, and 100 nM of LPS was added to the culture media for 18 h. Total mRNA was extracted and gene expression examined by microarray analysis using Illumina Human HT-12 expression beadchips (Illumina). Results: Pathway analysis revealed that EPA and DHA regulate genes involved in cell cycle regulation, apoptosis, immune response and inflammation, oxidative stress and cancer pathways in a differential and dose-dependent manner. Conclusions: EPA and DHA appear to exert differential effects on gene expression in THP-1 macrophages. Specific effects of n-3 FAs on gene expression levels are also dose-dependent. PMID:28441337

Concordance of transcriptional and apical benchmark dose levels for conazole-induced liver effects in mice.

PubMed

Bhat, Virunya S; Hester, Susan D; Nesnow, Stephen; Eastmond, David A

2013-11-01

The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time informs mode-of-action determinations and improves quantitative risk assessments. Previous global expression profiling identified a 330-probe cluster differentially expressed and commonly responsive to 3 hepatotumorigenic conazoles (cyproconazole, epoxiconazole, and propiconazole) at 30 days. Extended to 2 more conazoles (triadimefon and myclobutanil), the present assessment encompasses 4 tumorigenic and 1 nontumorigenic conazole. Transcriptional benchmark dose levels (BMDL(T)) were estimated for a subset of the cluster with dose-responsive behavior and a ≥ 5-fold increase or decrease in signal intensity at the highest dose. These genes primarily encompassed CAR/RXR activation, P450 metabolism, liver hypertrophy- glutathione depletion, LPS/IL-1-mediated inhibition of RXR, and NRF2-mediated oxidative stress pathways. Median BMDL(T) estimates from the subset were concordant (within a factor of 2.4) with apical benchmark doses (BMDL(A)) for increased liver weight at 30 days for the 5 conazoles. The 30-day median BMDL(T) estimates were within one-half order of magnitude of the chronic BMDLA for hepatocellular tumors. Potency differences seen in the dose-responsive transcription of certain phase II metabolism, bile acid detoxification, and lipid oxidation genes mirrored each conazole's tumorigenic potency. The 30-day BMDL(T) corresponded to tumorigenic potency on a milligram per kilogram day basis with cyproconazole > epoxiconazole > propiconazole > triadimefon > myclobutanil (nontumorigenic). These results support the utility of measuring short-term gene expression changes to inform quantitative risk assessments from long-term exposures.

APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR ROUTE TO ROUTE DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)

EPA Science Inventory

Route-to-route extrapolations are a crucial step in many risk assessments. Often the doses which result In toxicological end points in one route must be compared with doses resulting from typical environmental exposures by another route. In this case we used EPA's Dose Estimati...

Guidance for Classifying Studies Conducted Using the OECD Test Guideline 223 (TG223) (Acute Avian Oral Sequential Dose Study)

EPA Pesticide Factsheets

Guidance based on comparison of results from the TG223 validation studies to results from avian acute oral studies previously submitted to EPA for two test chemicals following EPA's 850.2100 (public draft) guidelines.

IRIS Toxicological Review of Inorganic Arsenic (Cancer) (2010 External Review Draft)

EPA Science Inventory

EPA's Science Advisory Board (SAB) conducted a review of the scientific basis supporting the human health cancer hazard and dose-response assessment of inorganic arsenic that will appear on the Integrated Risk Information System (IRIS) database. EPA revised the assessment and is...

Benchmark concentrations for methyl mercury obtained from the 9-year follow-up of the Seychelles Child Development Study.

PubMed

van Wijngaarden, Edwin; Beck, Christopher; Shamlaye, Conrad F; Cernichiari, Elsa; Davidson, Philip W; Myers, Gary J; Clarkson, Thomas W

2006-09-01

Methyl mercury (MeHg) is highly toxic to the developing nervous system. Human exposure is mainly from fish consumption since small amounts are present in all fish. Findings of developmental neurotoxicity following high-level prenatal exposure to MeHg raised the question of whether children whose mothers consumed fish contaminated with background levels during pregnancy are at an increased risk of impaired neurological function. Benchmark doses determined from studies in New Zealand, and the Faroese and Seychelles Islands indicate that a level of 4-25 parts per million (ppm) measured in maternal hair may carry a risk to the infant. However, there are numerous sources of uncertainty that could affect the derivation of benchmark doses, and it is crucial to continue to investigate the most appropriate derivation of safe consumption levels. Earlier, we published the findings from benchmark analyses applied to the data collected on the Seychelles main cohort at the 66-month follow-up period. Here, we expand on the main cohort analyses by determining the benchmark doses (BMD) of MeHg level in maternal hair based on 643 Seychellois children for whom 26 different neurobehavioral endpoints were measured at 9 years of age. Dose-response models applied to these continuous endpoints incorporated a variety of covariates and included the k-power model, the Weibull model, and the logistic model. The average 95% lower confidence limit of the BMD (BMDL) across all 26 endpoints varied from 20.1 ppm (range=17.2-22.5) for the logistic model to 20.4 ppm (range=17.9-23.0) for the k-power model. These estimates are somewhat lower than those obtained after 66 months of follow-up. The Seychelles Child Development Study continues to provide a firm scientific basis for the derivation of safe levels of MeHg consumption.

Eicosapentaenoic Acid-Enriched Phosphatidylcholine Attenuated Hepatic Steatosis Through Regulation of Cholesterol Metabolism in Rats with Nonalcoholic Fatty Liver Disease.

PubMed

Liu, Yanjun; Shi, Di; Tian, Yingying; Liu, Yuntao; Zhan, Qiping; Xu, Jie; Wang, Jingfeng; Xue, Changhu

2017-02-01

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Disturbed cholesterol metabolism plays a crucial role in the development of NAFLD. The present study was conducted to evaluate the effects of EPA-PC extracted from sea cucumber on liver steatosis and cholesterol metabolism in NAFLD. Male Wistar rats were randomly divided into seven groups (normal control group, model group, lovastatin group, low- and high-dose EPA groups, and low- and high-dose EPA-PC groups). Model rats were established by administering a diet containing 1% orotic acid. To determine the possible cholesterol metabolism promoting mechanism of EPA-PC, we analyzed the transcription of key genes and transcriptional factors involved in hepatic cholesterol metabolism. EPA-PC dramatically alleviated hepatic lipid accumulation, reduced the serum TC concentration, and elevated HDLC levels in NAFLD rats. Fecal neutral cholesterol excretion was also promoted by EPA-PC administration. Additionally, EPA-PC decreased the mRNA expression of hydroxymethyl glutaric acid acyl (HMGR) and cholesterol 7α-hydroxylase (CYP7A), and increased the transcription of sterol carrying protein 2 (SCP2). Moreover, EPA-PC stimulated the transcription of peroxisome proliferators-activated receptor α (PPARα) and adenosine monophosphate activated protein kinase (AMPK) as well as its modulators, liver kinase B1 (LKB1) and Ca 2+ /calmodulin-dependent kinase kinase (CAMKK). Based on the results, the promoting effects of EPA-PC on NAFLD may be partly associated with the suppression of cholesterol synthesis via HMGR inhibition and the enhancement of fecal cholesterol excretion through increased SCP2 transcription. The underlying mechanism may involve stimulation of PPARα and AMPK.

IRIS Toxicological Review of Tetrahydrofuran (THF) (External ...

EPA Pesticide Factsheets

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of tetrahydrofuran (THF) that when finalized will appear on the Integrated Risk Information System (IRIS) database. EPA is undertaking an Integrated Risk Information System (IRIS) health assessment for tetrahydrofuran. IRIS is an EPA database 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 paradigm, i.e., hazard identification and dose-response evaluation. IRIS assessments are used in combination with specific situational exposure assessment information to evaluate potential public health risk associated with environmental contaminants.

RESRAD for Radiological Risk Assessment. Comparison with EPA CERCLA Tools - PRG and DCC Calculators

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

Yu, C.; Cheng, J. -J.; Kamboj, S.

The purpose of this report is two-fold. First, the risk assessment methodology for both RESRAD and the EPA’s tools is reviewed. This includes a review of the EPA’s justification for 2 using a dose-to-risk conversion factor to reduce the dose-based protective ARAR from 15 to 12 mrem/yr. Second, the models and parameters used in RESRAD and the EPA PRG and DCC Calculators are compared in detail, and the results are summarized and discussed. Although there are suites of software tools in the RESRAD family of codes and the EPA Calculators, the scope of this report is limited to the RESRADmore » (onsite) code for soil contamination and the EPA’s PRG and DCC Calculators also for soil contamination.« less

SU-E-J-30: Benchmark Image-Based TCP Calculation for Evaluation of PTV Margins for Lung SBRT Patients

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

Li, M; Chetty, I; Zhong, H

2014-06-01

Purpose: Tumor control probability (TCP) calculated with accumulated radiation doses may help design appropriate treatment margins. Image registration errors, however, may compromise the calculated TCP. The purpose of this study is to develop benchmark CT images to quantify registration-induced errors in the accumulated doses and their corresponding TCP. Methods: 4DCT images were registered from end-inhale (EI) to end-exhale (EE) using a “demons” algorithm. The demons DVFs were corrected by an FEM model to get realistic deformation fields. The FEM DVFs were used to warp the EI images to create the FEM-simulated images. The two images combined with the FEM DVFmore » formed a benchmark model. Maximum intensity projection (MIP) images, created from the EI and simulated images, were used to develop IMRT plans. Two plans with 3 and 5 mm margins were developed for each patient. With these plans, radiation doses were recalculated on the simulated images and warped back to the EI images using the FEM DVFs to get the accumulated doses. The Elastix software was used to register the FEM-simulated images to the EI images. TCPs calculated with the Elastix-accumulated doses were compared with those generated by the FEM to get the TCP error of the Elastix registrations. Results: For six lung patients, the mean Elastix registration error ranged from 0.93 to 1.98 mm. Their relative dose errors in PTV were between 0.28% and 6.8% for 3mm margin plans, and between 0.29% and 6.3% for 5mm-margin plans. As the PTV margin reduced from 5 to 3 mm, the mean TCP error of the Elastix-reconstructed doses increased from 2.0% to 2.9%, and the mean NTCP errors decreased from 1.2% to 1.1%. Conclusion: Patient-specific benchmark images can be used to evaluate the impact of registration errors on the computed TCPs, and may help select appropriate PTV margins for lung SBRT patients.« less

Evaluation of triclosan in Minnesota lakes and rivers: Part II - human health risk assessment.

PubMed

Yost, Lisa J; Barber, Timothy R; Gentry, P Robinan; Bock, Michael J; Lyndall, Jennifer L; Capdevielle, Marie C; Slezak, Brian P

2017-08-01

Triclosan, an antimicrobial compound found in consumer products, has been detected in low concentrations in Minnesota municipal wastewater treatment plant (WWTP) effluent. This assessment evaluates potential health risks for exposure of adults and children to triclosan in Minnesota surface water, sediments, and fish. Potential exposures via fish consumption are considered for recreational or subsistence-level consumers. This assessment uses two chronic oral toxicity benchmarks, which bracket other available toxicity values. The first benchmark is a lower bound on a benchmark dose associated with a 10% risk (BMDL 10 ) of 47mg per kilogram per day (mg/kg-day) for kidney effects in hamsters. This value was identified as the most sensitive endpoint and species in a review by Rodricks et al. (2010) and is used herein to derive an estimated reference dose (RfD (Rodricks) ) of 0.47mg/kg-day. The second benchmark is a reference dose (RfD) of 0.047mg/kg-day derived from a no observed adverse effect level (NOAEL) of 10mg/kg-day for hepatic and hematopoietic effects in mice (Minnesota Department of Health [MDH] 2014). Based on conservative assumptions regarding human exposures to triclosan, calculated risk estimates are far below levels of concern. These estimates are likely to overestimate risks for potential receptors, particularly because sample locations were generally biased towards known discharges (i.e., WWTP effluent). Copyright © 2017 Elsevier Inc. All rights reserved.

Stochastic Human Exposure and Dose Simulation for Air Toxics

EPA Science Inventory

The Stochastic Human Exposure and Dose Simulation model for Air Toxics (SHEDS-AirToxics) is a multimedia, multipathway population-based exposure and dose model for air toxics developed by the US EPA's National Exposure Research Laboratory (NERL). SHEDS-AirToxics uses a probabili...

U.S. EPA framework for determining mutagenic mode of action for carcinogens

EPA Science Inventory

U.S. EPA's Guidelines for Carcinogen Risk Assessment (Cancer Guidelines) specify that information on a chemical's mode of action (MOA) is key to the risk assessment process. MOA determines conditions under which a chemical is considered to be carcinogenic, appropriate low dose ex...

ASSESSING THE EFFECTS OF DICHLOROACETIC ACID (DCA) USING A MULTI-ENDPOINT MEDAKA ASSAY

EPA Science Inventory

In regulating the safety of water, EPA makes decisions on what chemical contaminants to regulate and at what levels. To make these decisions, the EPA needs hazard identification and dose-response information. Current rodent methods for generating required information have limita...

EPA's SHEDS-multimedia model: children's cumulative pyrethroid exposure estimates and evaluation against NHANES biomarker data

EPA Science Inventory

The U.S. EPA's SHEDS-Multimedia model was applied to enhance the understanding of children's exposures and doses to multiple pyrethroid pesticides, including major contributing chemicals and pathways. This paper presents combined dietary and residential exposure estimates and cum...

Summary of U.S. EPA Dioxin Workshop − Feb 2009

EPA Science Inventory

The U.S. Environmental Protection Agency (U.S. EPA) and Argonne National Laboratories, through an inter-Agency agreement with the U.S. Department of Energy, convened a workshop that identified and addressed issues related to the dose-response assessment of 2,3,7,8-tetrachlorodibe...

The Analysis of Genomic Dose-Response Data in the EPA ToxCast™ Program

EPA Science Inventory

The U.S. EPA must assess the potential adverse effects of thousands of chemicals, often with limited toxicity information. Accurate toxicity predictions will help prioritize chemicals for further testing, focusing resources on the greater potential hazards or risks. In vitro geno...

Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach.

PubMed

Lachenmeier, Dirk W; Rehm, Jürgen

2015-01-30

A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure (MOE) approach was conducted. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dose values ranged from 2 mg/kg bodyweight for heroin to 531 mg/kg bodyweight for alcohol (ethanol). For individual exposure the four substances alcohol, nicotine, cocaine and heroin fall into the "high risk" category with MOE < 10, the rest of the compounds except THC fall into the "risk" category with MOE < 100. On a population scale, only alcohol would fall into the "high risk" category, and cigarette smoking would fall into the "risk" category, while all other agents (opiates, cocaine, amphetamine-type stimulants, ecstasy, and benzodiazepines) had MOEs > 100, and cannabis had a MOE > 10,000. The toxicological MOE approach validates epidemiological and social science-based drug ranking approaches especially in regard to the positions of alcohol and tobacco (high risk) and cannabis (low risk).

Comparative risk assessment of tobacco smoke constituents using the margin of exposure approach: the neglected contribution of nicotine

PubMed Central

Baumung, Claudia; Rehm, Jürgen; Franke, Heike; Lachenmeier, Dirk W.

2016-01-01

Nicotine was not included in previous efforts to identify the most important toxicants of tobacco smoke. A health risk assessment of nicotine for smokers of cigarettes was conducted using the margin of exposure (MOE) approach and results were compared to literature MOEs of various other tobacco toxicants. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Dose-response modelling of human and animal data was used to derive the benchmark dose. The MOE was calculated using probabilistic Monte Carlo simulations for daily cigarette smokers. Benchmark dose values ranged from 0.004 mg/kg bodyweight for symptoms of intoxication in children to 3 mg/kg bodyweight for mortality in animals; MOEs ranged from below 1 up to 7.6 indicating a considerable consumer risk. The dimension of the MOEs is similar to those of other tobacco toxicants with high concerns relating to adverse health effects such as acrolein or formaldehyde. Owing to the lack of toxicological data in particular relating to cancer, long term animal testing studies for nicotine are urgently necessary. There is immediate need of action concerning the risk of nicotine also with regard to electronic cigarettes and smokeless tobacco. PMID:27759090

Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach

PubMed Central

Lachenmeier, Dirk W.; Rehm, Jürgen

2015-01-01

A comparative risk assessment of drugs including alcohol and tobacco using the margin of exposure (MOE) approach was conducted. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Median lethal dose values from animal experiments were used to derive the benchmark dose. The human intake was calculated for individual scenarios and population-based scenarios. The MOE was calculated using probabilistic Monte Carlo simulations. The benchmark dose values ranged from 2 mg/kg bodyweight for heroin to 531 mg/kg bodyweight for alcohol (ethanol). For individual exposure the four substances alcohol, nicotine, cocaine and heroin fall into the “high risk” category with MOE < 10, the rest of the compounds except THC fall into the “risk” category with MOE < 100. On a population scale, only alcohol would fall into the “high risk” category, and cigarette smoking would fall into the “risk” category, while all other agents (opiates, cocaine, amphetamine-type stimulants, ecstasy, and benzodiazepines) had MOEs > 100, and cannabis had a MOE > 10,000. The toxicological MOE approach validates epidemiological and social science-based drug ranking approaches especially in regard to the positions of alcohol and tobacco (high risk) and cannabis (low risk). PMID:25634572

Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells[S

PubMed Central

Jaudszus, Anke; Gruen, Michael; Watzl, Bernhard; Ness, Christina; Roth, Alexander; Lochner, Alfred; Barz, Dagmar; Gabriel, Holger; Rothe, Michael; Jahreis, Gerhard

2013-01-01

Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. PMID:23349208

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

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

Smith, Grace L.; Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas; Jiang, Jing

Purpose: High-quality treatment for intact cervical cancer requires external radiation therapy, brachytherapy, and chemotherapy, carefully sequenced and completed without delays. We sought to determine how frequently current treatment meets quality benchmarks and whether new technologies have influenced patterns of care. Methods and Materials: By searching diagnosis and procedure claims in MarketScan, an employment-based health care claims database, we identified 1508 patients with nonmetastatic, intact cervical cancer treated from 1999 to 2011, who were <65 years of age and received >10 fractions of radiation. Treatments received were identified using procedure codes and compared with 3 quality benchmarks: receipt of brachytherapy, receipt ofmore » chemotherapy, and radiation treatment duration not exceeding 63 days. The Cochran-Armitage test was used to evaluate temporal trends. Results: Seventy-eight percent of patients (n=1182) received brachytherapy, with brachytherapy receipt stable over time (Cochran-Armitage P{sub trend}=.15). Among patients who received brachytherapy, 66% had high–dose rate and 34% had low–dose rate treatment, although use of high–dose rate brachytherapy steadily increased to 75% by 2011 (P{sub trend}<.001). Eighteen percent of patients (n=278) received intensity modulated radiation therapy (IMRT), and IMRT receipt increased to 37% by 2011 (P{sub trend}<.001). Only 2.5% of patients (n=38) received IMRT in the setting of brachytherapy omission. Overall, 79% of patients (n=1185) received chemotherapy, and chemotherapy receipt increased to 84% by 2011 (P{sub trend}<.001). Median radiation treatment duration was 56 days (interquartile range, 47-65 days); however, duration exceeded 63 days in 36% of patients (n=543). Although 98% of patients received at least 1 benchmark treatment, only 44% received treatment that met all 3 benchmarks. With more stringent indicators (brachytherapy, ≥4 chemotherapy cycles, and duration not exceeding 56 days), only 25% of patients received treatment that met all benchmarks. Conclusion: In this cohort, most cervical cancer patients received treatment that did not comply with all 3 benchmarks for quality treatment. In contrast to increasing receipt of newer radiation technologies, there was little improvement in receipt of essential treatment benchmarks.« less

POPULATION EXPOSURE AND DOSE MODEL FOR AIR TOXICS: A BENZENE CASE STUDY

EPA Science Inventory

The EPA's National Exposure Research Laboratory (NERL) is developing a human exposure and dose model called the Stochastic Human Exposure and Dose Simulation model for Air Toxics (SHEDS-AirToxics) to characterize population exposure to air toxics in support of the National Air ...

Comparison of U.S. Environmental Protection Agency's CAP88 PC Versions 3.0 and 4.0.

PubMed

Jannik, Tim; Farfan, Eduardo B; Dixon, Ken; Newton, Joseph; Sailors, Christopher; Johnson, Levi; Moore, Kelsey; Stahman, Richard

2015-08-01

The Savannah River National Laboratory (SRNL) with the assistance of Georgia Regents University, completed a comparison of the U.S. Environmental Protection Agency's (U.S. EPA) environmental dosimetry code CAP88 PC V3.0 with the recently developed V4.0. CAP88 is a set of computer programs and databases used for estimation of dose and risk from radionuclide emissions to air. At the U.S. Department of Energy's Savannah River Site, CAP88 is used by SRNL for determining compliance with U.S. EPA's National Emission Standards for Hazardous Air Pollutants (40 CFR 61, Subpart H) regulations. Using standardized input parameters, individual runs were conducted for each radionuclide within its corresponding database. Some radioactive decay constants, human usage parameters, and dose coefficients changed between the two versions, directly causing a proportional change in the total effective dose. A detailed summary for select radionuclides of concern at the Savannah River Site (60Co, 137Cs, 3H, 129I, 239Pu, and 90Sr) is provided. In general, the total effective doses will decrease for alpha/beta emitters because of reduced inhalation and ingestion rates in V4.0. However, for gamma emitters, such as 60Co and 137Cs, the total effective doses will increase because of changes U.S. EPA made in the external ground shine calculations.

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED PARTICLES FOR DIFFERENT DOSE METRICS: COMPARISON OF NUMBER, SURFACE AREA AND MASS DOSE OF TYPICAL AMBIENT BI-MODAL AEROSOLS

EPA Science Inventory

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED PARTICLES FOR DIFFERENT DOSE METRICS: COMPARISON OF NUMBER, SURFACE AREA AND MASS DOSE OF TYPICAL AMBIENT BI-MODAL AEROSOLS.
Chong S. Kim, SC. Hu*, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, ...

Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.

PubMed

Mocking, R J T; Harmsen, I; Assies, J; Koeter, M W J; Ruhé, H G; Schene, A H

2016-03-15

Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114-0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I(2)=73.36, P<0.001), meta-regression showed that higher EPA dose (β=0.00037 (0.00009-0.00065), P=0.009), higher percentage antidepressant users (β=0.0058 (0.00017-0.01144), P=0.044) and earlier publication year (β=-0.0735 (-0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

EPA Science Inventory

Use of Mechanistic Data to Help Define Dose-Response Curves

The cancer risk assessment process described by the U.S. EPA necessitates a description of the dose-response curve for tumors in humans at low (environmental) exposures. This description can either be a default l...

Development of a flattening filter free multiple source model for use as an independent, Monte Carlo, dose calculation, quality assurance tool for clinical trials.

PubMed

Faught, Austin M; Davidson, Scott E; Popple, Richard; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S

2017-09-01

The Imaging and Radiation Oncology Core-Houston (IROC-H) Quality Assurance Center (formerly the Radiological Physics Center) has reported varying levels of compliance from their anthropomorphic phantom auditing program. IROC-H studies have suggested that one source of disagreement between institution submitted calculated doses and measurement is the accuracy of the institution's treatment planning system dose calculations and heterogeneity corrections used. In order to audit this step of the radiation therapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Varian flattening filter free (FFF) 6 MV and FFF 10 MV therapeutic x-ray beams were commissioned based on central axis depth dose data from a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open-field measurements in a water tank for field sizes ranging from 3 × 3 cm 2 to 40 × 40 cm 2 . The models were then benchmarked against IROC-H's anthropomorphic head and neck phantom and lung phantom measurements. Validation results, assessed with a ±2%/2 mm gamma criterion, showed average agreement of 99.9% and 99.0% for central axis depth dose data for FFF 6 MV and FFF 10 MV models, respectively. Dose profile agreement using the same evaluation technique averaged 97.8% and 97.9% for the respective models. Phantom benchmarking comparisons were evaluated with a ±3%/2 mm gamma criterion, and agreement averaged 90.1% and 90.8% for the respective models. Multiple source models for Varian FFF 6 MV and FFF 10 MV beams have been developed, validated, and benchmarked for inclusion in an independent dose calculation quality assurance tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.

A Matter of Timing: Identifying Significant Multi-Dose Radiotherapy Improvements by Numerical Simulation and Genetic Algorithm Search

PubMed Central

Angus, Simon D.; Piotrowska, Monika Joanna

2014-01-01

Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17–18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy. PMID:25460164

A matter of timing: identifying significant multi-dose radiotherapy improvements by numerical simulation and genetic algorithm search.

PubMed

Angus, Simon D; Piotrowska, Monika Joanna

2014-01-01

Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17-18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy.

BMDExpress Data Viewer: A Visualization Tool to Analyze BMDExpress Datasets

EPA Science Inventory

Regulatory agencies increasingly apply benchmark dose (BMD) modeling to determine points of departure in human risk assessments. BMDExpress applies BMD modeling to transcriptomics datasets and groups genes to biological processes and pathways for rapid assessment of doses at whic...

Comparison of U.S. Environmental Protection Agency’s CAP88 PC versions 3.0 and 4.0

DOE PAGES

Jannik, Tim; Farfan, Eduardo B.; Dixon, Ken; ...

2015-08-01

The Savannah River National Laboratory (SRNL) with the assistance of Georgia Regents University, completed a comparison of the U.S. Environmental Protection Agency's (EPA) environmental dosimetry code CAP88 PC V3.0 with the recently developed V4.0. CAP88 is a set of computer programs and databases used for estimation of dose and risk from radionuclide emissions to air. At the U.S. Department of Energy's Savannah River Site, CAP88 is used by SRNL for determining compliance with EPA's National Emission Standards for Hazardous Air Pollutants (40 CFR 61, Subpart H) regulations. Using standardized input parameters, individual runs were conducted for each radionuclide within itsmore » corresponding database. Some radioactive decay constants, human usage parameters, and dose coefficients changed between the two versions, directly causing a proportional change in the total effective 137Cs, 3H, 129I, 239Pu, and 90Sr) is provided. In general, the total effective doses will decrease for alpha/beta emitters because of reduced inhalation and ingestion rates in V4.0. However, for gamma emitters, such as 60Co and 137Cs, the total effective doses will increase because of changes EPA made in the external ground shine calculations.« less

IRIS Toxicological Review of Inorganic Arsenic (Cancer) ...

EPA Pesticide Factsheets

EPA's Science Advisory Board (SAB) conducted a review of the scientific basis supporting the human health cancer hazard and dose-response assessment of inorganic arsenic that will appear on the Integrated Risk Information System (IRIS) database. EPA revised the assessment and is now returning the assessment to the SAB and releasing the document to the public for a focused review of EPA's responses to the SAB recommendations. This draft IRIS health assessment addresses only cancer human health effects that may result from chronic exposure to this chemical.

EPA Peer Consultation Workshop Report on the Review of the Draft IRIS Toxicological Review of Dibutyl Phthalate (DBP)

EPA Science Inventory

The U.S. EPA finalized comments gathered from a public peer review of the scientific basis supporting the human health hazard and dose-response assessment of dibutyl phthalate (DBP) that will appear on the Integrated Risk Information System (IRIS) database. The peer review has en...

IRIS Toxicological Review of 2,2',4,4'-Tetrabromodiphenyl ...

EPA Pesticide Factsheets

The U.S. EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessments of congeners of polybrominated diphenyl ethers (PDBEs), this review is about 2,2',4,4'-Tetrabromodiphenyl Ether, or commonly referred to as tetraBDE (BDE-47). Following the external peer review this assessment will appear in the Integrated Risk Information System (IRIS) database. Peer review will ensure that science is used credibly and appropriately in derivation of the dose-response assessments and toxicological characterization. EPA is updating the Integrated Risk Information System (IRIS) health assessments for the PBDEs.

Comparison of Vocal Vibration-Dose Measures for Potential-Damage Risk Criteria

ERIC Educational Resources Information Center

Titze, Ingo R.; Hunter, Eric J.

2015-01-01

Purpose: School-teachers have become a benchmark population for the study of occupational voice use. A decade of vibration-dose studies on the teacher population allows a comparison to be made between specific dose measures for eventual assessment of damage risk. Method: Vibration dosimetry is reformulated with the inclusion of collision stress.…

A revised probabilistic estimate of the maternal methyl mercury intake dose corresponding to a measured cord blood mercury concentration.

PubMed

Stern, Alan H

2005-02-01

In 2001, the U.S. Environmental Protection Agency (EPA) adopted a revised reference dose (RfD) for methyl mercury (MeHg) of 0.1 microg/kg/day. The RfD is based on neurologic developmental effects measured in children associated with exposure in utero to MeHg from the maternal diet. The RfD derivation proceeded from a point of departure based on measured concentration of mercury in fetal cord blood (micrograms per liter). The RfD, however, is a maternal dose (micrograms per kilogram per day). Reconstruction of the maternal dose corresponding to this cord blood concentration, including the variability around this estimate, is a critical step in the RfD derivation. The dose reconstruction employed by the U.S. EPA using the one-compartment pharmacokinetic model contains two areas of significant uncertainty: It does not directly account for the influence of the ratio of cord blood: maternal blood Hg concentration, and it does not resolve uncertainty regarding the most appropriate central tendency estimates for pregnancy and third-trimester-specific model parameters. A probabilistic reassessment of this dose reconstruction was undertaken to address these areas of uncertainty and generally to reconsider the specification of model input parameters. On the basis of a thorough review of the literature and recalculation of the one-compartment model including sensitivity analyses, I estimated that the 95th and 99th percentiles (i.e., the lower 5th and 1st percentiles) of the maternal intake dose corresponding to a fetal cord blood Hg concentration of 58 microg/L are 0.3 and 0.2 microg/kg/day, respectively. For the 99th percentile, this is half the value previously estimated by the U.S. EPA.

BMDExpress Data Viewer: A Visualization Tool to Analyze BMDExpress Datasets(SoTC)

EPA Science Inventory

Background: Benchmark Dose (BMD) modelling is a mathematical approach used to determine where a dose-response change begins to take place relative to controls following chemical exposure. BMDs are being increasingly applied in regulatory toxicology to estimate acceptable exposure...

BMDExpress Data Viewer: A Visualization Tool to Analyze BMDExpress Datasets (STC symposium)

EPA Science Inventory

Background: Benchmark Dose (BMD) modelling is a mathematical approach used to determine where a dose-response change begins to take place relative to controls following chemical exposure. BMDs are being increasingly applied in regulatory toxicology to estimate acceptable exposure...

SHEDS-PM: A POPULATION EXPOSURE MODEL FOR PREDICTING DISTRIBUTIONS OF PM EXPOSURE AND DOSE FROM BOTH OUTDOOR AND INDOOR SOURCES

EPA Science Inventory

The US EPA National Exposure Research Laboratory (NERL) has developed a population exposure and dose model for particulate matter (PM), called the Stochastic Human Exposure and Dose Simulation (SHEDS) model. SHEDS-PM uses a probabilistic approach that incorporates both variabi...

NEXT GENERATION MULTIMEDIA/MULTIPATHWAY EXPOSURE MODELING

EPA Science Inventory

The Stochastic Human Exposure and Dose Simulation model for pesticides (SHEDS-Pesticides) supports the efforts of EPA to better understand human exposures and doses to multimedia, multipathway pollutants. It is a physically-based, probabilistic computer model that predicts, for u...

Altered operant responding for motor reinforcement and the determination of benchmark doses following perinatal exposure to low-level 2,3,7,8-tetrachlorodibenzo-p-dioxin.

PubMed

Markowski, V P; Zareba, G; Stern, S; Cox, C; Weiss, B

2001-06-01

Pregnant Holtzman rats were exposed to a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the 18th day of gestation. Their adult female offspring were trained to respond on a lever for brief opportunities to run in specially designed running wheels. Once they had begun responding on a fixed-ratio 1 (FR1) schedule of reinforcement, the fixed-ratio requirement for lever pressing was increased at five-session intervals to values of FR2, FR5, FR10, FR20, and FR30. We examined vaginal cytology after each behavior session to track estrous cyclicity. Under each of the FR values, perinatal TCDD exposure produced a significant dose-related reduction in the number of earned opportunities to run, the lever response rate, and the total number of revolutions in the wheel. Estrous cyclicity was not affected. Because of the consistent dose-response relationship at all FR values, we used the behavioral data to calculate benchmark doses based on displacements from modeled zero-dose performance of 1% (ED(01)) and 10% (ED(10)), as determined by a quadratic fit to the dose-response function. The mean ED(10) benchmark dose for earned run opportunities was 10.13 ng/kg with a 95% lower bound of 5.77 ng/kg. The corresponding ED(01) was 0.98 ng/kg with a 95% lower bound of 0.83 ng/kg. The mean ED(10) for total wheel revolutions was calculated as 7.32 ng/kg with a 95% lower bound of 5.41 ng/kg. The corresponding ED(01) was 0.71 ng/kg with a 95% lower bound of 0.60. These values should be viewed from the perspective of current human body burdens, whose average value, based on TCDD toxic equivalents, has been calculated as 13 ng/kg.

Development of a chronic noncancer oral reference dose and drinking water screening level for sulfolane using benchmark dose modeling.

PubMed

Thompson, Chad M; Gaylor, David W; Tachovsky, J Andrew; Perry, Camarie; Carakostas, Michael C; Haws, Laurie C

2013-12-01

Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000-36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference dose (RfD) based on benchmark dose modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark dose modeling were 0.01-0.04 mg kg(-1) per day, although modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg(-1) per day. The lowest, most conservative, RfD of 0.01 mg kg(-1) per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l(-1). It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane. Copyright © 2012 John Wiley & Sons, Ltd.

A SMALL FISH MULTI-ENDPOINT BIOASSAY FOR ASSESSING THE EFFECTS OF WATER CONTAMINANTS PRESENT IN LOW CONCENTRATIONS: MEDAKA AND DICHLOROACETIC ACID

EPA Science Inventory

In regulating the safety of water under SDWA and the CWA, the EPA makes decisions on what chemical contaminants to regulate and at what levels. To make these decisions the EPA needs hazard identification and dose-response information. Current methods that rely on rodent models fo...

Peer Review for EPA’s Proposed Approaches to Inform the Derivation of a Maximum Contaminant Level Goal for Perchlorate in Drinking Water

EPA Science Inventory

EPA is developing approaches to inform the derivation of a Maximum Contaminant Level Goal (MCLG) for perchlorate in drinking water under the Safe Drinking Water Act. EPA previously conducted an independent, external, scientific peer review of the draft biologically-based dose-res...

DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY III. STATISTICAL MODELS

EPA Science Inventory

Although quantitative modeling has been central to cancer risk assessment for years, the concept of do@e-response modeling for developmental effects is relatively new. he benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpo...

PERCEPTION OF MERCURY RISK INFORMATION

EPA Science Inventory

Approximately 8% of American women have blood Mercury levels exceeding the EPA reference dose (a dose below which symptoms would be unlikely). The children of these women are at risk of neurological deficits (lower IQ scores) primarily because of the mother's consumption of conta...

BMDExpress Data Viewer - A visualization Tool to Analyze BMDExpress Datasets (Health Canada Science Forum)

EPA Science Inventory

Benchmark Dose (BMD) modelling is a mathematical approach used to determine where a dose-response change begins to take place relative to controls following chemical exposure. BMDs are being increasingly applied in regulatory toxicology to determine points of departure. BMDExpres...

Concordance of Transcriptional and Apical Benchmark Dose Levels for Conazole-Induced Liver Effects in Mice

EPA Science Inventory

ABSTRACT The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time informs mode of action determinations and improves quantitative risk assessments. Previous transcription-based microarra...

A comparative study: In vitro effects of EPA and DHA on immune functions of head-kidney macrophages isolated from large yellow croaker (Larmichthys crocea).

PubMed

Li, Qingfei; Ai, Qinghui; Mai, Kangsen; Xu, Wei; Zheng, Yuefu

2013-09-01

Comparative effects of different concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on immune responses of head-kidney macrophages isolated from large yellow croaker were studied in vitro. After exposing to serum-free medium for 1 day, cultured cells were incubated in medium supplemented with graded levels of EPA or DHA (0, 5, 25, 100, 200 and 1000 μM, respectively) in the form of fatty acid bovine serum albumin (FA-BSA) complex for 12 h, 24 h and 36 h, respectively. Control samples were incubated in the absence of EPA or DHA (2% bovine serum albumin, BSA). Following stimulation, cell viability, lipid peroxidation, secretary phopholipase A2 (sPLA2) and prostaglandin E2 (PGE2) production as well as some immune parameters including phagocytosis, respiratory burst activity and interleukin 1β (IL-1β) production were determined. Results showed that EPA and DHA affected cell viability in dose-dependent and time-dependent manners. In particular, cell viability was significantly decreased after 24 h and 36 h incubation with 1000 μM EPA or DHA (P < 0.05). Higher levels of EPA (200 and 1000 μM) caused a significant increase in the production of malondialdehyde (MDA) (P < 0.05), while DHA did not significantly affect the MDA production. EPA significantly increased the intracellular superoxide anion synthesis which, on the contrary, was significantly reduced by DHA. Phagocytosis percentage (PP) values were significantly higher in treatments with 5 μM DHA (P < 0.05), but significantly decreased by 200 and 1000 μM EPA and DHA compared to the control group (P < 0.05). Decreased PGE2 production was produced by cells treated with relatively low doses of EPA or DHA. When high levels of stimulants (1000 μM EPA or DHA) were used, PGE2 levels were elevated and reached a significant level (P < 0.05). Both EPA and DHA significantly inhibited the production of sPLA2, where DHA exerted the more potent inhibitory effects than EPA. No pronounced effect was observed on IL-1β production among all the treatments, and IL-1β level in cell culture supernatant was fairly low (only approximately 6 pg/ml). Those findings suggested that EPA and DHA could influence the immunity and physiological conditions of macrophages from head kidney of large yellow croaker in vitro. Copyright © 2013. Published by Elsevier Ltd.

Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.

PubMed

Bradley, Ann E; Shoenfelt, Joanna L; Durda, Judi L

2016-04-01

Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

LINKING EXPOSURES TO INTERNAL DOSES USING BIOMARKERS

EPA Science Inventory

Biomonitoring is a useful tool to help assess human exposures/internal doses to chemicals in the environment. This research contributes to EPA's mission to protect human health by understanding what chemicals people are exposed to in their daily environments. In this task, we wil...

A POPULATION EXPOSURE MODEL FOR PARTICULATE MATTER: SHEDS-PM

EPA Science Inventory

The US EPA National Exposure Research Laboratory (NERL) has developed a population exposure and dose model for particulate matter (PM) that will be publicly available in Fall 2002. The Stochastic Human Exposure and Dose Simulation (SHEDS-PM) model uses a probabilistic approach ...

UNCERTAINTY ANALYSIS OF TCE USING THE DOSE EXPOSURE ESTIMATING MODEL (DEEM) IN ACSL

EPA Science Inventory

The ACSL-based Dose Exposure Estimating Model(DEEM) under development by EPA is used to perform art uncertainty analysis of a physiologically based pharmacokinetic (PSPK) model of trichloroethylene (TCE). This model involves several circulating metabolites such as trichloroacet...

TOLUENE DOSE-EFFECT META ANALYSIS AND IMPORTANCE OF EFFECTS

EPA Science Inventory

TOLUENE DOSE-EFFECT META ANALYSES AND IMPORTANCE OF EFFECTS
Benignus, V.A., Research Psychologist, ORD, NHEERL, Human Studies Division,
919-966-6242, benignus.vernon@epa.gov
Boyes, W.K., Supervisory Health Scientist, ORD, NHEERL, Neurotoxicology Division
919-541-...

DIFFUSION AND PERCEPTION OF MERCURY RISK INFORMATION

EPA Science Inventory

Approximately 8% of American women have blood Mercury levels exceeding the EPA reference dose (a dose below which symptoms would be unlikely). The children of these women are at risk of neurological deficits (lower IQ scores) primarily because of the mother’s consumption of...

Modification and benchmarking of SKYSHINE-III for use with ISFSI cask arrays

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

Hertel, N.E.; Napolitano, D.G.

1997-12-01

Dry cask storage arrays are becoming more and more common at nuclear power plants in the United States. Title 10 of the Code of Federal Regulations, Part 72, limits doses at the controlled area boundary of these independent spent-fuel storage installations (ISFSI) to 0.25 mSv (25 mrem)/yr. The minimum controlled area boundaries of such a facility are determined by cask array dose calculations, which include direct radiation and radiation scattered by the atmosphere, also known as skyshine. NAC International (NAC) uses SKYSHINE-III to calculate the gamma-ray and neutron dose rates as a function of distance from ISFSI arrays. In thismore » paper, we present modifications to the SKYSHINE-III that more explicitly model cask arrays. In addition, we have benchmarked the radiation transport methods used in SKYSHINE-III against {sup 60}Co gamma-ray experiments and MCNP neutron calculations.« less

EPA's Response to Health Risks from Dioxin and Related ...

EPA Pesticide Factsheets

In 2003, EPA produced an external review draft of a multi-year comprehensive reassessment of dioxin exposure and human health effects. This reassessment, Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds, was submitted to the National Academy of Sciences (NAS) for review in October 2004. In 2006, the NAS expert panel published its review titled Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment. The NAS expert panel’s Key Findings, as listed in the Public Summary of its review, identified “three areas that require substantial improvement to support a scientifically robust health assessment: •Justification of approaches to dose-response modeling for cancer and non-cancer end points. •Transparency and clarity in selection of key data sets for analysis. •Transparency, thoroughness, and clarity in quantitative uncertainty analysis.” The NAS also recommended that “EPA routinely monitor new scientific information related to TCDD…with the understanding that future revisions should provide a risk assessment based on the current state-of-the-science.” The objective of this project is to respond to NAS coments on dose-response modeling conducted in the EPA Reassessment of the health effects associated with dioxin exposure. In order to do this, we will address the Key Findings of the NAS review in a transparent and open manner.

Effect of supplementation with flaxseed oil and different doses of fish oil for 2 weeks on plasma phosphatidylcholine fatty acids in young women.

PubMed

Hodson, Leanne; Crowe, Francesca L; McLachlan, Kirsten J; Skeaff, C Murray

2018-06-01

Although assumed, it remains unclear that fatty acid (FA) biomarkers of n-3 long-chain PUFA reflect wide ranges of intake. However, to be utilised as biomarkers, to predict dietary intake, dose-response curves that cover a spectrum of intakes are required. The aim of the study was to investigate whether the FA composition of plasma phosphatidylcholine (PC) is a sensitive biomarker of n-3 FAs from fish oil, across a range of supplementation doses, and alpha-linolenic acid (ALA) supplementation, in young, healthy women. A total of 303 young women were randomised to intakes ranging between 0.33 and 4.50 g EPA+DHA/day from fish oil (not all doses used in each year) or flaxseed oil (5.90-6.60 g/d) daily for 14 days in a series of trials, over 5 years. Fasting blood was collected at baseline (day 0) and day 14 and plasma PC FA composition, total and HDL-cholesterol and triglyceride concentrations measured. Fourteen days supplementation with fish oil significantly (P < 0.01) increased, in a dose-dependent fashion, plasma PC EPA, DPA and DHA at all doses except 1 and 3 mL/day. For the combined group of women who consumed any fish oil there was a 16% (P < 0.01) decrease in plasma triacylglycerol concentrations after 14 days supplementation. Flaxseed oil supplementation for 14 day resulted in significant (P < 0.01) increases in ALA, EPA and DPA, whilst DHA remained unchanged. Our data demonstrate plasma PC is a sensitive biomarker of n-3 FA intake and reflects changes within 14 days across a range of intakes.

TH-A-19A-04: Latent Uncertainties and Performance of a GPU-Implemented Pre-Calculated Track Monte Carlo Method

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

Renaud, M; Seuntjens, J; Roberge, D

Purpose: Assessing the performance and uncertainty of a pre-calculated Monte Carlo (PMC) algorithm for proton and electron transport running on graphics processing units (GPU). While PMC methods have been described in the past, an explicit quantification of the latent uncertainty arising from recycling a limited number of tracks in the pre-generated track bank is missing from the literature. With a proper uncertainty analysis, an optimal pre-generated track bank size can be selected for a desired dose calculation uncertainty. Methods: Particle tracks were pre-generated for electrons and protons using EGSnrc and GEANT4, respectively. The PMC algorithm for track transport was implementedmore » on the CUDA programming framework. GPU-PMC dose distributions were compared to benchmark dose distributions simulated using general-purpose MC codes in the same conditions. A latent uncertainty analysis was performed by comparing GPUPMC dose values to a “ground truth” benchmark while varying the track bank size and primary particle histories. Results: GPU-PMC dose distributions and benchmark doses were within 1% of each other in voxels with dose greater than 50% of Dmax. In proton calculations, a submillimeter distance-to-agreement error was observed at the Bragg Peak. Latent uncertainty followed a Poisson distribution with the number of tracks per energy (TPE) and a track bank of 20,000 TPE produced a latent uncertainty of approximately 1%. Efficiency analysis showed a 937× and 508× gain over a single processor core running DOSXYZnrc for 16 MeV electrons in water and bone, respectively. Conclusion: The GPU-PMC method can calculate dose distributions for electrons and protons to a statistical uncertainty below 1%. The track bank size necessary to achieve an optimal efficiency can be tuned based on the desired uncertainty. Coupled with a model to calculate dose contributions from uncharged particles, GPU-PMC is a candidate for inverse planning of modulated electron radiotherapy and scanned proton beams. This work was supported in part by FRSQ-MSSS (Grant No. 22090), NSERC RG (Grant No. 432290) and CIHR MOP (Grant No. MOP-211360)« less

Latent uncertainties of the precalculated track Monte Carlo method

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

Renaud, Marc-André; Seuntjens, Jan; Roberge, David

Purpose: While significant progress has been made in speeding up Monte Carlo (MC) dose calculation methods, they remain too time-consuming for the purpose of inverse planning. To achieve clinically usable calculation speeds, a precalculated Monte Carlo (PMC) algorithm for proton and electron transport was developed to run on graphics processing units (GPUs). The algorithm utilizes pregenerated particle track data from conventional MC codes for different materials such as water, bone, and lung to produce dose distributions in voxelized phantoms. While PMC methods have been described in the past, an explicit quantification of the latent uncertainty arising from the limited numbermore » of unique tracks in the pregenerated track bank is missing from the paper. With a proper uncertainty analysis, an optimal number of tracks in the pregenerated track bank can be selected for a desired dose calculation uncertainty. Methods: Particle tracks were pregenerated for electrons and protons using EGSnrc and GEANT4 and saved in a database. The PMC algorithm for track selection, rotation, and transport was implemented on the Compute Unified Device Architecture (CUDA) 4.0 programming framework. PMC dose distributions were calculated in a variety of media and compared to benchmark dose distributions simulated from the corresponding general-purpose MC codes in the same conditions. A latent uncertainty metric was defined and analysis was performed by varying the pregenerated track bank size and the number of simulated primary particle histories and comparing dose values to a “ground truth” benchmark dose distribution calculated to 0.04% average uncertainty in voxels with dose greater than 20% of D{sub max}. Efficiency metrics were calculated against benchmark MC codes on a single CPU core with no variance reduction. Results: Dose distributions generated using PMC and benchmark MC codes were compared and found to be within 2% of each other in voxels with dose values greater than 20% of the maximum dose. In proton calculations, a small (≤1 mm) distance-to-agreement error was observed at the Bragg peak. Latent uncertainty was characterized for electrons and found to follow a Poisson distribution with the number of unique tracks per energy. A track bank of 12 energies and 60000 unique tracks per pregenerated energy in water had a size of 2.4 GB and achieved a latent uncertainty of approximately 1% at an optimal efficiency gain over DOSXYZnrc. Larger track banks produced a lower latent uncertainty at the cost of increased memory consumption. Using an NVIDIA GTX 590, efficiency analysis showed a 807 × efficiency increase over DOSXYZnrc for 16 MeV electrons in water and 508 × for 16 MeV electrons in bone. Conclusions: The PMC method can calculate dose distributions for electrons and protons to a statistical uncertainty of 1% with a large efficiency gain over conventional MC codes. Before performing clinical dose calculations, models to calculate dose contributions from uncharged particles must be implemented. Following the successful implementation of these models, the PMC method will be evaluated as a candidate for inverse planning of modulated electron radiation therapy and scanned proton beams.« less

Latent uncertainties of the precalculated track Monte Carlo method.

PubMed

Renaud, Marc-André; Roberge, David; Seuntjens, Jan

2015-01-01

While significant progress has been made in speeding up Monte Carlo (MC) dose calculation methods, they remain too time-consuming for the purpose of inverse planning. To achieve clinically usable calculation speeds, a precalculated Monte Carlo (PMC) algorithm for proton and electron transport was developed to run on graphics processing units (GPUs). The algorithm utilizes pregenerated particle track data from conventional MC codes for different materials such as water, bone, and lung to produce dose distributions in voxelized phantoms. While PMC methods have been described in the past, an explicit quantification of the latent uncertainty arising from the limited number of unique tracks in the pregenerated track bank is missing from the paper. With a proper uncertainty analysis, an optimal number of tracks in the pregenerated track bank can be selected for a desired dose calculation uncertainty. Particle tracks were pregenerated for electrons and protons using EGSnrc and geant4 and saved in a database. The PMC algorithm for track selection, rotation, and transport was implemented on the Compute Unified Device Architecture (cuda) 4.0 programming framework. PMC dose distributions were calculated in a variety of media and compared to benchmark dose distributions simulated from the corresponding general-purpose MC codes in the same conditions. A latent uncertainty metric was defined and analysis was performed by varying the pregenerated track bank size and the number of simulated primary particle histories and comparing dose values to a "ground truth" benchmark dose distribution calculated to 0.04% average uncertainty in voxels with dose greater than 20% of Dmax. Efficiency metrics were calculated against benchmark MC codes on a single CPU core with no variance reduction. Dose distributions generated using PMC and benchmark MC codes were compared and found to be within 2% of each other in voxels with dose values greater than 20% of the maximum dose. In proton calculations, a small (≤ 1 mm) distance-to-agreement error was observed at the Bragg peak. Latent uncertainty was characterized for electrons and found to follow a Poisson distribution with the number of unique tracks per energy. A track bank of 12 energies and 60000 unique tracks per pregenerated energy in water had a size of 2.4 GB and achieved a latent uncertainty of approximately 1% at an optimal efficiency gain over DOSXYZnrc. Larger track banks produced a lower latent uncertainty at the cost of increased memory consumption. Using an NVIDIA GTX 590, efficiency analysis showed a 807 × efficiency increase over DOSXYZnrc for 16 MeV electrons in water and 508 × for 16 MeV electrons in bone. The PMC method can calculate dose distributions for electrons and protons to a statistical uncertainty of 1% with a large efficiency gain over conventional MC codes. Before performing clinical dose calculations, models to calculate dose contributions from uncharged particles must be implemented. Following the successful implementation of these models, the PMC method will be evaluated as a candidate for inverse planning of modulated electron radiation therapy and scanned proton beams.

Source-term development for a contaminant plume for use by multimedia risk assessment models

NASA Astrophysics Data System (ADS)

Whelan, Gene; McDonald, John P.; Taira, Randal Y.; Gnanapragasam, Emmanuel K.; Yu, Charley; Lew, Christine S.; Mills, William B.

2000-02-01

Multimedia modelers from the US Environmental Protection Agency (EPA) and US Department of Energy (DOE) are collaborating to conduct a comprehensive and quantitative benchmarking analysis of four intermedia models: MEPAS, MMSOILS, PRESTO, and RESRAD. These models represent typical analytically based tools that are used in human-risk and endangerment assessments at installations containing radioactive and hazardous contaminants. The objective is to demonstrate an approach for developing an adequate source term by simplifying an existing, real-world, 90Sr plume at DOE's Hanford installation in Richland, WA, for use in a multimedia benchmarking exercise between MEPAS, MMSOILS, PRESTO, and RESRAD. Source characteristics and a release mechanism are developed and described; also described is a typical process and procedure that an analyst would follow in developing a source term for using this class of analytical tool in a preliminary assessment.

MODELING HUMAN EXPOSURES AND DOSE USING A 2-DIMENSIONAL MONTE-CARLO MODEL (SHEDS)

EPA Science Inventory

Since 1998, US EPA's National Exposure Research Laboratory (NERL) has been developing the Stochastic Human Exposure and Dose Simulation (SHEDS) model for various classes of pollutants. SHEDS is a physically-based probabilistic model intended for improving estimates of human ex...

ANALYSIS OF RESPIRATORY DESPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS

EPA Science Inventory

ANALYSIS OF RESPIRATORY DEPOSITION DOSE OF INHALED AMBIENT AEROSOLS FOR DIFFERENT SIZE FRACTIONS. Chong S. Kim, SC. Hu**, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711; **IIT Research Institute, Chicago, IL; *S...

MODEL DEVELOPMENT AND APPLICATION FOR ASSESSING HUMAN EXPOSURE AND DOSE TO TOXIC CHEMICALS AND POLLUTANTS

EPA Science Inventory

This project aims to strengthen the general scientific foundation of EPA's exposure and risk assessment processes by developing state-of-the-art exposure to dose computational models. This research will produce physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PD)...

RISK PERCEPTION AND DIFFUSION OF MERCURY RISK INFORMATION

EPA Science Inventory

The most recent NHANES data reveals that approximately 8% of American women have blood Mercury levels exceeding the EPA reference dose (a dose below which symptoms would be unlikely). The children of these women are at risk of neurological deficits (lower IQ scores) primarily bec...

PM POPULATION EXPOSURE AND DOSE MODELS

EPA Science Inventory

The overall objective of this study is the development of a refined probabilistic exposure and dose model for particulate matter (PM) suitable for predicting PM10 and PM2.5 population exposures. This modeling research will be conducted both in-house by EPA scientists and through...

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED AMBIENT AEROSOLS FOR DIFFERENT DOSE METRICS

EPA Science Inventory

ANALYSIS OF RESPIRATORY DEPOSITION OF INHALED AMBIENT AEROSOLS FOR DIFFERENT DOSE METRICS.
Chong S. Kim, SC. Hu**, PA Jaques*, US EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711; **IIT Research Institute, Chicago, IL; *South...

SU-E-T-577: Commissioning of a Deterministic Algorithm for External Photon Beams

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

Zhu, T; Finlay, J; Mesina, C

Purpose: We report commissioning results for a deterministic algorithm for external photon beam treatment planning. A deterministic algorithm solves the radiation transport equations directly using a finite difference method, thus improve the accuracy of dose calculation, particularly under heterogeneous conditions with results similar to that of Monte Carlo (MC) simulation. Methods: Commissioning data for photon energies 6 – 15 MV includes the percentage depth dose (PDD) measured at SSD = 90 cm and output ratio in water (Spc), both normalized to 10 cm depth, for field sizes between 2 and 40 cm and depths between 0 and 40 cm. Off-axismore » ratio (OAR) for the same set of field sizes was used at 5 depths (dmax, 5, 10, 20, 30 cm). The final model was compared with the commissioning data as well as additional benchmark data. The benchmark data includes dose per MU determined for 17 points for SSD between 80 and 110 cm, depth between 5 and 20 cm, and lateral offset of up to 16.5 cm. Relative comparisons were made in a heterogeneous phantom made of cork and solid water. Results: Compared to the commissioning beam data, the agreement are generally better than 2% with large errors (up to 13%) observed in the buildup regions of the FDD and penumbra regions of the OAR profiles. The overall mean standard deviation is 0.04% when all data are taken into account. Compared to the benchmark data, the agreements are generally better than 2%. Relative comparison in heterogeneous phantom is in general better than 4%. Conclusion: A commercial deterministic algorithm was commissioned for megavoltage photon beams. In a homogeneous medium, the agreement between the algorithm and measurement at the benchmark points is generally better than 2%. The dose accuracy for a deterministic algorithm is better than a convolution algorithm in heterogeneous medium.« less

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam.

PubMed

Arnold, Scott M; Collins, Michael A; Graham, Cynthia; Jolly, Athena T; Parod, Ralph J; Poole, Alan; Schupp, Thomas; Shiotsuka, Ronald N; Woolhiser, Michael R

2012-12-01

Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×10(6) (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10(-7)) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers. Copyright © 2012 Elsevier Inc. All rights reserved.

AVERAGE ANNUAL SOLAR UV DOSE OF THE CONTINENTAL US CITIZEN

EPA Science Inventory

The average annual solar UV dose of US citizens is not known, but is required for relative risk assessments of skin cancer from UV-emitting devices. We solved this problem using a novel approach. The EPA's "National Human Activity Pattern Survey" recorded the daily ou...

Acute Delayed Neurotoxicity Evaluation of Two Jet Engine Oils using a Modified Navy and EPA Protocol

DTIC Science & Technology

1992-08-01

Clinical Observations..................................................... 9 Sacrifice and Histopathology ...Single Dose ............... 13 5 Neural Histop.-Ohologic Incidence Summary (Repeated Assay) ..................... 15 6 Neural Histopathologic Lesions...Average Severity Scores (Repeated Assay) ......... 16 7 Neural Histopathologic Incidence Summary (Single-Dose Assay) .................. 17 8 Neural

EMP Attachment 3 DOE-SC PNNL Site Dose Assessment Guidance

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

Snyder, Sandra F.

2011-12-21

This Dose Assessment Guidance (DAG) describes methods to use to determine the Maximally-Exposed Individual (MEI) location and to estimate dose impact to that individual under the U.S. Department of Energy Office of Science (DOE-SC) Pacific Northwest National Laboratory (PNNL) Site Environmental Monitoring Plan (EMP). This guidance applies to public dose from radioactive material releases to the air from PNNL Site operations. This document is an attachment to the Pacific Northwest National Laboratory (PNNL) Environmental Monitoring Plan (EMP) and describes dose assessment guidance for radiological air emissions. The impact of radiological air emissions from the U.S. Department of Energy Office ofmore » Science (DOE-SC) PNNL Site is indicated by dose estimates to a maximally exposed member of the public, referred to as the maximally exposed individual (MEI). Reporting requirements associated with dose to members of the public from radiological air emissions are in 40 CFR Part 61.94, WAC 246-247-080, and DOE Order 458.1. The DOE Order and state standards for dose from radioactive air emissions are consistent with U.S. Environmental Protection Agency (EPA) dose standards in 40 CFR 61.92 (i.e., 10 mrem/yr to a MEI). Despite the fact that the current Contract Requirements Document (CRD) for the DOE-SC PNNL Site operations does not include the requirement to meet DOE CRD 458.1, paragraph 2.b, public dose limits, the DOE dose limits would be met when EPA limits are met.« less

Current modeling practice may lead to falsely high benchmark dose estimates.

PubMed

Ringblom, Joakim; Johanson, Gunnar; Öberg, Mattias

2014-07-01

Benchmark dose (BMD) modeling is increasingly used as the preferred approach to define the point-of-departure for health risk assessment of chemicals. As data are inherently variable, there is always a risk to select a model that defines a lower confidence bound of the BMD (BMDL) that, contrary to expected, exceeds the true BMD. The aim of this study was to investigate how often and under what circumstances such anomalies occur under current modeling practice. Continuous data were generated from a realistic dose-effect curve by Monte Carlo simulations using four dose groups and a set of five different dose placement scenarios, group sizes between 5 and 50 animals and coefficients of variations of 5-15%. The BMD calculations were conducted using nested exponential models, as most BMD software use nested approaches. "Non-protective" BMDLs (higher than true BMD) were frequently observed, in some scenarios reaching 80%. The phenomenon was mainly related to the selection of the non-sigmoidal exponential model (Effect=a·e(b)(·dose)). In conclusion, non-sigmoid models should be used with caution as it may underestimate the risk, illustrating that awareness of the model selection process and sound identification of the point-of-departure is vital for health risk assessment. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of the Carcinogenicity of Ethylene Oxide (2006 ...

EPA Pesticide Factsheets

EPA conducted a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of ethylene oxide (cancer) that when finalized will appear on the Integrated Risk Information System (IRIS) database. EPA is announcing a 30-day public comment period for this document. The release of this draft document is solely for the purpose of seeking public comment and for review by the EPA Science Advisory Board (SAB) via a meeting to be held later in 2006. The time and place of the SAB meeting will be announced in a separate Federal Register notice. This document has not been formally disseminated by EPA and does not represent, and should not be construed to represent, any Agency policy or determination. EPA will consider any public comments submitted in accordance with the requirements specified in the Notice of Public Comment Period when revising this draft document.

Evaluating MoE and its Uncertainty and Variability for Food Contaminants (EuroTox presentation)

EPA Science Inventory

Margin of Exposure (MoE), is a metric for quantifying the relationship between exposure and hazard. Ideally, it is the ratio of the dose associated with hazard and an estimate of exposure. For example, hazard may be characterized by a benchmark dose (BMD), and, for food contami...

Benchmark Dose Analysis from Multiple Datasets: The Cumulative Risk Assessment for the N-Methyl Carbamate Pesticides

EPA Science Inventory

The US EPA’s N-Methyl Carbamate (NMC) Cumulative Risk assessment was based on the effect on acetylcholine esterase (AChE) activity of exposure to 10 NMC pesticides through dietary, drinking water, and residential exposures, assuming the effects of joint exposure to NMCs is dose-...

75 FR 40729 - Residues of Quaternary Ammonium Compounds, N-Alkyl (C12-14

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-14

.... Systemic toxicity occurs after absorption and distribution of the chemical to tissues in the body. Such... identified (the LOAEL) or a Benchmark Dose (BMD) approach is sometimes used for risk assessment. Uncertainty.... No systemic effects observed up to 20 mg/ kg/day, highest dose of technical that could be tested...

Concordance of transcriptional and apical benchmark dose levels for conazole-ind uced liver effects in mice

EPA Science Inventory

The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time can inform mode of action and improve quantitative risk assessment. Previous research identified a 330-gene cluster commonly resp...

Issues in the Design and Interpretation of Chronic Toxicity and Carcinogenicity Studies in Rodents: Approaches to Dose Selection

EPA Science Inventory

For more than three decades chronic studies in rodents have been the benchmark for assessing the potential long-term toxicity, and particularly the carcinogenicity, of chemicals. With doses typically administered for about 2 years (18 months to lifetime), the rodent bioassay has ...

SU-E-I-32: Benchmarking Head CT Doses: A Pooled Vs. Protocol Specific Analysis of Radiation Doses in Adult Head CT Examinations

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

Fujii, K; UCLA School of Medicine, Los Angeles, CA; Bostani, M

Purpose: The aim of this study was to collect CT dose index data from adult head exams to establish benchmarks based on either: (a) values pooled from all head exams or (b) values for specific protocols. One part of this was to investigate differences in scan frequency and CT dose index data for inpatients versus outpatients. Methods: We collected CT dose index data (CTDIvol) from adult head CT examinations performed at our medical facilities from Jan 1st to Dec 31th, 2014. Four of these scanners were used for inpatients, the other five were used for outpatients. All scanners used Tubemore » Current Modulation. We used X-ray dose management software to mine dose index data and evaluate CTDIvol for 15807 inpatients and 4263 outpatients undergoing Routine Brain, Sinus, Facial/Mandible, Temporal Bone, CTA Brain and CTA Brain-Neck protocols, and combined across all protocols. Results: For inpatients, Routine Brain series represented 84% of total scans performed. For outpatients, Sinus scans represented the largest fraction (36%). The CTDIvol (mean ± SD) across all head protocols was 39 ± 30 mGy (min-max: 3.3–540 mGy). The CTDIvol for Routine Brain was 51 ± 6.2 mGy (min-max: 36–84 mGy). The values for Sinus were 24 ± 3.2 mGy (min-max: 13–44 mGy) and for Facial/Mandible were 22 ± 4.3 mGy (min-max: 14–46 mGy). The mean CTDIvol for inpatients and outpatients was similar across protocols with one exception (CTA Brain-Neck). Conclusion: There is substantial dose variation when results from all protocols are pooled together; this is primarily a function of the differences in technical factors of the protocols themselves. When protocols are analyzed separately, there is much less variability. While analyzing pooled data affords some utility, reviewing protocols segregated by clinical indication provides greater opportunity for optimization and establishing useful benchmarks.« less

MODELS AND MODELING METHODS FOR ASSESSING HUMAN EXPOSURE AND DOSE TO TOXIC CHEMICALS AND POLLUTANTS

EPA Science Inventory

This project aims to strengthen the general scientific foundation of EPA's exposure and risk assessment, management, and policy processes by developing state-of-the-art exposure to dose mathematical models and solution methods. The results of this research will be to produce a mo...

THYROID INSUFFICIENCY AND GENE EXPRESSION IN DEVELOPING RAT BRAIN: A DOSE RESPONSE STUDY.

EPA Science Inventory

Thyroid Insufficiency and Gene Expression in Developing Rat Brain: A Dose Response Study. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption is an area of major concern in environmental neurotoxicity. Deficits in thyroid hormone (TH) levels h...

Proposed Oral Reference Dose (RfD) for Barium and Compounds (Final Report, 2004)

EPA Science Inventory

This document is the final report from the 2004 external peer review of the Proposed Oral Reference Dose (RfD) for Barium and Compounds, prepared by the U.S. Environmental Protection Agency (EPA), National Center for Environmental Assessment (NCEA), for the Integrated Risk...

ASSESSING CHILDREN'S EXPOSURES TO PESTICIDES: AN IMPORTANT APPLICATION OF THE STOCHASTIC HUMAN EXPOSURE AND DOSE SIMULATION MODEL (SHEDS)

EPA Science Inventory

Accurately quantifying human exposures and doses of various populations to environmental pollutants is critical for the Agency to assess and manage human health risks. For example, the Food Quality Protection Act of 1996 (FQPA) requires EPA to consider aggregate human exposure ...

CONCEPTUAL BASIS FOR MULTI-ROUTE INTAKE DOSE MODELING USING AN ENERGY EXPENDITURE APPROACH

EPA Science Inventory

This paper provides the conceptual basis for a modeling logic that is currently being developed in the National Exposure Research Laboratory (NERL) of the U.S. Environmental Protection Agency ( EPA) for use in intake dose assessments involving substances that can enter the body...

ESTIMATING CHILDREN'S DERMAL AND NON-DIETARY INGESTION EXPOSURE AND DOSE WITH EPA'S SHEDS MODEL

EPA Science Inventory

A physically-based stochastic model (SHEDS) has been developed to estimate pesticide exposure and dose to children via dermal residue contact and non-dietary ingestion. Time-location-activity data are sampled from national survey results to generate a population of simulated ch...

Intercomparison of Monte Carlo radiation transport codes to model TEPC response in low-energy neutron and gamma-ray fields.

PubMed

Ali, F; Waker, A J; Waller, E J

2014-10-01

Tissue-equivalent proportional counters (TEPC) can potentially be used as a portable and personal dosemeter in mixed neutron and gamma-ray fields, but what hinders this use is their typically large physical size. To formulate compact TEPC designs, the use of a Monte Carlo transport code is necessary to predict the performance of compact designs in these fields. To perform this modelling, three candidate codes were assessed: MCNPX 2.7.E, FLUKA 2011.2 and PHITS 2.24. In each code, benchmark simulations were performed involving the irradiation of a 5-in. TEPC with monoenergetic neutron fields and a 4-in. wall-less TEPC with monoenergetic gamma-ray fields. The frequency and dose mean lineal energies and dose distributions calculated from each code were compared with experimentally determined data. For the neutron benchmark simulations, PHITS produces data closest to the experimental values and for the gamma-ray benchmark simulations, FLUKA yields data closest to the experimentally determined quantities. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes.

PubMed

Mason, R Preston; Jacob, Robert F; Shrivastava, Sandeep; Sherratt, Samuel C R; Chattopadhyay, Amitabha

2016-12-01

Cholesterol crystalline domains characterize atherosclerotic membranes, altering vascular signaling and function. Omega-3 fatty acids reduce membrane lipid peroxidation and subsequent cholesterol domain formation. We evaluated non-peroxidation-mediated effects of eicosapentaenoic acid (EPA), other TG-lowering agents, docosahexaenoic acid (DHA), and other long-chain fatty acids on membrane fluidity, bilayer width, and cholesterol domain formation in model membranes. In membranes prepared at 1.5:1 cholesterol-to-phospholipid (C/P) mole ratio (creating pre-existing domains), EPA, glycyrrhizin, arachidonic acid, and alpha linolenic acid promoted the greatest reductions in cholesterol domains (by 65.5%, 54.9%, 46.8%, and 45.2%, respectively) compared to controls; other treatments had modest effects. EPA effects on cholesterol domain formation were dose-dependent. In membranes with 1:1 C/P (predisposing domain formation), DHA, but not EPA, dose-dependently increased membrane fluidity. DHA also induced cholesterol domain formation without affecting temperature-induced changes in-bilayer unit cell periodicity relative to controls (d-space; 57Å-55Å over 15-30°C). Together, these data suggest simultaneous formation of distinct cholesterol-rich ordered domains and cholesterol-poor disordered domains in the presence of DHA. By contrast, EPA had no effect on cholesterol domain formation and produced larger d-space values relative to controls (60Å-57Å; p<0.05) over the same temperature range, suggesting a more uniform maintenance of lipid dynamics despite the presence of cholesterol. These data indicate that EPA and DHA had different effects on membrane bilayer width, membrane fluidity, and cholesterol crystalline domain formation; suggesting omega-3 fatty acids with differing chain length or unsaturation may differentially influence membrane lipid dynamics and structural organization as a result of distinct phospholipid/sterol interactions. Copyright © 2016. Published by Elsevier B.V.

The time course of erythrocyte membrane fatty acid concentrations during and after treatment of non-human primates with increasing doses of an omega-3 rich phospholipid preparation derived from krill-oil.

PubMed

Hals, Petter-Arnt; Wang, Xiaoli; Piscitelli, Fabiana; Di Marzo, Vincenzo; Xiao, Yong-Fu

2017-01-21

A commonly used measure to reflect the intake of the long-chain omega-3 fatty acids EPA and DHA is the omega-3 index, defined as the sum of EPA + DHA as % of total fatty acids in erythrocyte membrane. When the omega-3 index changes it follows that the relative fractions of other fatty acids in the membrane are also changed. In the present study, increasing doses of a preparation of omega-3 rich phospholipids extracted from krill oil were administered orally to non-human primates for 12 weeks and the time course of EPA, DHA and 22 other fatty acids in erythrocytes was determined bi-weekly during treatment and for 8 weeks after cessation of treatment. Plasma concentrations of six endocannabinoid-type mediators being downstream metabolites of some fatty acids analyzed in erythrocytes were also determined. Six diabetic, dyslipidemic non-human primates were included, three in a vehicle control group and three being treated with the omega-3 rich phospholipid preparation. The vehicle control and test items were given daily by gavage and the test item doses were 50, 150 and 450 mg phospholipids/kg/day. Each dose level was given for four weeks. Blood was sampled at baseline and thereafter bi-weekly. Fatty acids were determined in erythrocytes by methylation followed by gas-chromatography. Endocannabinoids and endocannabinoid-like mediators were analyzed in plasma by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. The treatment resulted in a dose-related increase in the fraction of EPA and DHA in erythrocyte membranes and a dose-related decrease of other poly-unsaturated fatty acids, in particular omega-6 polyunsaturated fatty acids. Erythrocyte concentrations of saturated fatty acids remained unchanged throughout the experiment. Plasma concentrations of endocannabinoids and endocannabinoid-like mediators changed accordingly as those being downstream arachidonic acid decreased, downstream of the saturated palmitic and oleic acids remained unchanged while a downstream EPA metabolite increased. Increasing the omega-3 index by administering an omega-3 rich phospholipid extracted from krill oil did not alter the ratio of unsaturated vs. saturated fatty acids in the erythrocyte membranes but only the relative concentrations of unsaturated fatty acids, in particular unsaturated omega-6 fatty acids. Concentrations of saturated fatty acids remained unchanged.

NASA Data for Water Resources Applications

NASA Technical Reports Server (NTRS)

Toll, David; Houser, Paul; Arsenault, Kristi; Entin, Jared

2004-01-01

Water Management Applications is one of twelve elements in the Earth Science Enterprise National Applications Program. NASA Goddard Space Flight Center is supporting the Applications Program through partnering with other organizations to use NASA project results, such as from satellite instruments and Earth system models to enhance the organizations critical needs. The focus thus far has been: 1) estimating water storage including snowpack and soil moisture, 2) modeling and predicting water fluxes such as evapotranspiration (ET), precipitation and river runoff, and 3) remote sensing of water quality, including both point source (e.g., turbidity and productivity) and non-point source (e.g., land cover conversion such as forest to agriculture yielding higher nutrient runoff). The objectives of the partnering cover three steps of: 1) Evaluation, 2) Verification and Validation, and 3) Benchmark Report. We are working with the U.S. federal agencies including the Environmental Protection Agency (EPA), the Bureau of Reclamation (USBR) and the Department of Agriculture (USDA). We are using several of their Decision Support Systems (DSS) tools. This includes the DSS support tools BASINS used by EPA, Riverware and AWARDS ET ToolBox by USBR and SWAT by USDA and EPA. Regional application sites using NASA data across the US. are currently being eliminated for the DSS tools. The current NASA data emphasized thus far are from the Land Data Assimilation Systems WAS) and MODIS satellite products. We are currently in the first two steps of evaluation and verification validation. Water Management Applications is one of twelve elements in the Earth Science Enterprise s National Applications Program. NASA Goddard Space Flight Center is supporting the Applications Program through partnering with other organizations to use NASA project results, such as from satellite instruments and Earth system models to enhance the organizations critical needs. The focus thus far has been: 1) estimating water storage including snowpack and soil moisture, 2) modeling and predicting water fluxes such as evapotranspiration (ET), precipitation and river runoff, and 3) remote sensing of water quality, including both point source (e.g., turbidity and productivity) and non-point source (e.g., land cover conversion such as forest to agriculture yielding higher nutrient runoff). The objectives of the partnering cover three steps of 1) Evaluation, 2) Verification and Validation, and 3) Benchmark Report. We are working with the U.S. federal agencies the Environmental Protection Agency (EPA), the Bureau of Reclamation (USBR) and the Department of Agriculture (USDA). We are using several of their Decision Support Systems (DSS) tools. T us includes the DSS support tools BASINS used by EPA, Riverware and AWARDS ET ToolBox by USBR and SWAT by USDA and EPA. Regional application sites using NASA data across the US. are currently being evaluated for the DSS tools. The current NASA data emphasized thus far are from the Land Data Assimilation Systems (LDAS) and MODIS satellite products. We are currently in the first two steps of evaluation and verification and validation.

RISK ASSESSMENT FOR THE DYE AND PIGMENT ...

EPA Pesticide Factsheets

This risk assessment calculates the maximum loadings of constituents found in dyes and pigment industries waste streams which can be disposed in different types of waste management units without causing health benchmarks to be exceeded at plausible receptor locations. The assessment focuses on potential risks from volatilization and leaching to groundwater of constituents disposed in surface impoundments and landfills with either clay liners or composite liners. This product will be used by EPA decision makers to assist in determining whether certain waste streams generated by the dyes and pigments industries should be designated as hazardous.

A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk.

PubMed

Alexander, Dominik D; Miller, Paige E; Van Elswyk, Mary E; Kuratko, Connye N; Bylsma, Lauren C

2017-01-01

To conduct meta-analyses of randomized controlled trials (RCTs) to estimate the effect of eicosapentaenoic and docosahexaenoic acid (EPA+DHA) on coronary heart disease (CHD), and to conduct meta-analyses of prospective cohort studies to estimate the association between EPA+DHA intake and CHD risk. A systematic literature search of Ovid/Medline, PubMed, Embase, and the Cochrane Library from January 1, 1947, to November 2, 2015, was conducted; 18 RCTs and 16 prospective cohort studies examining EPA+DHA from foods or supplements and CHD, including myocardial infarction, sudden cardiac death, coronary death, and angina, were identified. Random-effects meta-analysis models were used to generate summary relative risk estimates (SRREs) and 95% CIs. Heterogeneity was examined in subgroup and sensitivity analyses and by meta-regression. Dose-response was evaluated in stratified dose or intake analyses. Publication bias assessments were performed. Among RCTs, there was a nonstatistically significant reduction in CHD risk with EPA+DHA provision (SRRE=0.94; 95% CI, 0.85-1.05). Subgroup analyses of data from RCTs indicated a statistically significant CHD risk reduction with EPA+DHA provision among higher-risk populations, including participants with elevated triglyceride levels (SRRE=0.84; 95% CI, 0.72-0.98) and elevated low-density lipoprotein cholesterol (SRRE=0.86; 95% CI, 0.76-0.98). Meta-analysis of data from prospective cohort studies resulted in a statistically significant SRRE of 0.82 (95% CI, 0.74-0.92) for higher intakes of EPA+DHA and risk of any CHD event. Results indicate that EPA+DHA may be associated with reducing CHD risk, with a greater benefit observed among higher-risk populations in RCTs. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Protective Action Guides (PAGs)

EPA Pesticide Factsheets

The Protective Action Guide (PAG) manual contains radiation dose guidelines that would trigger public safety measures. EPA developed Protective Action Guides to help responders plan for radiation emergencies.

Environmental exposures and health impacts of PFAS ...

EPA Pesticide Factsheets

Environmental exposures and health impacts of PFAS The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.

Quantifying Children's Aggregate (Dietary and Residential) Exposure and Dose to Permethin: Application and Evaluation of EPA's Probabilistic SHED-Multimedia Model

EPA Science Inventory

Reliable, evaluated human exposure and dose models are important for understanding the health risks from chemicals. A case study focusing on permethrin was conducted because of this insecticide’s widespread use and potential health effects. SHEDS-Multimedia was applied to estimat...

Nonmonotonic Dose Responses as They Apply to Estrogen, Androgen, and Thyroid Pathways and EPA Testing and Assessment Procedures

EPA Pesticide Factsheets

A state of the science document providing a judgment on the degree to which nonmonotonic dose-responses are evidenced in the scientific literature and to evaluate the extent to which they may impact U.S. EPA’s chemical testing and risk assessment.

Incorporating a Capability for Estimating Inhalation Doses in ...

EPA Pesticide Factsheets

Report and Data Files This report presents the approach to be used to incorporate in the U.S. Environmental Protection Agency’s TEVA-SPOT software (U.S.EPA 2014) a capability for estimating inhalation doses that result from the most important sources of contaminated aerosols and volatile contaminants during a contamination event.

Patient radiation doses in interventional cardiology in the U.S.: Advisory data sets and possible initial values for U.S. reference levels

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

Miller, Donald L.; Hilohi, C. Michael; Spelic, David C.

2012-10-15

Purpose: To determine patient radiation doses from interventional cardiology procedures in the U.S and to suggest possible initial values for U.S. benchmarks for patient radiation dose from selected interventional cardiology procedures [fluoroscopically guided diagnostic cardiac catheterization and percutaneous coronary intervention (PCI)]. Methods: Patient radiation dose metrics were derived from analysis of data from the 2008 to 2009 Nationwide Evaluation of X-ray Trends (NEXT) survey of cardiac catheterization. This analysis used deidentified data and did not require review by an IRB. Data from 171 facilities in 30 states were analyzed. The distributions (percentiles) of radiation dose metrics were determined for diagnosticmore » cardiac catheterizations, PCI, and combined diagnostic and PCI procedures. Confidence intervals for these dose distributions were determined using bootstrap resampling. Results: Percentile distributions (advisory data sets) and possible preliminary U.S. reference levels (based on the 75th percentile of the dose distributions) are provided for cumulative air kerma at the reference point (K{sub a,r}), cumulative air kerma-area product (P{sub KA}), fluoroscopy time, and number of cine runs. Dose distributions are sufficiently detailed to permit dose audits as described in National Council on Radiation Protection and Measurements Report No. 168. Fluoroscopy times are consistent with those observed in European studies, but P{sub KA} is higher in the U.S. Conclusions: Sufficient data exist to suggest possible initial benchmarks for patient radiation dose for certain interventional cardiology procedures in the U.S. Our data suggest that patient radiation dose in these procedures is not optimized in U.S. practice.« less

Impact of arachidonic versus eicosapentaenoic acid on exotonin-induced lung vascular leakage: relation to 4-series versus 5-series leukotriene generation.

PubMed

Grimminger, F; Wahn, H; Mayer, K; Kiss, L; Walmrath, D; Seeger, W

1997-02-01

Escherichia coli hemolysin (HlyA) is a proteinaceous pore-forming exotoxin that is implicated as a significant pathogenicity factor in extraintestinal E. coli infections including sepsis. In perfused rabbit lungs, subcytolytic concentrations of the toxin evoke thromboxane-mediated vasoconstriction and prostanoid-independent protracted vascular permeability increase (11). In the present study, the influence of submicromolar concentrations of free arachidonic acid (AA) and eicosapentaenoic acid (EPA) on the HlyA-induced leakage response was investigated. HlyA at concentration from 0.02 to 0.06 hemolytic units/ml provoked a dose-dependent, severalfold increase in the capillary filtration coefficient (Kfc), accompanied by the release of leukotriene(LT)B4, LTC4, and LTE4 into the recirculating buffer fluid. Simultaneous application of 100 nmol/L AA markedly augmented the HlyA-elicited leakage response, concomitant with an amplification of LTB4 release and a change in the kinetics of cysteinyl-LT generation. In contrast, 50 to 200 nmol/L EPA suppressed in a dose-dependent manner the HlyA-induced increase in Kfc values. This was accompanied by a blockage of 4-series LT generation and a dose-dependent appearance of LTB5, LTC5, and LTE5. In addition, EPA fully antagonized the AA-induced amplification of the HlyA-provoked Kfc increase, again accompanied by a shift from 4-series to 5-series LT generation. We conclude that the vascular leakage provoked by HlyA in rabbit lungs is differentially influenced by free AA versus free EPA, related to the generation of 4- versus 5-series leukotrienes. The composition of lipid emulsions used for parenteral nutrition may thus influence inflammatory capillary leakage.

Dose-dependent effects of fish oil on cardio-metabolic biomarkers in healthy middle-aged and elderly Chinese people: a double-blind randomized controlled trial.

PubMed

Song, Jia; Hu, Manjiang; Li, Cheng; Yang, Bo; Ding, Qing; Wang, Chunhong; Mao, Limei

2018-06-20

n-3PUFA consumption has been widely accepted as a nutritional strategy for the secondary prevention of cardiovascular events in patients at high risk of cardiovascular disease (CVD), but little is known about the dose-response relationship between dietary n-3PUFA and serum biomarkers associated with cardiovascular health in the general population. The present study involved a 12-week double-blind, randomized controlled trial to explore the effects of fish oil with different doses (0.31, 0.62 and 1.24 g d-1 of EPA and DHA) on serum fatty acids and cardio-metabolic biomarkers including adiponectin, inflammatory markers, lipid profiles and fasting glucose in healthy middle-aged and elderly Chinese people. 240 volunteers met our inclusion criteria. A total of 39 subjects dropped out and 201 finally completed the intervention. No significant differences in baseline characteristics and daily intakes of dietary nutrients were detected among all groups. After a 12-week intervention, fish oil dose-dependently enhanced serum EPA, DHA, n-3PUFA and adiponectin (except for 0.31 g d-1), but decreased serum n-6/n-3PUFA, TG and fasting glucose. Changes in the above indicators from the baseline to week 12 in fish oil groups significantly differed from those in the control. Meanwhile, all the doses of EPA and DHA led to decreases in serum CRP; only 1.24 g d-1 led to an increase in HDL-C with a concurrent decrease in TC/HDL-C even though these changes were not significantly different among all groups. All the findings suggested that fish oil dose-dependently regulated serum PUFA and cardio-metabolic biomarkers including adiponectin, CRP, lipid profiles and fasting glucose in healthy middle-aged and elderly Chinese people who consumed insufficient dietary n-3PUFA, and the most desirable changes were observed for 1.24 g d-1.

Minimal food effect for eicosapentaenoic acid and docosahexaenoic acid bioavailability from omega-3-acid ethyl esters with an Advanced Lipid TechnologiesTM (ALT®)-based formulation.

PubMed

Lopez-Toledano, Miguel A; Thorsteinsson, Thorsteinn; Daak, Ahmed A; Maki, Kevin C; Johns, Colleen; Rabinowicz, Adrian L; Sancilio, Frederick D

The absorption of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) omega-3-acid ethyl esters (EEs) is influenced by food. There is a need for a formulation of EE that is less impacted by food effect. SC401 is a novel Advanced Lipid Technologies-based formulation of EPA-EE and DHA-EE. In the presence of an aqueous medium, Advanced Lipid Technologies forms stable micelles in situ independent of bile salt secretion. This effect is hypothesized to improve EPA-EE and DHA-EE bioavailability while it helps mitigate the food effect associated with their consumption. The aim of the article was to assess the effect of food on the bioavailability of DHA and EPA after a single oral dose of 1530 mg omega-3 fatty acids EE (SC401) in 24 healthy subjects under fasted and low-fat (9% of total calories from fat) and high-fat (50% of total calories from fat) meal conditions. This was a randomized, open-label, single-dose, 3-period, 3-way crossover study. Blood samples for pharmacokinetic analyses were taken at predose and at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12 and 24 hours postdose. To assess the safety of the intervention, active monitoring of adverse events, physical examinations, vital signs, clinical laboratory assessments (chemistry, hematology, and urinalysis), and 12-lead electrocardiograms were conducted. SC401 showed high bioavailability of both EPA and DHA in fasted, low-fat meal, and high-fat meal conditions. No differences were found in SC401 DHA AUC 0-t (t = 24 hours) among the 3 conditions (91.69% high-fat/fasted, 97.12% low-fat/fasted, and 105.92% low-fat/high-fat; P > .05 in all cases). In contrast, SC401 EPA AUC 0-t was affected by food intake (179.06% high-fat/fasted, P < .0001; 150.05% low-fat/fasted, P < .0001) and the amount of fat taken with SC401 (83.80% low-fat/high-fat; P = .0009). SC401 was safe and well tolerated. A single dose of SC401 resulted in high levels of EPA and DHA total lipids in plasma in fasting and fed conditions. SC401 overcame the food effect for DHA and partially ameliorated it for EPA. SC401 represents a convenient option for treatment of severe hypertriglyceridemia, especially for patients under a restricted intake of dietary fat. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Children’s Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making

PubMed Central

Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-01-01

Background: Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)’s National Drinking Water Advisory Council (NDWAC) recommended establishment of a “health-based, household action level” for lead in drinking water based on children’s exposure. Objectives: The primary objective was to develop a coupled exposure–dose modeling approach that can be used to determine what drinking water lead concentrations keep children’s blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. Methods: A modeling approach using the EPA’s Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Results: Modeled BLLs compared well with nationally representative BLLs (0–23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. Conclusions: This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605 PMID:28934096

Characterizing Vegetation Model Skill and Uncertainty in Simulated Ecosystem Response to Climate Change in the United States

NASA Astrophysics Data System (ADS)

Drapek, R. J.; Kim, J. B.

2013-12-01

We simulated ecosystem response to climate change in the USA and Canada at a 5 arc-minute grid resolution using the MC1 dynamic global vegetation model and nine CMIP3 future climate projections as input. The climate projections were produced by 3 GCMs simulating 3 SRES emissions scenarios. We examined MC1 outputs for the conterminous USA by summarizing them by EPA level II and III ecoregions to characterize model skill and evaluate the magnitude and uncertainties of simulated ecosystem response to climate change. First, we evaluated model skill by comparing outputs from the recent historical period with benchmark datasets. Distribution of potential natural vegetation simulated by MC1 was compared with Kuchler's map. Above ground live carbon simulated by MC1 was compared with the National Biomass and Carbon Dataset. Fire return intervals calculated by MC1 were compared with maximum and minimum values compiled for the United States. Each EPA Level III Ecoregion was scored for average agreement with corresponding benchmark data and an average score was calculated for all three types of output. Greatest agreement with benchmark data happened in the Western Cordillera, the Ozark / Ouachita-Appalachian Forests, and the Southeastern USA Plains (EPA Level II Ecoregions). The lowest agreement happened in the Everglades and the Tamaulipas-Texas Semiarid Plain. For simulated ecosystem response to future climate projections we examined MC1 output for shifts in vegetation type, vegetation carbon, runoff, and biomass consumed by fire. Each ecoregion was scored for the amount of change from historical conditions for each variable and an average score was calculated. Smallest changes were forecast for Western Cordillera and Marine West Coast Forest ecosystems. Largest changes were forecast for the Cold Deserts, the Mixed Wood Plains, and the Central USA Plains. By combining scores of model skill for the historical period for each EPA Level 3 Ecoregion with scores representing the magnitude of ecosystem changes in the future, we identified high and low uncertainty ecoregions. The largest anticipated changes and the lowest measures of model skill coincide in the Central USA Plains and the Mixed Wood Plains. The combination of low model skill and high degree of ecosystem change elevate the importance of our uncertainty in this ecoregion. The highest projected changes coincide with relatively high model skill in the Cold Deserts. Climate adaptation efforts are the most likely to pay off in these regions. Finally, highest model skill and lowest anticipated changes coincide in the Western Cordillera and the Marine West Coast Forests. These regions may be relatively low-risk for climate change impacts when compared to the other ecoregions. These results represent only the first step in this type of analysis; there exist many ways to strengthen it. One, MC1 calibrations can be optimized using a structured optimization technique. Two, a larger set of climate projections can be used to capture a fuller range of GCMs and emissions scenarios. And three, employing an ensemble of vegetation models would make the analysis more robust.

Quantitative simulation of intracellular signaling cascades in a Virtual Liver: estimating dose dependent changes in hepatocellular proliferation and apoptosis

EPA Science Inventory

The US EPA Virtual Liver (v-Liver™) is developing an approach to predict dose-dependent hepatotoxicity as an in vivo tissue level response using in vitro data. The v-Liver accomplishes this using an in silico agent-based systems model that dynamically integrates environmental exp...

EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) A PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC ( PBPK/PD ) MODEL FOR ASSESSING HUMAN EXPOSURE AND RISK

EPA Science Inventory

The Exposure Related Dose Estimating Model (ERDEM) is a PBPK/PD modeling system that was developed by EPA's National Exposure Research Laboratory (NERL). The ERDEM framework provides the flexibility either to use existing models and to build new PBPK and PBPK/PD models to address...

IRIS Toxicological Review of Dichloromethane (Methylene ...

EPA Pesticide Factsheets

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of Dichloromethane that when finalized will appear on the Integrated Risk Information System (IRIS) database. The draft Toxicological Review of Dichloromethane provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to dichloromethane.

Environmental consequences of postulated plutonium releases from Westinghouse PFDL, Cheswick, Pennsylvania, as a result of severe natural phenomena

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

McPherson, R.B.; Watson, E.C.

1979-06-01

Potential environmental consequences in terms of radiation dose to people are presented for postulated accidents due to earthquakes, tornadoes, high straight-line winds, and floods. Maximum plutonium deposition values are given for significant locations around the site. All important potential exposure pathways are examined. The most likely calculated 50-year collective committed dose equivalents are all much lower than the collective dose equivalent expected from 50 years of exposure to natural background radiation and medical x-rays except Earthquake No. 4 and the 260-mph tornado. The most likely maximum residual plutonium contamination estimated to be deposited offsite following Earthquake No. 4, and themore » 200-mph and 260-mph tornadoes are above the Environmental Protection Agency's (EPA) proposed guideline for plutonium in the general environment of 0.2 ..mu..Ci/m/sup 2/. The deposition values following the other severe natural phenomena are below the EPA proposed guideline.« less

Benchmarking the minimum Electron Beam (eBeam) dose required for the sterilization of space foods

NASA Astrophysics Data System (ADS)

Bhatia, Sohini S.; Wall, Kayley R.; Kerth, Chris R.; Pillai, Suresh D.

2018-02-01

As manned space missions extend in length, the safety, nutrition, acceptability, and shelf life of space foods are of paramount importance to NASA. Since food and mealtimes play a key role in reducing stress and boredom of prolonged missions, the quality of food in terms of appearance, flavor, texture, and aroma can have significant psychological ramifications on astronaut performance. The FDA, which oversees space foods, currently requires a minimum dose of 44 kGy for irradiated space foods. The underlying hypothesis was that commercial sterility of space foods could be achieved at a significantly lower dose, and this lowered dose would positively affect the shelf life of the product. Electron beam processed beef fajitas were used as an example NASA space food to benchmark the minimum eBeam dose required for sterility. A 15 kGy dose was able to achieve an approximately 10 log reduction in Shiga-toxin-producing Escherichia coli bacteria, and a 5 log reduction in Clostridium sporogenes spores. Furthermore, accelerated shelf life testing (ASLT) to determine sensory and quality characteristics under various conditions was conducted. Using Multidimensional gas-chromatography-olfactometry-mass spectrometry (MDGC-O-MS), numerous volatiles were shown to be dependent on the dose applied to the product. Furthermore, concentrations of off -flavor aroma compounds such as dimethyl sulfide were decreased at the reduced 15 kGy dose. The results suggest that the combination of conventional cooking combined with eBeam processing (15 kGy) can achieve the safety and shelf-life objectives needed for long duration space-foods.

Skin cancer and inorganic arsenic: uncertainty-status of risk.

PubMed

Brown, K G; Guo, H R; Kuo, T L; Greene, H L

1997-02-01

The current U.S. EPA standard for inorganic arsenic in drinking water is 50 ppb (microgram/L), dating to the National Interim Primary Drinking Water Regulation of 1976. The current EPA risk analysis predicts an increased lifetime skin cancer risk on the order of 3 or 4 per 1000 from chronic exposure at that concentration. Revision of the standard to only a few ppb, perhaps even less than 1 ppb, may be indicated by the EPA analysis to reduce the lifetime risk to an acceptable level. The cost to water utilities, and ultimately to their consumers, to conform to such a large reduction in the standard could easily reach several billion dollars, so it is particularly important to assess accurately the current risk and the risk reduction that would be achieved by a lower standard. This article addresses the major sources of uncertainty in the EPA analysis with respect to this objective. Specifically, it focuses on uncertainty and variability in the exposure estimates for the landmark study of Tseng and colleagues in Taiwan, analyzed using a reconstruction of the their exposure data. It is concluded that while the available dataset is suitable to establish the hazard of skin cancer, it is too highly summarized for reliable dose-response assessment. A new epidemiologic study is needed, designed for the requirements of dose-response assessment.

75 FR 11174 - Pesticide Product Registration Approval

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-10

..., contraceptive (EPA File Symbol 56228-GN), containing 1.0 milliliter doses in pre-packaged syringes at .03... product, Gonacon Immunocontraceptive Vaccine contraceptive. During the public comment period for this...

Effects of aspirin in combination with EPA and DHA on HDL-C cholesterol and ApoA1 exchange in individuals with type 2 diabetes mellitus.

PubMed

Block, Robert C; Holub, Ashley; Abdolahi, Amir; Tu, Xin M; Mousa, Shaker A; Oda, Michael N

2017-11-01

Low-dose aspirin is an effective drug for the prevention of cardiovascular disease (CVD) events but individuals with diabetes mellitus can be subject to 'aspirin resistance'. Thus, aspirin's effect in these individuals is controversial. Higher blood levels of seafood-derived omega-3 polyunsaturated fatty acids (ω3) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have beneficial effects in reducing risk of CVD events but few studies have examined the interaction of plasma EPA and DHA with aspirin ingestion. Our study examined the combinatory effects of EPA, DHA, and aspirin ingestion on HDL-cholesterol (HDL-C) and apoA-I exchange (shown to be associated with CVD event risk). 30 adults with Type 2 diabetes mellitus ingested aspirin (81mg/day) for 7 consecutive days, EPA+DHA (2.6g/day) for 28 days, then both for 7 days. Plasma was collected at baseline and at 5 subsequent visits including 4h after each aspirin ingestion. Mixed model methods were used to determine HDL-C-concentrations and apoA-I exchange compared to the baseline visit values. LOWESS curves were used for non-linear analyses of outcomes to help discern change patterns, which was followed by piecewise linear functions for formal testing of curvilinear relationships. Significant changes (p < 0.05) compared to baseline in both HDL-C-concentrations and apoA-I exchange were present at different times. After 7 days of aspirin-only ingestion, apoA-I exchange was significantly modified by increasing levels of DHA concentration, with increased apoA-I exchange observed up until log(DHA) of 4.6 and decreased exchange thereafter (p = 0.03). These LOWESS curve effects were not observed for EPA or HDL-C (p > 0.05). Aspirin's effects on apoA-I exchange were the greatest when EPA or DHA concentrations were moderate compared to high or low. Comparison of EPA, DHA, and EPA+DHA LOWESS curves, demonstrated that the majority of the effect is due to DHA. Our results strongly suggest that plasma concentrations of EPA and DHA influence aspirin effects on lipid mediators of CVD event risk where their concentrations are most beneficial when moderate, not high or low. These effects on HDL-C cholesterol and apoA-I exchange are novel. Personalized dosing of DHA in those who take aspirin may be a beneficial option for patients with type 2 diabetes mellitus. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: a preliminary 1H MRS study.

PubMed

McNamara, Robert K; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Chu, Wen-Jang; Weber, Wade A; Welge, Jeffrey A; Strawn, Jeffrey R; Adler, Caleb M; DelBello, Melissa P

2016-05-01

To use proton magnetic resonance spectroscopy ((1)H MRS) to investigate the effects of fish oil (FO) supplementation on cortical metabolite concentrations in adolescents with major depressive disorder (MDD). Metabolite concentrations were determined by (1)H MRS in the anterior cingulate cortex and bilateral dorsolateral prefrontal cortex (DLPFC) of adolescents with MDD before and following 10-week open-label supplementation with low (2.4 g/day, n = 7) or high (16.2 g/day, n = 7) dose FO. Depressive symptom severity scores and erythrocyte fatty acid levels were also determined. Baseline erythrocyte eicosapentaenoic acid (EPA) composition was positively correlated, and arachidonic acid (AA) and the AA/EPA ratio were inversely correlated, with choline (Cho) concentrations in the right DLPFC. Docosahexaenoic acid (DHA) composition was inversely correlated with myo-inositol (mI) concentrations in the left DLPFC. Erythrocyte EPA and DHA composition increased, and AA decreased, significantly following low-dose and high-dose FO supplementation. In the intent-to-treat sample, depressive symptom severity scores decreased significantly in the high-dose group (-40%, P < 0.0001) and there was a trend in the low-dose group (-20%, P = 0.06). There were no significant baseline-endpoint changes in metabolite levels in each voxel. In the low-dose group there were changes with large effect sizes, including a decrease in mI in the left DLPFC (-12%, P = 0.18, d = 0.8) and increases in glutamate + glutamine (Glx) (+12%, P = 0.19, d = 0.8) and Cho (+15%, P = 0.08, d = 1.2) in the right DLPFC. In the high-dose group, there was a trend for increases in Cho in the right DLPFC (+10%, P = 0.09, d = 1.2). These preliminary data suggest that increasing the LCn-3 fatty acid status of adolescent MDD patients is associated with subtle changes in Glx, mI, and Cho concentrations in the DLPFC that warrant further evaluation in a larger controlled trial.

How Analysis Informs Regulation:Success and Failure of ...

EPA Pesticide Factsheets

How Analysis Informs Regulation:Success and Failure of Evolving Approaches to Polyfluoroalkyl Acid Contamination The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.

Developing Decontamination Tools and Approaches to ...

EPA Pesticide Factsheets

Developing Decontamination Tools and Approaches to Address Indoor Pesticide Contamination from Improper Bed Bug Treatments The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.

A Method for Improved Interpretation of "Spot" Biomarker Data ...

EPA Pesticide Factsheets

A Method for Improved Interpretation of "Spot" Biomarker Data The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.

The grout/glass performance assessment code system (GPACS) with verification and benchmarking

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

Piepho, M.G.; Sutherland, W.H.; Rittmann, P.D.

1994-12-01

GPACS is a computer code system for calculating water flow (unsaturated or saturated), solute transport, and human doses due to the slow release of contaminants from a waste form (in particular grout or glass) through an engineered system and through a vadose zone to an aquifer, well and river. This dual-purpose document is intended to serve as a user`s guide and verification/benchmark document for the Grout/Glass Performance Assessment Code system (GPACS). GPACS can be used for low-level-waste (LLW) Glass Performance Assessment and many other applications including other low-level-waste performance assessments and risk assessments. Based on all the cses presented, GPACSmore » is adequate (verified) for calculating water flow and contaminant transport in unsaturated-zone sediments and for calculating human doses via the groundwater pathway.« less

Linking log files with dosimetric accuracy--A multi-institutional study on quality assurance of volumetric modulated arc therapy.

PubMed

Pasler, Marlies; Kaas, Jochem; Perik, Thijs; Geuze, Job; Dreindl, Ralf; Künzler, Thomas; Wittkamper, Frits; Georg, Dietmar

2015-12-01

To systematically evaluate machine specific quality assurance (QA) for volumetric modulated arc therapy (VMAT) based on log files by applying a dynamic benchmark plan. A VMAT benchmark plan was created and tested on 18 Elekta linacs (13 MLCi or MLCi2, 5 Agility) at 4 different institutions. Linac log files were analyzed and a delivery robustness index was introduced. For dosimetric measurements an ionization chamber array was used. Relative dose deviations were assessed by mean gamma for each control point and compared to the log file evaluation. Fourteen linacs delivered the VMAT benchmark plan, while 4 linacs failed by consistently terminating the delivery. The mean leaf error (±1SD) was 0.3±0.2 mm for all linacs. Large MLC maximum errors up to 6.5 mm were observed at reversal positions. Delivery robustness index accounting for MLC position correction (0.8-1.0) correlated with delivery time (80-128 s) and depended on dose rate performance. Dosimetric evaluation indicated in general accurate plan reproducibility with γ(mean)(±1 SD)=0.4±0.2 for 1 mm/1%. However single control point analysis revealed larger deviations and attributed well to log file analysis. The designed benchmark plan helped identify linac related malfunctions in dynamic mode for VMAT. Log files serve as an important additional QA measure to understand and visualize dynamic linac parameters. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

NESHAP Dose-Release Factor Isopleths for Five Source-to-Receptor Distances from the Center of Site and H-Area for all Compass Sectors at SRS using CAP88-PC Version 4.0

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

Trimor, P.

The Environmental Protection Agency (EPA) requires the use of the computer model CAP88-PC to estimate the total effective doses (TED) for demonstrating compliance with 40 CFR 61, Subpart H (EPA 2006), the National Emission Standards for Hazardous Air Pollutants (NESHAP) regulations. As such, CAP88 Version 4.0 was used to calculate the receptor dose due to routine atmospheric releases at the Savannah River Site (SRS). For estimation, NESHAP dose-release factors (DRFs) have been supplied to Environmental Compliance and Area Closure Projects (EC&ACP) for many years. DRFs represent the dose to a maximum receptor exposed to 1 Ci of a specified radionuclidemore » being released into the atmosphere. They are periodically updated to include changes in the CAP88 version, input parameter values, site meteorology, and location of the maximally exposed individual (MEI). This report presents the DRFs of tritium oxide released at two onsite locations, center-of-site (COS) and H-Area, at 0 ft. elevation to maximally exposed individuals (MEIs) located 1000, 3000, 6000, 9000, and 12000 meters from the release areas for 16 compass sectors. The analysis makes use of area-specific meteorological data (Viner 2014).« less

A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova(®) compared to Lovaza(®) in a pharmacokinetic single-dose evaluation) study.

PubMed

Davidson, Michael H; Johnson, Judith; Rooney, Michael W; Kyle, Michael L; Kling, Douglas F

2012-01-01

Omega-3 (OM-3) fatty acid products are indicated for the treatment of severe hypertriglyceridemia; however, the omega-3-acid ethyl ester (OM-3 EE) formulations require significant pancreatic lipase stimulation with high-fat meals for adequate intestinal absorption of the metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A novel omega-3 free fatty acid (OM-3 FFA) formulation (Epanova(®), Omthera Pharmaceuticals Inc., Princeton, NJ) was developed to maximize EPA and DHA bioavailability during a low-fat diet. To compare the relative bioavailability of EPA and DHA from single 4-gram doses of OM-3 FFA and a prescription OM-3 EE (Lovaza(®), GlaxoSmithKline, Research Triangle Park, NC). This was a randomized, open-label, single dose, 4-way crossover, bioavailability study of OM-3 FFA and OM-3 EE administered during periods of low-fat and high-fat consumption to 54 overweight adults. Bioavailability was determined by the ln-transformed area under the plasma concentration versus time curve (AUC(0-t)) during a 24-hour interval for EPA and DHA (baseline-adjusted). The baseline-adjusted AUC(0-t) for total EPA + DHA during the low-fat period was 4.0-fold greater with OM-3 FFA compared with OM-3 EE (2650.2 vs 662.0 nmol·h/mL, respectively; P < .0001). During the high-fat period, AUC(0-t) for OM-3 FFA was approximately 1.3-fold greater than OM-3 EE (P < .0001). During the low-fat period, 30 of 51 (58.8%) subjects dosed with OM-3 FFA maintained an AUC(0-t) that was ≥50% of the respective high-fat AUC(0-t) in contrast to only 3 of 50 (6.0%) subjects dosed with OM-3 EE. During a low-fat consumption period, the OM-3 FFA formulation provided dramatically improved bioavailability over the OM-3 EE formulation in overweight subjects. These findings offer a potential therapeutic advantage of the OM-3 FFA formulation for the treatment of severe hypertriglyceridemia as these patients are expected to adhere to a low-fat diet. Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Gamma irradiator dose mapping simulation using the MCNP code and benchmarking with dosimetry.

PubMed

Sohrabpour, M; Hassanzadeh, M; Shahriari, M; Sharifzadeh, M

2002-10-01

The Monte Carlo transport code, MCNP, has been applied in simulating dose rate distribution in the IR-136 gamma irradiator system. Isodose curves, cumulative dose values, and system design data such as throughputs, over-dose-ratios, and efficiencies have been simulated as functions of product density. Simulated isodose curves, and cumulative dose values were compared with dosimetry values obtained using polymethyle-methacrylate, Fricke, ethanol-chlorobenzene, and potassium dichromate dosimeters. The produced system design data were also found to agree quite favorably with those of the system manufacturer's data. MCNP has thus been found to be an effective transport code for handling of various dose mapping excercises for gamma irradiators.

Federal Guidance for Radiation Protection

EPA Pesticide Factsheets

EPA produces federal guidance technical reports, which standardize dose and risk assessment and issues radiation protection guidance to federal agencies. This page provides links to federal guidance policy recommendations and technical reports.

Toxicogenomics and cancer risk assessment: a framework for key event analysis and dose-response assessment for nongenotoxic carcinogens.

PubMed

Bercu, Joel P; Jolly, Robert A; Flagella, Kelly M; Baker, Thomas K; Romero, Pedro; Stevens, James L

2010-12-01

In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose-response. The dose-response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose-response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework. Copyright © 2010 Elsevier Inc. All rights reserved.

Change in blood levels of eicosapentaenoic acid and posttraumatic stress symptom: A secondary analysis of data from a placebo-controlled trial of omega3 supplements.

PubMed

Matsuoka, Yutaka J; Hamazaki, Kei; Nishi, Daisuke; Hamazaki, Tomohito

2016-11-15

Eicosapentaenoic acid (EPA) is suggested to be protective against posttraumatic stress disorder (PTSD) from two observational studies. We previously conducted a randomized controlled trial and found no effect of docosahexaenoic acid (DHA) for prevention of PTSD. This secondary analysis aimed to determine whether change in blood levels of EPA is associated with PTSD symptoms. The percentages of EPA, DHA, and arachidonic acid (AA) were measured in erythrocyte membranes at baseline and posttreatment in 110 participants with severe physical injury who were randomly assigned to receive either a daily dose of 1,470mg DHA and 147mg EPA or of placebo for 12 weeks. Associations between change in erythrocyte fatty acid levels during the trial controlling for each baseline level and PTSD severity at 12 weeks were analyzed by treatment arm. In the omega3 supplements arm, changes in EPA+DHA (p=.023) and EPA (p=.001) as well as the EPA:AA ratio (p=.000) and EPA: DHA ratio (p=.013) were inversely correlated with PTSD severity. Change in AA was positively correlated with PTSD severity (p=.001). This trial was conducted at a single-center in Japan and PTSD symptoms in most participants were not serious. Increased erythrocyte level of EPA during the trial was associated with low severity of PTSD symptoms in patients receiving omega3 supplements. Copyright © 2016 Elsevier B.V. All rights reserved.

#2) EPA Perspective - Exposure and Effects Prediction and ...

EPA Pesticide Factsheets

Outline •Biomarkers as a risk assessment tool–exposure assessment & risk characterization•CDC’s NHANES as a source of biomarker data–history, goals & available data•Review of NHANES publications (1999-2013)–chemicals, uses, trends & challenges•NHANES biomarker case study–recommendations for future research The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.

2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) Dose-Response Studies: Preliminary Literature Search Results and Request for Additional Studies

EPA Science Inventory

EPA invited the public to comment on the preliminary list of in vivo mammalian dose-response citations for 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). This list was compiled as a first step in the development of EPA’s response to the National Academy of Sciences comments (NAS, 2...

Chemical Risk Assessment: Selected Federal Agencies’ Procedures, Assumptions, and Policies

DTIC Science & Technology

2001-08-01

adverse effects of exposures to hazardous substances or situations. It is a complex but valuable set of tools for federal regulatory agencies, helping...Act DES diethylstilbestrol DOT Department of Transportation ED effective dose EPA Environmental Protection Agency EPCRA Emergency Planning and...ISO International Organization for Standardization LED lowest effective dose LOAEL lowest observed adverse effect level LOEL lowest observed effect

Eicosapentaenoic acid (EPA) induced apoptosis in HepG2 cells through ROS-Ca(2+)-JNK mitochondrial pathways.

PubMed

Zhang, Yuanyuan; Han, Lirong; Qi, Wentao; Cheng, Dai; Ma, Xiaolei; Hou, Lihua; Cao, Xiaohong; Wang, Chunling

2015-01-24

Eicosapentaenoic acid (EPA), a well-known dietary n-3 PUFAS, has been considered to inhibit proliferation of tumor cells. However, the molecular mechanism related to EPA-induced liver cancer cells apoptosis has not been reported. In this study, we investigated the effect of EPA on HepG2 cells proliferation and apoptosis mechanism through mitochondrial pathways. EPA inhibited proliferation of HepG2 cells in a dose-dependent manner and had no significant effect on the cell viability of humor normal liver L-02 cells. It was found that EPA initially evoked ROS formation, leading to [Ca(2+)]c accumulation and the mitochondrial permeability transition pore (MPTP) opening; EPA-induced HepG2 cells apoptosis was inhibited by N-acetylcysteine (NAC, an inhibitor of ROS), 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM, a chelator of calcium) and CsA (inhibitor of MPTP). The relationship between ROS production, the increase of cytoplasmic Ca and MPTP opening was detected. It seems that ROS may act as an upstream regulator of EPA-induced [Ca(2+)]c generation, moreover, generation of ROS, overload of mitochondrial [Ca(2+)]c, and JNK activated cause the opening of MPTP. Western blotting results showed that EPA elevated the phosphorylation status of JNK, processes associated with the ROS generation. Simultaneously, the apoptosis induced by EPA was related to release of cytochrome C from mitochondria to cytoplasm through the MPTP and activation of caspase-9 and caspase-3. These results suggest that EPA induces apoptosis through ROS-Ca(2+)-JNK mitochondrial pathways. Copyright © 2014 Elsevier Inc. All rights reserved.

IRIS Toxicological Review for Carbon Tetrachloride ...

EPA Pesticide Factsheets

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. Comments received from other Federal agencies and White House Offices are provided below with external peer review panel comments. EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of carbon tetrachloride that will appear on the Integrated Risk Information System (IRIS) database.

Litigation Technical Support and Services, Rocky Mountain Arsenal. Biota Remedial Investigation (Version 3.2). Volume 2

DTIC Science & Technology

1989-05-01

Trimethyl phosphate (TMP), a known mutagen, is a minor contaminant in the processing of azodrin (EPA, 1985h). Tke EPA (1985h) states that azodrin is...day (Sax, 1984)) for cholinesterase inhibition based on a chronic rat feeding study that showed minor depressive trends in AChE at dose levels of 0.09...3 (Giesy at al., 1979). At 10 ppb cadmium, growth reduction was observed in a fern (Salmina natans) and duckweed ( Lemna maldixiana) (Hutchinson and

IRIS Toxicological Review of Ethylene Glycol Mono-Butyl ...

EPA Pesticide Factsheets

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 other Federal agencies and White House Offices are provided below with external peer review panel comments. EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of EGBE that will appear on the Integrated Risk Information System (IRIS) database.

Hand rub dose needed for a single disinfection varies according to product: a bias in benchmarking using indirect hand hygiene indicator.

PubMed

Girard, Raphaële; Aupee, Martine; Erb, Martine; Bettinger, Anne; Jouve, Alice

2012-12-01

The 3ml volume currently used as the hand hygiene (HH) measure has been explored as the pertinent dose for an indirect indicator of HH compliance. A multicenter study was conducted in order to ascertain the required dose using different products. The average contact duration before drying was measured and compared with references. Effective hand coverage had to include the whole hand and the wrist. Two durations were chosen as points of reference: 30s, as given by guidelines, and the duration validated by the European standard EN 1500. Each product was to be tested, using standardized procedures, by three nosocomial infection prevention teams, for three different doses (3, 2 and 1.5ml). Data from 27 products and 1706 tests were analyzed. Depending on the product, the dose needed to ensure a 30-s contact duration in 75% of tests ranging from 2ml to more than 3ml, and to ensure a contact duration exceeding the EN 1500 times in 75% of tests ranging from 1.5ml to more than 3ml. The aftermath interpretation is the following: if different products are used, the volume utilized does not give an unbiased estimation of the HH compliance. Other compliance evaluation methods remain necessary for efficient benchmarking. Copyright © 2012 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

What is a food and what is a medicinal product in the European Union? Use of the benchmark dose (BMD) methodology to define a threshold for "pharmacological action".

PubMed

Lachenmeier, Dirk W; Steffen, Christian; el-Atma, Oliver; Maixner, Sibylle; Löbell-Behrends, Sigrid; Kohl-Himmelseher, Matthias

2012-11-01

The decision criterion for the demarcation between foods and medicinal products in the EU is the significant "pharmacological action". Based on six examples of substances with ambivalent status, the benchmark dose (BMD) method is evaluated to provide a threshold for pharmacological action. Using significant dose-response models from literature clinical trial data or epidemiology, the BMD values were 63mg/day for caffeine, 5g/day for alcohol, 6mg/day for lovastatin, 769mg/day for glucosamine sulfate, 151mg/day for Ginkgo biloba extract, and 0.4mg/day for melatonin. The examples for caffeine and alcohol validate the approach because intake above BMD clearly exhibits pharmacological action. Nevertheless, due to uncertainties in dose-response modelling as well as the need for additional uncertainty factors to consider differences in sensitivity within the human population, a "borderline range" on the dose-response curve remains. "Pharmacological action" has proven to be not very well suited as binary decision criterion between foods and medicinal product. The European legislator should rethink the definition of medicinal products, as the current situation based on complicated case-by-case decisions on pharmacological action leads to an unregulated market flooded with potentially illegal food supplements. Copyright © 2012 Elsevier Inc. All rights reserved.

IRIS Toxicological Review of Propionaldehyde (External Review Draft)

EPA Science Inventory

EPA conducted a peer review of the scientific basis supporting the human health hazard and dose-response assessment of propionaldehyde that will appear on the Integrated Risk Information System (IRIS) database.

Benchmark solutions for the galactic heavy-ion transport equations with energy and spatial coupling

NASA Technical Reports Server (NTRS)

Ganapol, Barry D.; Townsend, Lawrence W.; Lamkin, Stanley L.; Wilson, John W.

1991-01-01

Nontrivial benchmark solutions are developed for the galactic heavy ion transport equations in the straightahead approximation with energy and spatial coupling. Analytical representations of the ion fluxes are obtained for a variety of sources with the assumption that the nuclear interaction parameters are energy independent. The method utilizes an analytical LaPlace transform inversion to yield a closed form representation that is computationally efficient. The flux profiles are then used to predict ion dose profiles, which are important for shield design studies.

Probabilistic Analysis of Radiation Doses for Shore-Based Individuals in Operation Tomodachi

DTIC Science & Technology

2013-05-01

Based Upon Oxygen Consumption Rates. EPA/600/R-06/129F, U.S. Environmental Protection Agency, Washington, D.C. May. USEPA (U.S. Environmental...pascal (Pa) pound-force per square inch (psi) 6.894 757 × 103 pascal (Pa) Angle/ Temperature /Time hour (h) 3.6 × 103 second (s) degree of arc (o...equivalent and effective dose is the sievert (Sv). (1 Sv = 1 J kg–1). 1 DTRA-TR-12-002: Probabilistic Analysis of Radiation Doses for Shore-Based

IRIS Toxicological Review of 1,2,3-Trichloropropane (External ...

EPA Pesticide Factsheets

EPA conducted a peer review of the scientific basis supporting the human health hazard and dose-response assessment of 1,2,3-trichloropropane (TCP) that once finalized will appear on the Integrated Risk Information System (IRIS) database. Peer review is meant to ensure that science is used credibly and appropriately in derivation of the dose-response assessments and toxicological characterization. This Tox Review provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to 1,2,3-trichloropropane.

Benchmark solutions for the galactic ion transport equations: Energy and spatially dependent problems

NASA Technical Reports Server (NTRS)

Ganapol, Barry D.; Townsend, Lawrence W.; Wilson, John W.

1989-01-01

Nontrivial benchmark solutions are developed for the galactic ion transport (GIT) equations in the straight-ahead approximation. These equations are used to predict potential radiation hazards in the upper atmosphere and in space. Two levels of difficulty are considered: (1) energy independent, and (2) spatially independent. The analysis emphasizes analytical methods never before applied to the GIT equations. Most of the representations derived have been numerically implemented and compared to more approximate calculations. Accurate ion fluxes are obtained (3 to 5 digits) for nontrivial sources. For monoenergetic beams, both accurate doses and fluxes are found. The benchmarks presented are useful in assessing the accuracy of transport algorithms designed to accommodate more complex radiation protection problems. In addition, these solutions can provide fast and accurate assessments of relatively simple shield configurations.

IRIS Toxicological Review of Chloroprene (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of chloroprene that will appear on the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Chloroprene (2000 External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of chloroprene that will appear on the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Trimethylbenzenes (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of trimethylbenzenes that will appear in the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Ammonia (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of ammonia that will appear in the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Pentachlorophenol (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of pentachlorophenol that will appear in the Integrated Risk Information System (IRIS) database.

Perspectives on the Application of Mechanistic Information in Chemical Hazard and Dose-Response Assessments

EPA Science Inventory

This overview summarizes several EPA Assessment publications reviewing approaches for applying mechanistic information in human health risk assessment and exploring opportunities for progress in this area.

Biota Modeling in EPA's Preliminary Remediation Goal and Dose Compliance Concentration Calculators for Use in EPA Superfund Risk Assessment: Explanation of Intake Rate Derivation, Transfer Factor Compilation, and Mass Loading Factor Sources

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

Manning, Karessa L.; Dolislager, Fredrick G.; Bellamy, Michael B.

The Preliminary Remediation Goal (PRG) and Dose Compliance Concentration (DCC) calculators are screening level tools that set forth Environmental Protection Agency's (EPA) recommended approaches, based upon currently available information with respect to risk assessment, for response actions at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) sites, commonly known as Superfund. The screening levels derived by the PRG and DCC calculators are used to identify isotopes contributing the highest risk and dose as well as establish preliminary remediation goals. Each calculator has a residential gardening scenario and subsistence farmer exposure scenarios that require modeling of the transfer of contaminants frommore » soil and water into various types of biota (crops and animal products). New publications of human intake rates of biota; farm animal intakes of water, soil, and fodder; and soil to plant interactions require updates be implemented into the PRG and DCC exposure scenarios. Recent improvements have been made in the biota modeling for these calculators, including newly derived biota intake rates, more comprehensive soil mass loading factors (MLFs), and more comprehensive soil to tissue transfer factors (TFs) for animals and soil to plant transfer factors (BV's). New biota have been added in both the produce and animal products categories that greatly improve the accuracy and utility of the PRG and DCC calculators and encompass greater geographic diversity on a national and international scale.« less

Potential uncertainty reduction in model-averaged benchmark dose estimates informed by an additional dose study.

PubMed

Shao, Kan; Small, Mitchell J

2011-10-01

A methodology is presented for assessing the information value of an additional dosage experiment in existing bioassay studies. The analysis demonstrates the potential reduction in the uncertainty of toxicity metrics derived from expanded studies, providing insights for future studies. Bayesian methods are used to fit alternative dose-response models using Markov chain Monte Carlo (MCMC) simulation for parameter estimation and Bayesian model averaging (BMA) is used to compare and combine the alternative models. BMA predictions for benchmark dose (BMD) are developed, with uncertainty in these predictions used to derive the lower bound BMDL. The MCMC and BMA results provide a basis for a subsequent Monte Carlo analysis that backcasts the dosage where an additional test group would have been most beneficial in reducing the uncertainty in the BMD prediction, along with the magnitude of the expected uncertainty reduction. Uncertainty reductions are measured in terms of reduced interval widths of predicted BMD values and increases in BMDL values that occur as a result of this reduced uncertainty. The methodology is illustrated using two existing data sets for TCDD carcinogenicity, fitted with two alternative dose-response models (logistic and quantal-linear). The example shows that an additional dose at a relatively high value would have been most effective for reducing the uncertainty in BMA BMD estimates, with predicted reductions in the widths of uncertainty intervals of approximately 30%, and expected increases in BMDL values of 5-10%. The results demonstrate that dose selection for studies that subsequently inform dose-response models can benefit from consideration of how these models will be fit, combined, and interpreted. © 2011 Society for Risk Analysis.

Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone.

PubMed

Poet, T S; Schlosser, P M; Rodriguez, C E; Parod, R J; Rodwell, D E; Kirman, C R

2016-04-01

The developmental effects of NMP are well studied in Sprague-Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose-response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose-response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose-response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Benchmark duration of work hours for development of fatigue symptoms in Japanese workers with adjustment for job-related stress.

PubMed

Suwazono, Yasushi; Dochi, Mirei; Kobayashi, Etsuko; Oishi, Mitsuhiro; Okubo, Yasushi; Tanaka, Kumihiko; Sakata, Kouichi

2008-12-01

The objective of this study was to calculate benchmark durations and lower 95% confidence limits for benchmark durations of working hours associated with subjective fatigue symptoms by applying the benchmark dose approach while adjusting for job-related stress using multiple logistic regression analyses. A self-administered questionnaire was completed by 3,069 male and 412 female daytime workers (age 18-67 years) in a Japanese steel company. The eight dependent variables in the Cumulative Fatigue Symptoms Index were decreased vitality, general fatigue, physical disorders, irritability, decreased willingness to work, anxiety, depressive feelings, and chronic tiredness. Independent variables were daily working hours, four subscales (job demand, job control, interpersonal relationship, and job suitability) of the Brief Job Stress Questionnaire, and other potential covariates. Using significant parameters for working hours and those for other covariates, the benchmark durations of working hours were calculated for the corresponding Index property. Benchmark response was set at 5% or 10%. Assuming a condition of worst job stress, the benchmark duration/lower 95% confidence limit for benchmark duration of working hours per day with a benchmark response of 5% or 10% were 10.0/9.4 or 11.7/10.7 (irritability) and 9.2/8.9 or 10.4/9.8 (chronic tiredness) in men and 8.9/8.4 or 9.8/8.9 (chronic tiredness) in women. The threshold amounts of working hours for fatigue symptoms under the worst job-related stress were very close to the standard daily working hours in Japan. The results strongly suggest that special attention should be paid to employees whose working hours exceed threshold amounts based on individual levels of job-related stress.

Agricultural use of municipal wastewater treatment plant ...

EPA Pesticide Factsheets

Agricultural use of municipal wastewater treatment plant sewage sludge as a source of per- and polyfluoroalkyl substance (PFAS) contamination in the environment The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.

SU-F-R-11: Designing Quality and Safety Informatics Through Implementation of a CT Radiation Dose Monitoring Program

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

Wilson, JM; Samei, E; Departments of Physics, Electrical and Computer Engineering, and Biomedical Engineering, and Medical Physics Graduate Program, Duke University, Durham, NC

2016-06-15

Purpose: Recent legislative and accreditation requirements have driven rapid development and implementation of CT radiation dose monitoring solutions. Institutions must determine how to improve quality, safety, and consistency of their clinical performance. The purpose of this work was to design a strategy and meaningful characterization of results from an in-house, clinically-deployed dose monitoring solution. Methods: A dose monitoring platform was designed by our imaging physics group that focused on extracting protocol parameters, dose metrics, and patient demographics and size. Compared to most commercial solutions, which focus on individual exam alerts and global thresholds, the program sought to characterize overall consistencymore » and targeted thresholds based on eight analytic interrogations. Those were based on explicit questions related to protocol application, national benchmarks, protocol and size-specific dose targets, operational consistency, outliers, temporal trends, intra-system variability, and consistent use of electronic protocols. Using historical data since the start of 2013, 95% and 99% intervals were used to establish yellow and amber parameterized dose alert thresholds, respectively, as a function of protocol, scanner, and size. Results: Quarterly reports have been generated for three hospitals for 3 quarters of 2015 totaling 27880, 28502, 30631 exams, respectively. Four adult and two pediatric protocols were higher than external institutional benchmarks. Four protocol dose levels were being inconsistently applied as a function of patient size. For the three hospitals, the minimum and maximum amber outlier percentages were [1.53%,2.28%], [0.76%,1.8%], [0.94%,1.17%], respectively. Compared with the electronic protocols, 10 protocols were found to be used with some inconsistency. Conclusion: Dose monitoring can satisfy requirements with global alert thresholds and patient dose records, but the real value is in optimizing patient-specific protocols, balancing image quality trade-offs that dose-reduction strategies promise, and improving the performance and consistency of a clinical operation. Data plots that capture patient demographics and scanner performance demonstrate that value.« less

Review and Design of Low-Dose Bacillus anthracis Inhalation ...

EPA Pesticide Factsheets

Report In July 2011, EPA NHSRC sponsored a Review and Design of Low-Dose Bacillus anthracis Inhalation Exposures meeting to review the research done to date and to identify gaps that future research should address regarding low-dose exposures. This effort brought together many organizations across the country, including EPA’s program offices, federal government agencies and laboratories, academia, and the private sector. Participants of the conference shared knowledge, explored differing opinions, and expanded understanding of the current state of research for low-dose exposure and future research needs. This report represents a summary of the presentations and discussions during the meeting.

EFFECT OF DOSE ON THE EXCRETION AND METABOLISM OF MONOMETHYLARSONIC ACID IN THE MOUSE

EPA Science Inventory

EFFECT OF DOSE ON THE EXCRETION AND METABOLISM OF MONOMETHYLARSONIC ACID IN THE MOUSE
M F Hughes1, V Devesa2, B C Edwards1, C T Mitchell1, E M Kenyon1, and D J Thomas1. 1US EPA, ORD, NHEERL, ETD, Research Triangle Park, NC; 2UNC-CH, CEMALB, Chapel Hill, NC

Monomethylar...

IRIS Toxicological Review of Urea (External Review Draft) ...

EPA Pesticide Factsheets

EPA conducted a peer review and public comment of the scientific basis of a draft report supporting the human health hazard and dose-response assessment of Urea that when finalized will appear on the Integrated Risk Information System (IRIS) database. The draft Toxicological Review of Urea provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to Urea.

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

EPA Pesticide Factsheets

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of Trichloroacetic acid (TCA) that when finalized will appear on the Integrated Risk Information System (IRIS) database. The draft Toxicological Review of trichloroacetic acid provides scientific support and rationale for the hazard and dose-response assessment pertaining to chronic exposure to trichloroacetic acid.

Biological activity of the azlactone derivative EPA-35 against Trypanosoma cruzi.

PubMed

de Azeredo, Camila Maria Oliveira; Ávila, Eloah Pereira; Pinheiro, Danielle Lobo Justo; Amarante, Giovanni Wilson; Soares, Maurilio José

2017-02-01

Chagas disease, caused by Trypanosoma cruzi, affects six to seven million people worldwide. Treatment is based on benznidazole, producing several side effects and debatable efficacy, highlighting the need for new alternative drugs. We investigated the activity of four C-4 functionalized azlactone derivatives (EPA-27, EPA-35, EPA-63 and EPA-91) as potential T. cruzi inhibitors. Screening with epimastigotes indicated EPA-35 as the best compound (IC50/24 h: 33 μM). This compound was 14.1 times more potent against intracellular amastigotes (IC50/24 h: 2.34 μM). Treatment of infected Vero cells for 72 h (up to 30 μM EPA-35) resulted in a dose-dependent decrease in number of trypomastigotes and amastigotes released in the supernatant, but the amastigote/trypomastigote ratio remained constant, indicating that amastigote growth was disturbed, but cell differentiation was unaffected. Analysis of treated epimastigotes by flow cytometry indicated that the plasma membrane remained intact, but there was a significant decrease in mitochondrial membrane potential. The pattern of cell distribution in the cell cycle stages (G1, G2, M) was unaltered in treated epimastigotes, indicating a trypanocidal rather than a trypanostatic activity. Scanning electron microscopy and flow cytometry showed epimastigotes with a round shape and decrease in cell size. Taken together, our data indicate that the EPA-35 is effective against T. cruzi. Synthetic transformation of EPA-35 into other derivatives may provide promising compounds for further evaluation against this parasite. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Comparative Analysis of EPA/DHA-PL Forage and Liposomes in Orotic Acid-Induced Nonalcoholic Fatty Liver Rats and Their Related Mechanisms.

PubMed

Chang, Mengru; Zhang, Tiantian; Han, Xiuqing; Tang, Qingjuan; Yanagita, Teruyoshi; Xu, Jie; Xue, Changhu; Wang, Yuming

2018-02-14

Nonalcoholic fatty liver disease (NAFLD) has become one predictive factor of death from various illnesses. The present study was to comparatively investigate the effects of eicosapentaenoic acid-enriched and docosahexaenoic acid-enriched phospholipids forage (EPA-PL and DHA-PL) and liposomes (lipo-EPA and lipo-DHA) on NAFLD and demonstrate the possible protective mechanisms involved. The additive doses of EPA-PL and DHA-PL in all treatment groups were 1% of total diets, respectively. The results showed that Lipo-EPA could significantly improve hepatic function by down-regulating orotic acid-induced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels by 55.6% and 34.2%, respectively (p < 0.01). Moreover, lipo-EPA exhibited excellent inhibition on the mRNA expression of SREBP-1c and FAS at the values of 0.454 ± 0.09 (p < 0.01) and 0.523 ± 0.08 (p < 0.01), respectively, thus ameliorating OA-induced NAFLD. Meanwhile, lipo-EPA could significantly suppress the SREBP-2 and HMGR levels (31.4% and 66.7%, p < 0.05, respectively). In addition, EPA-PL and lipo-DHA could also significantly suppress hepatic lipid accumulation mainly by enhancement of hepatic lipolysis and cholesterol efflux. Furthermore, DHA-PL played a certain role in inhibiting hepatic lipogenesis and accelerating cholesterol efflux. The results obtained in this work might contribute to the understanding of the biological activities of EPA/DHA-PL and liposomes and further investigation on its potential application values for food supplements.

A novel bioactive derivative of eicosapentaenoic acid (EPA) suppresses intestinal tumor development in ApcΔ14/+ mice.

PubMed

Nakanishi, Masako; Hanley, Matthew P; Zha, Ruochen; Igarashi, Yuichi; Hull, Mark A; Mathias, Gary; Sciavolino, Frank; Grady, James J; Rosenberg, Daniel W

2018-03-08

Familial adenomatous polyposis (FAP) is a genetic disorder characterized by the development of hundreds of polyps throughout the colon. Without prophylactic colectomy, most individuals with FAP develop colorectal cancer at an early age. Treatment with EPA in the free fatty acid form (EPA-FFA) has been shown to reduce polyp burden in FAP patients. Since high-purity EPA-FFA is subject to rapid oxidation, a stable form of EPA compound has been developed in the form of magnesium l-lysinate bis-eicosapentaenoate (TP-252). We assessed the chemopreventive efficacy of TP-252 on intestinal tumor formation using ApcΔ14/+ mice and compared it with EPA-FFA. TP-252 was supplemented in a modified AIN-93G diet at 1, 2 or 4% and EPA-FFA at 2.5% by weight and administered to mice for 11 weeks. We found that administration of TP-252 significantly reduced tumor number and size in the small intestine and colon in a dose-related manner and as effectively as EPA-FFA. To gain further insight into the cancer protection afforded to the colon, we performed a comprehensive lipidomic analysis of total fatty acid composition and eicosanoid metabolites. Treatment with TP-252 significantly decreased the levels of arachidonic acid (AA) and increased EPA concentrations within the colonic mucosa. Furthermore, a classification and regression tree (CART) analysis revealed that a subset of fatty acids, including EPA and docosahexaenoic acid (DHA), and their downstream metabolites, including PGE3 and 14-hydroxy-docosahexaenoic acid (HDoHE), were strongly associated with antineoplastic activity. These results indicate that TP-252 warrants further clinical development as a potential strategy for delaying colectomy in adolescent FAP patients.

Selection of appropriate tumour data sets for Benchmark Dose Modelling (BMD) and derivation of a Margin of Exposure (MoE) for substances that are genotoxic and carcinogenic: considerations of biological relevance of tumour type, data quality and uncertainty assessment.

PubMed

Edler, Lutz; Hart, Andy; Greaves, Peter; Carthew, Philip; Coulet, Myriam; Boobis, Alan; Williams, Gary M; Smith, Benjamin

2014-08-01

This article addresses a number of concepts related to the selection and modelling of carcinogenicity data for the calculation of a Margin of Exposure. It follows up on the recommendations put forward by the International Life Sciences Institute - European branch in 2010 on the application of the Margin of Exposure (MoE) approach to substances in food that are genotoxic and carcinogenic. The aims are to provide practical guidance on the relevance of animal tumour data for human carcinogenic hazard assessment, appropriate selection of tumour data for Benchmark Dose Modelling, and approaches for dealing with the uncertainty associated with the selection of data for modelling and, consequently, the derived Point of Departure (PoD) used to calculate the MoE. Although the concepts outlined in this article are interrelated, the background expertise needed to address each topic varies. For instance, the expertise needed to make a judgement on biological relevance of a specific tumour type is clearly different to that needed to determine the statistical uncertainty around the data used for modelling a benchmark dose. As such, each topic is dealt with separately to allow those with specialised knowledge to target key areas of guidance and provide a more in-depth discussion on each subject for those new to the concept of the Margin of Exposure approach. Copyright © 2013 ILSI Europe. Published by Elsevier Ltd.. All rights reserved.

Effects of landuse and precipitation on pesticides and water quality in playa lakes of the southern high plains.

PubMed

Anderson, Todd A; Salice, Christopher J; Erickson, Richard A; McMurry, Scott T; Cox, Stephen B; Smith, Loren M

2013-06-01

The 25000 playa wetlands within the Southern High Plains (SHP) of the United States of America (USA) are the dominant hydrogeomorphic feature in the region, providing habitat for numerous plants and wildlife. The SHP are among the most intensively cultivated regions; there are concerns over the degradation and/or loss of playa wetland habitat. We examined water quality in playa wetlands surrounded by both grassland and agriculture and measured water concentrations of pesticides used on cotton (acephate, trifluralin, malathion, pendimethalin, tribufos, bifenthrin, λ-cyhalothrin, acetamiprid, and thiamethoxam), the dominant crop in the SHP. Pesticides used on cotton were detected in water samples collected from all playas. Precipitation events and the amount of cultivation were related to pesticide concentrations in sediment and water. Our results show that pesticide concentrations were related in some circumstances to time, precipitation, and tilled-index for some but not all pesticides. We further compared measured pesticide concentrations in playas to toxicity benchmarks used by the US EPA in pesticide ecological risk assessments to obtain some insight into the potential for ecological effects. For all pesticides in water, the maximum measured concentrations exceeded at least one toxicity benchmark, while median concentrations did not exceed any benchmarks. This analysis indicates that there is a potential for adverse effects of pesticides to aquatic organisms. Copyright © 2013 Elsevier Ltd. All rights reserved.

IRIS Toxicological Review of Hexavalent Chromium (Peer Review Plan)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of hexavalent chromium that will appear on the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Biphenyl (External Review Draft) (September 2011)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of biphenyl that will appear in the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Methanol (Noncancer) (Final Report)

EPA Science Inventory

EPA conducted a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of Methanol (noncancer) , this is finalized and posted on the IRIS Web site.

IRIS Toxicological Review of n-Butanol (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of n-butanol that will appear in the Integrated Risk Information System (IRIS) database.

Rigorous-two-Steps scheme of TRIPOLI-4® Monte Carlo code validation for shutdown dose rate calculation

NASA Astrophysics Data System (ADS)

Jaboulay, Jean-Charles; Brun, Emeric; Hugot, François-Xavier; Huynh, Tan-Dat; Malouch, Fadhel; Mancusi, Davide; Tsilanizara, Aime

2017-09-01

After fission or fusion reactor shutdown the activated structure emits decay photons. For maintenance operations the radiation dose map must be established in the reactor building. Several calculation schemes have been developed to calculate the shutdown dose rate. These schemes are widely developed in fusion application and more precisely for the ITER tokamak. This paper presents the rigorous-two-steps scheme implemented at CEA. It is based on the TRIPOLI-4® Monte Carlo code and the inventory code MENDEL. The ITER shutdown dose rate benchmark has been carried out, results are in a good agreement with the other participant.

EPA's Stage 2 Disinfection Byproducts Rules (DBPR) and Northern Kentucky Water: An Economic and Scientific Review.

PubMed

Henry, Hugh

2013-01-01

Implementation of EPA's Stage 2 Disinfection Byproducts Rules (DBPR) in Northern Kentucky will cause a water rate increase of over 25%. Hence a review was undertaken, considering both economics and science in the context of President Obama's 2009 scientific integrity directive. The rules purport to avoid up to 0.49% of new bladder cancers by reducing the levels of DBPs in drinking water - a benefit so small that failure to implement will not cause unreasonable risk to health (URTH). It suggests at most one Northern Kentucky death avoided over 17 years for a cost of $136,000,000 ($1700 per household). Even this small benefit is probably overstated. EPA finds no "causal link" between DBPs and bladder cancer, and EPA acknowledges problems with the epidemiological data used in their calculation: the data appear contradictory and inconsistent, may be skewed toward "positive" results, and suggest different cancer sites than animal studies. Two similar international agencies disagree with EPA's conclusions. The science is based on the Linear No Threshold (LNT) dose response model for DBPs, but this may not be the correct model. 83% of EPA's epidemiological data show a statistical possibility that low levels of DBPs might be beneficial or have no effect.

Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide ...

EPA Pesticide Factsheets

EPA is seeking peer review of the scientific basis supporting the human health hazard and dose-response assessment of ethylene oxide (cancer) that will appear in the Integrated Risk Information System (IRIS) database. EPA seeks external peer review on how the Agency responded to the SAB panel recommendations, the exposure-response modeling of epidemiologic data, including new analyses since the 2007 external peer review, and on the adequacy, transparency, and clarity of the revised draft. The peer review will include an opportunity for the public to address the peer reviewers.

Benchmarking and validation of a Geant4-SHADOW Monte Carlo simulation for dose calculations in microbeam radiation therapy.

PubMed

Cornelius, Iwan; Guatelli, Susanna; Fournier, Pauline; Crosbie, Jeffrey C; Sanchez Del Rio, Manuel; Bräuer-Krisch, Elke; Rosenfeld, Anatoly; Lerch, Michael

2014-05-01

Microbeam radiation therapy (MRT) is a synchrotron-based radiotherapy modality that uses high-intensity beams of spatially fractionated radiation to treat tumours. The rapid evolution of MRT towards clinical trials demands accurate treatment planning systems (TPS), as well as independent tools for the verification of TPS calculated dose distributions in order to ensure patient safety and treatment efficacy. Monte Carlo computer simulation represents the most accurate method of dose calculation in patient geometries and is best suited for the purpose of TPS verification. A Monte Carlo model of the ID17 biomedical beamline at the European Synchrotron Radiation Facility has been developed, including recent modifications, using the Geant4 Monte Carlo toolkit interfaced with the SHADOW X-ray optics and ray-tracing libraries. The code was benchmarked by simulating dose profiles in water-equivalent phantoms subject to irradiation by broad-beam (without spatial fractionation) and microbeam (with spatial fractionation) fields, and comparing against those calculated with a previous model of the beamline developed using the PENELOPE code. Validation against additional experimental dose profiles in water-equivalent phantoms subject to broad-beam irradiation was also performed. Good agreement between codes was observed, with the exception of out-of-field doses and toward the field edge for larger field sizes. Microbeam results showed good agreement between both codes and experimental results within uncertainties. Results of the experimental validation showed agreement for different beamline configurations. The asymmetry in the out-of-field dose profiles due to polarization effects was also investigated, yielding important information for the treatment planning process in MRT. This work represents an important step in the development of a Monte Carlo-based independent verification tool for treatment planning in MRT.

IRIS Toxicological Review of Hexachloroethane (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of hexachloroethane that when finalized will appear on the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Libby Amphibole Asbestos (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of Libby Amphibole Asbestos that will appear in the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Hydrogen Cyanide (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review of the scientific basis supporting the human health hazard and dose-response assessment of hydrogen cyanide and cyanide salts that will appear on the Integrated Risk Information System (IRIS) database.

MANAGING EXPOSURES TO NEUROTOXIC AIR POLLUTANTS.

EPA Science Inventory

Researchers at EPA's National Health and Environmental Effects Research Laboratory are developing a biologically-based dose-response model to describe the neurotoxic effects of exposure to volatile organic compounds (VOCs). The model is being developed to improve risk assessment...

The Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals: Dietary Module Version 1: Technical Manual

EPA Pesticide Factsheets

SHEDS - Multimedia is EPA's premier physically-based, probabilistic model, that can simulate cumulative or aggregate exposures for a population across a variety of multimedia, multipathway environmental chemicals.

LLNL NESHAPs 2015 Annual Report - June 2016

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

Wilson, K. R.; Gallegos, G. M.; MacQueen, D. H.

2016-06-01

Lawrence Livermore National Security, LLC operates facilities at Lawrence Livermore National Laboratory (LLNL) in which radionuclides are handled and stored. These facilities are subject to the U.S. Environmental Protection Agency (EPA) National Emission Standards for Hazardous Air Pollutants (NESHAPs) in Code of Federal Regulations (CFR) Title 40, Part 61, Subpart H, which regulates radionuclide emissions to air from Department of Energy (DOE) facilities. Specifically, NESHAPs limits the emission of radionuclides to the ambient air to levels resulting in an annual effective dose equivalent of 10 mrem (100 μSv) to any member of the public. Using measured and calculated emissions, andmore » building-specific and common parameters, LLNL personnel applied the EPA-approved computer code, CAP88-PC, Version 4.0.1.17, to calculate the dose to the maximally exposed individual member of the public for the Livermore Site and Site 300.« less

Environmental consequences of postulate plutonium releases from Atomics International's Nuclear Materials Development Facility (NMDF), Santa Susana, California, as a result of severe natural phenomena

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

Jamison, J.D.; Watson, E.C.

1982-02-01

Potential environmental consequences in terms of radiation dose to people are presented for postulated plutonium releases caused by severe natural phenomena at the Atomics International's Nuclear Materials Development Facility (NMDF), in the Santa Susana site, California. The severe natural phenomena considered are earthquakes, tornadoes, and high straight-line winds. Plutonium deposition values are given for significant locations around the site. All important potential exposure pathways are examined. The most likely 50-year committed dose equivalents are given for the maximum-exposed individual and the population within a 50-mile radius of the plant. The maximum plutonium deposition values likely to occur offsite are alsomore » given. The most likely calculated 50-year collective committed dose equivalents are all much lower than the collective dose equivalent expected from 50 years of exposure to natural background radiation and medical x-rays. The most likely maximum residual plutonium contamination estimated to be deposited offsite following the earthquake, and the 150-mph and 170-mph tornadoes are above the Environmental Protection Agency's (EPA) proposed guideline for plutonium in the general environment of 0.2 ..mu..Ci/m/sup 2/. The deposition values following the 110-mph and the 130-mph tornadoes are below the EPA proposed guideline.« less

Environmental consequences of postulated plutonium releases from General Electric Company Vallecitos Nuclear Center, Vallecitos, California, as a result of severe natural phenomena

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

Jamison, J.D.; Watson, E.C.

1980-11-01

Potential environmental consequences in terms of radiation dose to people are presented for postulated plutonium releases caused by severe natural phenomena at the General Electric Company Vallecitos Nuclear Center, Vallecitos, California. The severe natural phenomena considered are earthquakes, tornadoes, and high straight-line winds. Maximum plutonium deposition values are given for significant locations around the site. All important potential exposure pathways are examined. The most likely 50-year committed dose equivalents are given for the maximum-exposed individual and the population within a 50-mile radius of the plant. The maximum plutonium deposition values likely to occur offsite are also given. The most likelymore » calculated 50-year collective committed dose equivalents are all much lower than the collective dose equivalent expected from 50 years of exposure to natural background radiation and medical x-rays. The most likely maximum residual plutonium contamination estimated to be deposited offsite following the earthquakes, and the 180-mph and 230-mph tornadoes are above the Environmental Protection Agency's (EPA) proposed guideline for plutonium in the general environment of 0.2 ..mu..Ci/m/sup 2/. The deposition values following the 135-mph tornado are below the EPA proposed guidelines.« less

An Improved Method of Heterogeneity Compensation for the Convolution / Superposition Algorithm

NASA Astrophysics Data System (ADS)

Jacques, Robert; McNutt, Todd

2014-03-01

Purpose: To improve the accuracy of convolution/superposition (C/S) in heterogeneous material by developing a new algorithm: heterogeneity compensated superposition (HCS). Methods: C/S has proven to be a good estimator of the dose deposited in a homogeneous volume. However, near heterogeneities electron disequilibrium occurs, leading to the faster fall-off and re-buildup of dose. We propose to filter the actual patient density in a position and direction sensitive manner, allowing the dose deposited near interfaces to be increased or decreased relative to C/S. We implemented the effective density function as a multivariate first-order recursive filter and incorporated it into GPU-accelerated, multi-energetic C/S implementation. We compared HCS against C/S using the ICCR 2000 Monte-Carlo accuracy benchmark, 23 similar accuracy benchmarks and 5 patient cases. Results: Multi-energetic HCS increased the dosimetric accuracy for the vast majority of voxels; in many cases near Monte-Carlo results were achieved. We defined the per-voxel error, %|mm, as the minimum of the distance to agreement in mm and the dosimetric percentage error relative to the maximum MC dose. HCS improved the average mean error by 0.79 %|mm for the patient volumes; reducing the average mean error from 1.93 %|mm to 1.14 %|mm. Very low densities (i.e. < 0.1 g / cm3) remained problematic, but may be solvable with a better filter function. Conclusions: HCS improved upon C/S's density scaled heterogeneity correction with a position and direction sensitive density filter. This method significantly improved the accuracy of the GPU based algorithm reaching the accuracy levels of Monte Carlo based methods with performance in a few tenths of seconds per beam. Acknowledgement: Funding for this research was provided by the NSF Cooperative Agreement EEC9731748, Elekta / IMPAC Medical Systems, Inc. and the Johns Hopkins University. James Satterthwaite provided the Monte Carlo benchmark simulations.

Radiation dose in coronary angiography and intervention: initial results from the establishment of a multi-centre diagnostic reference level in Queensland public hospitals

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

Crowhurst, James A, E-mail: jimcrowhurst@hotmail.com; School of Medicine, University of Queensland, St. Lucia, Brisbane, Queensland; Whitby, Mark

Radiation dose to patients undergoing invasive coronary angiography (ICA) is relatively high. Guidelines suggest that a local benchmark or diagnostic reference level (DRL) be established for these procedures. This study sought to create a DRL for ICA procedures in Queensland public hospitals. Data were collected for all Cardiac Catheter Laboratories in Queensland public hospitals. Data were collected for diagnostic coronary angiography (CA) and single-vessel percutaneous intervention (PCI) procedures. Dose area product (P{sub KA}), skin surface entrance dose (K{sub AR}), fluoroscopy time (FT), and patient height and weight were collected for 3 months. The DRL was set from the 75th percentilemore » of the P{sub KA.} 2590 patients were included in the CA group where the median FT was 3.5 min (inter-quartile range = 2.3–6.1). Median K{sub AR} = 581 mGy (374–876). Median P{sub KA} = 3908 uGym{sup 2} (2489–5865) DRL = 5865 uGym{sup 2}. 947 patients were included in the PCI group where median FT was 11.2 min (7.7–17.4). Median K{sub AR} = 1501 mGy (928–2224). Median P{sub KA} = 8736 uGym{sup 2} (5449–12,900) DRL = 12,900 uGym{sup 2}. This study established a benchmark for radiation dose for diagnostic and interventional coronary angiography in Queensland public facilities.« less

IRIS Toxicological Review of Acrylamide (External Review ...

EPA Pesticide Factsheets

EPA has conducted a peer review by EPA’s Science Advisory Board (SAB) of the scientific basis supporting the human health hazard and dose-response assessment of acrylamide that once finalized will appear on the Integrated Risk Information System (IRIS) database. Peer review is meant to ensure that the science is used credibly and appropriately in derivation of the dose-response assessments and toxicological characterization. The draft Toxicological Review of Acrylamide provides scientific support and rationale for the hazard identification and dose-response assessment pertaining to a chronic exposure to acrylamide.

Eicosapentaenoic acid (EPA) induced apoptosis in HepG2 cells through ROS–Ca{sup 2+}–JNK mitochondrial pathways

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

Zhang, Yuanyuan; Han, Lirong; Qi, Wentao

Highlights: • EPA evoked ROS formation, [Ca{sup 2+}]{sub c} accumulation, the opening of MPTP and the phosphorylation of JNK. • EPA-induced [Ca{sup 2+}]{sub c} elevation was depended on production of ROS. • EPA-induced ROS generation, [Ca{sup 2+}]{sub c} increase, and JNK activated caused MPTP opening. • The apoptosis induced by EPA was related to release of cytochrome C through the MPTP. • EPA induced HepG2 cells apoptosis through ROS–Ca{sup 2+}–JNK mitochondrial pathways. - Abstract: Eicosapentaenoic acid (EPA), a well-known dietary n−3 PUFAS, has been considered to inhibit proliferation of tumor cells. However, the molecular mechanism related to EPA-induced liver cancermore » cells apoptosis has not been reported. In this study, we investigated the effect of EPA on HepG2 cells proliferation and apoptosis mechanism through mitochondrial pathways. EPA inhibited proliferation of HepG2 cells in a dose-dependent manner and had no significant effect on the cell viability of humor normal liver L-02 cells. It was found that EPA initially evoked ROS formation, leading to [Ca{sup 2+}]{sub c} accumulation and the mitochondrial permeability transition pore (MPTP) opening; EPA-induced HepG2 cells apoptosis was inhibited by N-acetylcysteine (NAC, an inhibitor of ROS), 1,2-bis (2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA-AM, a chelator of calcium) and CsA (inhibitor of MPTP). The relationship between ROS production, the increase of cytoplasmic Ca and MPTP opening was detected. It seems that ROS may act as an upstream regulator of EPA-induced [Ca{sup 2+}]{sub c} generation, moreover, generation of ROS, overload of mitochondrial [Ca{sup 2+}]{sub c}, and JNK activated cause the opening of MPTP. Western blotting results showed that EPA elevated the phosphorylation status of JNK, processes associated with the ROS generation. Simultaneously, the apoptosis induced by EPA was related to release of cytochrome C from mitochondria to cytoplasm through the MPTP and activation of caspase-9 and caspase-3. These results suggest that EPA induces apoptosis through ROS–Ca{sup 2+}–JNK mitochondrial pathways.« less

Risk assessment of nonylphenol and its ethoxylates in U.S. river water and sediment

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

Weeks, J.A.; Adams, W.J.; Guiney, P.D.

1994-12-31

A comprehensive program addressing the risks of nonylphenol (NP) and its ethoxylates (NPE) in aquatic environments of the United States has been undertaken by the Alkyl Phenol Ethoxylates Panel of the Chemical Manufacturers Association cooperating with EPA. Several hundred million pounds of NPE surfactants are used in the US each year. Nonylphenol can be an intermediate product of degradation of nonylphenol ethoxylates. A survey of those river reaches most likely to contain NPE and NP residues was conducted based on a random sample of a subset of the EPA River Reach File defined by certain selection criteria. Applying enhanced analyticalmore » techniques, little or no NP and NPE were found in river water at most locations, while low levels were usually detected in sediment. Acute and chronic toxicity tests using a variety of organisms have also been completed. New results are presented for shrimp, fish, tadpoles, midges, and algae. The risk of NP to the aquatic environment is examined by comparison of observed levels with toxicity benchmarks, and by application of equilibrium partitioning theory to calculate sediment interstitial chemical concentrations.« less

Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

PubMed

Kawamoto, Taisuke; Ito, Yuichi; Morita, Osamu; Honda, Hiroshi

2017-01-01

Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

IRIS Toxicological Review of Dichloromethane (Methylene Chloride) (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of Dichloromethane that when finalized will appear on the Integrated Risk Information System (IRIS) database.

The Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals: Residential Module Version 4: User Guide, June 2012

EPA Pesticide Factsheets

SHEDS - Multimedia is EPA's premier physically-based, probabilistic model, that can simulate cumulative or aggregate exposures for a population across a variety of multimedia, multipathway environmental chemicals.

IRIS Toxicological Review of Tetrahydrofuran (THF) (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of tetrahydrofuran (THF) that when finalized will appear on the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Trichloroethylene (TCE) (External Review Draft)

EPA Science Inventory

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of Trichloroethylene (TCE) that when finalized will appear on the Integrated Risk Information System (IRIS) database.

SMALL FISH MULTI-ENDPOINT BIOASSAY DEVELOPMENT

EPA Science Inventory

The U.S. EPA is required to regulate waterborne chemical contaminants. To make decisions regarding what to regulate and what levels of contaminant are acceptable, the Office of Water needs several types of toxicological information: hazard identification data, and dose-response ...

The Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals: Residential Module Version 4: Technical Manual, May 2012

EPA Pesticide Factsheets

SHEDS - Multimedia is EPA's premier physically-based, probabilistic model, that can simulate cumulative or aggregate exposures for a population across a variety of multimedia, multipathway environmental chemicals.

Higher Throughput Toxicokinetics to Allow Extrapolation (EPA-Japan Bilateral EDSP meeting)

EPA Science Inventory

As part of "Ongoing EDSP Directions & Activities" I will present CSS research on high throughput toxicokinetics, including in vitro data and models to allow rapid determination of the real world doses that may cause endocrine disruption.

IRIS Toxicological Review of Cerium Oxide and Cerium Compounds (External Review Draft)

EPA Science Inventory

EPA conducted a peer review of the scientific basis supporting the human health hazard and dose-response assessment of cerium oxide and cerium compounds that will appear on the Integrated Risk Information System (IRIS) database.

The Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals: Dietary Module Version 1: User Guide, June 2012

EPA Pesticide Factsheets

SHEDS - Multimedia is EPA's premier physically-based, probabilistic model, that can simulate cumulative or aggregate exposures for a population across a variety of multimedia, multipathway environmental chemicals.

IRIS Toxicological Review of n-Butanol (Interagency Science ...

EPA Pesticide Factsheets

On September 8, 2011, the Toxicological Review of n-Butanol (External Review Draft) was 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, 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 with EPA's response and the interagency science consultation draft of the IRIS Toxicological Review of n-Butanol and the charge to external peer reviewers are posted on this site. EPA is undertaking an Integrated Risk Information System (IRIS) health assessment for n-butanol. IRIS is an EPA database 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 paradigm, i.e., hazard identification and dose-response evaluation. IRIS assessments are used in combination with specific situational exposure assessment information to evaluate potential public health risk associated with environmental contaminants.

The Effect of Marine Derived n-3 Fatty Acids on Adipose Tissue Metabolism and Function

PubMed Central

Todorčević, Marijana; Hodson, Leanne

2015-01-01

Adipose tissue function is key determinant of metabolic health, with specific nutrients being suggested to play a role in tissue metabolism. One such group of nutrients are the n-3 fatty acids, specifically eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Results from studies where human, animal and cellular models have been utilised to investigate the effects of EPA and/or DHA on white adipose tissue/adipocytes suggest anti-obesity and anti-inflammatory effects. We review here evidence for these effects, specifically focusing on studies that provide some insight into metabolic pathways or processes. Of note, limited work has been undertaken investigating the effects of EPA and DHA on white adipose tissue in humans whilst more work has been undertaken using animal and cellular models. Taken together it would appear that EPA and DHA have a positive effect on lowering lipogenesis, increasing lipolysis and decreasing inflammation, all of which would be beneficial for adipose tissue biology. What remains to be elucidated is the duration and dose required to see a favourable effect of EPA and DHA in vivo in humans, across a range of adiposity. PMID:26729182

Contributions to Integral Nuclear Data in ICSBEP and IRPhEP since ND 2013

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

Bess, John D.; Briggs, J. Blair; Gulliford, Jim

2016-09-01

The status of the International Criticality Safety Benchmark Evaluation Project (ICSBEP) and the International Reactor Physics Experiment Evaluation Project (IRPhEP) was last discussed directly with the international nuclear data community at ND2013. Since ND2013, integral benchmark data that are available for nuclear data testing has continued to increase. The status of the international benchmark efforts and the latest contributions to integral nuclear data for testing is discussed. Select benchmark configurations that have been added to the ICSBEP and IRPhEP Handbooks since ND2013 are highlighted. The 2015 edition of the ICSBEP Handbook now contains 567 evaluations with benchmark specifications for 4,874more » critical, near-critical, or subcritical configurations, 31 criticality alarm placement/shielding configuration with multiple dose points apiece, and 207 configurations that have been categorized as fundamental physics measurements that are relevant to criticality safety applications. The 2015 edition of the IRPhEP Handbook contains data from 143 different experimental series that were performed at 50 different nuclear facilities. Currently 139 of the 143 evaluations are published as approved benchmarks with the remaining four evaluations published in draft format only. Measurements found in the IRPhEP Handbook include criticality, buckling and extrapolation length, spectral characteristics, reactivity effects, reactivity coefficients, kinetics, reaction-rate distributions, power distributions, isotopic compositions, and/or other miscellaneous types of measurements for various types of reactor systems. Annual technical review meetings for both projects were held in April 2016; additional approved benchmark evaluations will be included in the 2016 editions of these handbooks.« less

Benchmarking of MCNP for calculating dose rates at an interim storage facility for nuclear waste.

PubMed

Heuel-Fabianek, Burkhard; Hille, Ralf

2005-01-01

During the operation of research facilities at Research Centre Jülich, Germany, nuclear waste is stored in drums and other vessels in an interim storage building on-site, which has a concrete shielding at the side walls. Owing to the lack of a well-defined source, measured gamma spectra were unfolded to determine the photon flux on the surface of the containers. The dose rate simulation, including the effects of skyshine, using the Monte Carlo transport code MCNP is compared with the measured dosimetric data at some locations in the vicinity of the interim storage building. The MCNP data for direct radiation confirm the data calculated using a point-kernel method. However, a comparison of the modelled dose rates for direct radiation and skyshine with the measured data demonstrate the need for a more precise definition of the source. Both the measured and the modelled dose rates verified the fact that the legal limits (<1 mSv a(-1)) are met in the area outside the perimeter fence of the storage building to which members of the public have access. Using container surface data (gamma spectra) to define the source may be a useful tool for practical calculations and additionally for benchmarking of computer codes if the discussed critical aspects with respect to the source can be addressed adequately.

Development of a Reference Dose for Perchlorate: Current Issues and Status

NASA Technical Reports Server (NTRS)

Pleus, R. C.; Goodman, G.; Mattie, D. R.

2000-01-01

The perchlorate anion (ClO4) is typically manufactured as the ammonium salt. The most common use of ammonium perchlorate is in the aerospace program as a component of solid rocket fuel. The perchlorate anion is exceedingly stable under environmental conditions and has been found in ground and surface waters in CA, NV, UT, AZ, TX, AK, NY, MD, WV and FL. The National Center for Environmental Assessment (NCEA) of the U.S. Environmental Protection Agency (US EPA) is in the process of developing an oral reference dose (RfD) for perchlorate. An oral RfD is a body-weight-adjusted dose that can be consumed daily over an entire lifetime with the expectation of no adverse health effects. Once developed, the new RfD will be used by US EPA as the basis of a safe-drinking-water level (SDWL) guideline. US EPA and regional regulatory agencies will then jointly or separately propose clean-up action levels for ground and surface waters at contaminated sites. The toxicological database on CIO4- as of March 1997 was determined by an expert peer-review panel to be inadequate for the purpose of deriving an oral RfD. For example, little or no experimental data existed on the subchronic, reproductive, or developmental toxicity of perchlorate. To fill gaps in the toxicological database, eight animal studies were designed by a government-industry consortium that included US EPA and AFRL. These studies were performed in 1997-1998. It has been known for many years that in the thyroid, high doses of perchlorate block the function of iodide by competing for iodide binding sites. Perchlorate was used in the 1950s-60s as a treatment for Graves' disease (a hyperthyroid condition). Because of what was already known about the pharmacological mode of action of perchlorate, specific concerns addressed in the design of the recent animal studies included the potential for developmental toxicity, notably neurological development. Upon review of complete study reports from four of the studies and incomplete data from the other two, US EPA/NCEA issued a document in December 1998 stating that the critical effects were hormone and histology data from the neurodevelopmental/behavioral toxicity study that had been performed in rats; an RfD was proposed based upon the observation of thyroid-follicular-cell hypertrophy in the 5-day-old pups (PND) of dams given perchlorate in drinking water at 0.1 mg/kg-day (the lowest dose tested) in this study. US EPA/NCEA also focused attention on a nonsignificant increase in motor activity observed in 14-day-old male pups in the same study at the same dose. In February 1999, a public workshop was convened at which an external peer-review panel determined that there was still insufficient data to support the development of a RfD. Additional studies were recommended. Since that time a clinical study revealed significant depression of thyroidal uptake of iodide in volunteers receiving potassium perchlorate at 10 mg/day for 14 days. Follow-up studies currently underway include a pathology working-group review of histology slides from the all of the previous studies, a motor activity study similar to the first behavioral study, an additional immunotoxicity study, male and female rat kinetic studies, a hormone interlaboratory study, and an effects study for thyroid and brain in developing rats. These studies are expected to be complete by mid-2000. A clinical study is planned to determine inhibition of iodide uptake and kinetic parameters in humans following 14-day perchlorate ingestion. The kinetics studies will provide data for developing physiologically based pharmacokinetic (PBPK) models for rats and humans needed to establish the RfD.

IRIS Toxicological Review of Beryllium and Compounds (2008 ...

EPA Pesticide Factsheets

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of Beryllium that when finalized will appear on the Integrated Risk Information System (IRIS) database. An IRIS Toxicological Review of Beryllium and Compounds was published in 1988 and reassessed in 1998. The current draft (2007) only focuses on the cancer assessment and does not re-evaluate posted reference doses or reference concentrations.

Dietary fish oil alters the lysophospholipid metabolomic profile and decreases urinary 11-dehydro thromboxane B₂ concentration in healthy Beagles.

PubMed

Hall, Jean A; Brockman, Jeffrey A; Jewell, Dennis E

2011-12-15

Increased concentrations of dietary fish oil and antioxidants have been shown previously to change circulating concentrations of individual fatty acids (FAs) and vitamin E. The purpose of this study was to further investigate the effects of vitamins E and C, in combination with dietary fish oil, on selected blood and urinary biomarkers. Fifty adult Beagle dogs (mean age 5.3 years, range 1.4-14.2 years) were randomized into five dietary treatment groups for 90 days. All foods were complete and balanced and met the nutrient profiles of AAFCO for adult dogs. For 60 days before study initiation, dogs consumed a pretrial food that contained 74 IU/kg vitaminE and 0mg/kg vitaminC. The five experimental foods were confirmed by analytical methods to contain ≥ 640 IU/kg vitaminE and 130 mg/kg vitaminC (as fed). Experimental foods ranged from low levels of EPA and DHA (pretrial food and lowest experimental food had 0.01% EPA and no detectable DHA) to the highest experimental food with 0.25% EPA and 0.17% DHA. Serum was analyzed for FAs, vitamin E, and cholesterol concentrations; urine was analyzed for 11-dehydro thromboxane B(2) (TXB(2)). Serum was also used for metabolomic analysis. FA intake ranged from 0.02 g/day EPA and 0.02 g/day DHA to 0.58 g/day EPA and 0.39 g/day DHA. Increasing dietary concentrations of EPA and DHA resulted in increased serum concentrations of EPA and DHA in a dose-dependent fashion. Greater dietary vitamin E intake resulted in increased serum vitamin E concentrations (P<0.01). Higher serum cholesterol was also associated with higher serum vitamin E concentrations (P<0.01). In turn, changes in serum cholesterol concentration were associated with diet-induced changes in serum FA concentrations (all P<0.01). At the beginning of the dietary treatment period the most significant predictor of urine 11-dehydro TXB(2) concentration was age, followed by lean-body mass. After dietary treatment with different amounts of fish oil, age (increases 11-dehydro TXB(2)) was followed by EPA concentration as a significant negative predictor of urine 11-dehydro TXB(2) concentration (increasing serum concentrations of EPA decrease 11-dehydro TXB(2)), and then lean-body mass (decreases 11-dehydro TXB(2)). Serum docosahexaenoyl-glycerophosphocholine concentration was increased by feeding fish oil in a dose-response manner. In summary, serum vitamin E concentration is enhanced primarily by feeding vitamin E and secondarily by serum cholesterol concentration. When feeding diets enriched with fish oil, the major negative predictor of urinary 11-dehydro TXB(2) concentration is serum EPA concentration. Plasma lysophospholipids can be dynamically regulated by dietary fish oil supplementation. Copyright © 2011 Elsevier B.V. All rights reserved.

Practical examples of modeling choices and their consequences for risk assessment

EPA Science Inventory

Although benchmark dose (BMD) modeling has become the preferred approach to identifying a point of departure (POD) over the No Observed Adverse Effect Level, there remain challenges to its application in human health risk assessment. BMD modeling, as currently implemented by the...

IRIS Toxicological Review of Methanol (External Review Draft, 2013)

EPA Science Inventory

EPA is conducting a peer review and public comment of the scientific basis supporting the human health hazard and dose-response assessment of methanol (non-cancer) that when finalized will appear on the Integrated Risk Information System (IRIS) database.

IRIS Toxicological Review of Methanol (Noncancer) (Revised External Review Draft)

EPA Science Inventory

EPA is seeking additional public comment and external peer review of the scientific basis supporting the human health hazard and dose-response assessment of methanol (noncancer).