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PubMed2005

Workgroup report: workshop on source apportionment of particulate matter health effects--intercomparison of results and implications.

Although the association between exposure to ambient fine particulate matter with aerodynamic diameter < 2.5 microm (PM2.5) and human mortality is well established, the most responsible particle types/sources are not yet certain. In May 2003, the U.S. Environmental Protection Agency's Particulate Matter Centers Program sponsored the Workshop on the Source Apportionment of PM Health Effects. The goal was to evaluate the consistency of the various source apportionment methods in assessing source contributions to daily PM2.5 mass-mortality associations. Seven research institutions, using varying methods, participated in the estimation of source apportionments of PM2.5 mass samples collected in Washington, DC, and Phoenix, Arizona, USA. Apportionments were evaluated for their respective associations with mortality using Poisson regressions, allowing a comparative assessment of the extent to which variations in the apportionments contributed to variability in the source-specific mortality results. The various research groups generally identified the same major source types, each with similar elemental makeups. Intergroup correlation analyses indicated that soil-, sulfate-, residual oil-, and salt-associated mass were most unambiguously identified by various methods, whereas vegetative burning and traffic were less consistent. Aggregate source-specific mortality relative risk (RR) estimate confidence intervals overlapped each other, but the sulfate-related PM2.5 component was most consistently significant across analyses in these cities. Analyses indicated that source types were a significant predictor of RR, whereas apportionment group differences were not. Variations in the source apportionments added only some 15% to the mortality regression uncertainties. These results provide supportive evidence that existing PM2.5 source apportionment methods can be used to derive reliable insights into the source components that contribute to PM2.5 health effects.

Air Pollutants↗
PubMed1996

Use of genetic toxicology data in U.S. EPA risk assessment: the mercury study report as an example.

Assessment of human health risks of environmental agents has often been limited to consideration of the potential for the agent to cause cancer or general systemic toxicity after long-term exposure. The U.S. Environmental Protection Agency (U.S. EPA) is increasingly moving toward the development of integrated assessments, which consider all potential health end points including developmental toxicity, neurotoxicity, immunotoxicity, reproductive effects, and germ cell mutagenicity. The U.S. EPA has a responsibility to assess risks to nonhuman species or ecosystems when appropriate data are available. An example of a recent integrated human health and ecological risk assessment can be found in the U.S. EPA Mercury Study Report to Congress. This report covers the following topics in separate volumes: an inventory of anthropogenic mercury emissions in the United States; an exposure assessment using measured and predicted values and including indirect dietary exposure; an evaluation of human health risks; an assessment of ecologic risk wherein water criteria are presented for several wildlife species; an overall integrated characterization of human and nonhuman risk; and a discussion of risk management considerations. In the evaluation of human health risk, genetic toxicology data were considered for three forms of mercury: elemental, inorganic (divalent), and methylmercury. These data were used in judgments of two types of potential health effects (carcinogenicity and germ cell mutagenicity). In assessment of potential carcinogenicity of inorganic and methylmercury, genetic toxicity data were key. Data for clastogenicity in the absence of mutagenicity supported the characterization of inorganic and methylmercury as materials that produce carcinogenic effects only at high, toxic doses. The evidence for clastogenicity, coupled with information on metabolism and distribution, resulted in a judgment of a moderate degree of concern (or weight of evidence) that inorganic mercury can act as a human germ cell mutagen. For methylmercury, the degree of concern for germ cell mutagenicity is high.

Animals↗
PubMedDate not supplied

Quality assurance responsibilities as defined by the EPA Good Automated Laboratory Practices (GALPs).

In December 1990, the Environmental Protection Agency's (EPA) Office of Information Resources Management (OIRM) issued a draft of the Good Automated Laboratory Practices (GALP). The GALPs developed from a union of existing Federal and EPA regulations and policies, including: the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) & Toxic Substance Control Act (TSCA), Good Laboratory Practices (GLP), the EPA Information Resources Management Policy (IRMP), and the Computer Security Act of 1987. The GALPs consolidate the regulations and policies to provide a single source of reference, and sever as an extension of the GLP standards (40 CFR 160 & 792). Whereas the GLPs describe acceptable laboratory management practices, the GALPs describe acceptable automated data management practices, and give guidance for standardizing and implementing procedures to ensure the quality and integrity of automated data collection and storage. The GALPs have been formatted to parallel the structure of the GLPs. Just as the GLPs define the responsibilities of the Quality Assurance Unit (QAU) in maintaining good laboratory practices, the GALPs define the responsibilities of the QAU in maintaining good automated data practices. The QAU is charged with (i) maintaining copies of written procedures for the automated data collection system, (ii) performing inspections of laboratory operations utilizing the automated data collection system and reporting findings, (iii) ensuring authorization and documentation of deviations from written procedures, (iv) auditing data and reports from the automated data collection system to ensure they accurately represent the raw data, and (v) maintaining records of the above-defined QAU functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Laboratory Information Systems↗
PubMed2006

Assessment of in vivo assays for endocrine disruption.

The United States Environmental Protection Agency (USEPA) has developed a screening and testing programme to detect endocrine-disrupting chemicals. This programme is organized into two phases: a tier 1 screening battery and, for those chemicals that are positive in this phase, a tier 2 testing battery. Similarly, the Organization for Economic Cooperation and Development (OECD) has set up a task force to identify, prioritize and validate test methods for the detection of endocrine disrupters. This chapter describes the mammalian in vivo assays recommended by these organizations. The tier 1 screening recommended by both agencies comprises the uterotrophic assay for the detection of oestrogens and anti-oestrogens, and the Hershberger assay for the detection of anti-androgens. Both of these assays are nearing the end of a comprehensive validation process and show consistency across testing laboratories. A further assay recommended by the USEPA is the female pubertal assay, designed to assess steroidogenesis, anti-thyroid activity and anti-oestrogenicity, while the OECD recommends an enhanced version of their standard regulatory test guideline number 407, the 28-day rat toxicity test. The tier 2 test recommended by both agencies is an enhanced version of the two-generation regulatory study. This is a large time- and animal-consuming study, and in order to obtain the maximum information regarding the potential for endocrine-disrupting activity of a chemical, it should be modified depending on the results of the tier 1 assays.

Androgen Antagonists↗
PubMed1990

Effects of burnrate, wood species, altitude, and stove type on woodstove emissions.

During the winter of 1986-87, the U.S. Environmental Protection Agency (EPA) conducted an emission measurement program in Boise, ID, as part of the Integrated Air Cancer Project (IACP). This program was designed to identify the potential mutagenic impact of residential wood burning on ambient and indoor air. One facet of this field sampling effort involved obtaining emission samples from chimneys serving wood burning appliances in Boise. As a companion to the field source sampling, a parallel project was undertaken in an instrumented woodstove test laboratory to quantify woodstove emissions during operations typical of Boise usage. Two woodstoves were operated in a test laboratory over a range of burnrates, burning either eastern oak or white pine from the Boise, ID, area. A conventional stove, manufactured in the Boise area, was tested at altitudes of 90 and 825 m. A catalytic stove was tested only at the high altitude facility. All emission tests were started with kindling a fire in a cold stove using black and white newsprint. Emissions were collected using the wood stove dilution sampling system (WSDSS) for a continuous period of about 8 hours, encompassing start-up and several wood additions. The results showed wide variability probably due primarily to the difficulty in duplicating conditions during start-up. Total WSDSS emissions showed the expected inverse correlations with burnrate for the conventional stove and nearly flat for the catalytic stove. While there appeared to be little or no correlation of total WSDSS emissions with altitude, the sum of the 16 polynuclear aromatic hydrocarbons (PAHs) quantified showed an inverse correlation with altitude: higher PAH emissions at the lower altitude.

Air Pollutants↗
PubMed2004

Selecting appropriate animal models and experimental designs for endocrine disruptor research and testing studies.

Evidence that chemicals in the environment may cause developmental and reproductive abnormalities in fish and wildlife by disrupting normal endocrine functions has increased concern about potential adverse human health effects from such chemicals. US laws have now been enacted that require the US Environmental Protection Agency (EPA) to develop and validate a screening program to identify chemicals in food and water with potential endocrine-disrupting activity. EPA subsequently proposed an Endocrine Disruptor Screening Program that uses in vitro and in vivo test systems to identify chemicals that may adversely affect humans and ecologically important animal species. However, the endocrine system can be readily modulated by many experimental factors, including diet and the genetic background of the selected animal strain or stock. It is therefore desirable to minimize or avoid factors that cause or contribute to experimental variation in endocrine disruptor research and testing studies. Standard laboratory animal diets contain high and variable levels of phytoestrogens, which can modulate physiologic and behavioral responses similar to both endogenous estrogen as well as exogenous estrogenic chemicals. Other studies have determined that some commonly used outbred mice and rats are less responsive to estrogenic substances than certain inbred mouse and rat strains for various estrogen-sensitive endpoints. It is therefore critical to select appropriate biological models and diets for endocrine disruptor studies that provide optimal sensitivity and specificity to accomplish the research or testing objectives. An introduction is provided to 11 other papers in this issue that review these and other important laboratory animal experimental design considerations in greater detail, and that review laboratory animal and in vitro models currently being used or evaluated for endocrine disruptor research and testing. Selection of appropriate animal models and experimental design parameters for endocrine disruptor research and testing will minimize confounding experimental variables, increase the likelihood of replicable experimental results, and contribute to more reliable and relevant test systems.

Animals↗
PubMed2003

Uncertainties for endocrine disrupters: our view on progress.

The hypothesis that hormonally active compounds in the environment--endocrine disrupters--are having a significant impact on human and ecological health has captured the public's attention like no other toxicity concern since the publication of Rachel Carson's Silent Spring 1962. In the early 1990s, Theo Colborn and others began to synthesize information about the potential impacts of endocrine-mediated toxicity in the scientific literature (Colborn and Clement, 1992) and the popular press (Colborn et al., 1997). Recognizing the possibility of an emerging health threat, the U.S. Environmental Protection Agency (EPA) convened two international workshops in 1995 (Ankley et al., 1997; Kavlock et al., 1996) that identified research needs relative to future risk assessments for endocrine-disrupting chemicals (EDCs). These workshops identified effects on reproductive, neurological, and immunological function, as well as carcinogenesis as the major endpoints of concern and made a number of recommendations for research. Subsequently, the EPA developed a research strategy to begin addressing the recommendations (EPA, 1998a), and the federal government as a whole, working through the White House's Committee on the Environment and Natural Resources, increased funding levels and coordinated research programs to fill the major data gaps (Reiter et al., 1998). In parallel with these research efforts that were attempting to define the scope and nature of the endocrine disruptor hypothesis, the U.S. Congress added provisions to the Food Quality Protection Act (FQPA) and the Safe Drinking Water Act of 1996 to require the testing of food-use pesticides and drinking water contaminants, respectively, for estrogenicity and other hormonal activity. These bills were enacted into law, giving the EPA the mandate to implement them. The EPA, with the help of an external advisory committee, the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), determined that other hormonal activity should include androgens and compounds that affect thyroid function, and expanded the mandate to include all chemicals under EPA's jurisdiction, potentially including the 70,000 chemicals regulated under the Toxic Substances Control Act (Endocrine Disruptor Screening and Testing Advisory Committee [EDSTAC], 1998). EDSTAC recommended an extensive process of prioritization, screening, and testing of chemicals for endocrine-disrupting activity, including a screening battery that involves a combination of at least eight in vitro and in vivo assays spanning a number of taxa (EDSTAC, 1998). What started out as a hypothesis has become one of the biggest testing programs conceived in the history of toxicology and the only one that has ever been based on mechanism of action as its premise. As we pass the 10th anniversary of the emergence of the endocrine disruptor hypothesis, it is useful to look back on the progress that has been made in answering the nine questions posed as data gaps in the EPA's research strategy (EPA, 1998a)--not only to see what we have learned, but also to examine whether the questions are still appropriate for the goal, what gaps remain, and what directions should be emphasized in the future.

Animals↗
PubMed2002

Refinements in acute dietary exposure assessments for chlorpyrifos.

Food pesticide residue data are used by the U.S. Environmental Protection Agency (EPA) to determine potential dietary risk from chronic and acute exposures. An acute dietary risk assessment determines the pesticide exposure resulting from a single-day consumption of food, and uses stepwise refinement of residue estimates to better judge actual exposures. All exposure refinements use estimates of the fraction of crops treated and food residues measured increasingly closer to the point of actual food consumption, without changes in the pesticide uses. Exposure distributions at all levels of data refinement were extremely right skewed. At the highest level evaluated, estimated exposures at the 99.9th percentile were 0.00087 mg/kgBW/day compared to 0.2648 mg/kgBW/day at the tolerance level for children 1-6 years, theoretically the highest-exposed population sub-group. The estimated exposure at the 99.9th percentile of the U.S. population was approximately twice the exposure at the 99th percentile and 33 times the exposure at the 90th percentile. This evaluation showed the calculated exposure at the highest tier of assessment was 300 times lower than the tolerance level assessment for children 1-6 years at the 99.9th percentile. Reduction in exposure estimates between these tiers was due to a combination of the following factors: food residue measurements in a specially designed market-basket study, government-sponsored monitoring data, probabilistic methodologies, market share information, and food processing data. This case study demonstrates that an improved understanding of the uncertainties of acute dietary exposure from pesticides is possible by using well-established statistical tools and applying them to comprehensive exposure information, including residue monitoring data, consumption data, and pesticide use information.

Child↗
PubMed2006

Statistical procedures for determination and verification of minimum reporting levels for drinking water methods.

The United States Environmental Protection Agency's Office of Ground Water and Drinking Water has developed a single-laboratory quantitation procedure: the lowest concentration minimum reporting level (LCMRL). The LCMRL is the lowest true concentration for which future recovery is predicted to fall, with high confidence (99%), between 50% and 150%. The procedure takes into account precision and accuracy. Multiple concentration replicates are processed through the entire analytical method and the data are plotted as measured sample concentration (y-axis) versus true concentration (x-axis). If the data support an assumption of constant variance over the concentration range, an ordinary least-squares regression line is drawn; otherwise, a variance-weighted least-squares regression is used. Prediction interval lines of 99% confidence are drawn about the regression. At the points where the prediction interval lines intersect with data quality objective lines of 50% and 150% recovery, lines are dropped to the x-axis. The higher of the two values is the LCMRL. The LCMRL procedure is flexible because the data quality objectives (50-150%) and the prediction interval confidence (99%) can be varied to suit program needs. The LCMRL determination is performed during method development only. A simpler procedure for verification of data quality objectives at a given minimum reporting level (MRL) is also presented. The verification procedure requires a single set of seven samples taken through the entire method procedure. If the calculated prediction interval is contained within data quality recovery limits (50-150%), the laboratory performance at the MRL is verified.

Analysis of Variance↗
PubMed2001

Method development and implementation for co-planar polychlorinated biphenyls (PCBs).

The Emission Measurement Center (EMC) in the Environmental Protection Agency's Office of Air Quality Planning and Standards was directed to conduct an emissions test program at a sewage sludge incinerator in support of a Maximum Achievable Control Technology (MACT) standard. One pollutant category of concern at these facilities was polychlorinated biphenyls, or PCBs. An objective of the test program was to measure co-planar PCBs in the incinerator emissions, the sewage sludge introduced to the incinerator, and the scrubber water effluent used in controlling the incinerator emissions. Co-planar PCB congeners are those having four or more chlorine atoms with only a few substitutions in the ortho positions, i.e. positions designated 2, 2', 6, and 6'. Thirteen PCB compounds are sometimes referred to as the "WHO PCBs," because the World Health Organization (WHO) has derived toxic equivalency factors for these congeners. Studies have shown that these dioxin-like compounds can react with the aryl hydrocarbon receptor. This same reaction is believed to initiate adverse health effects for dioxin and furan congeners. In order to conduct the co-planer PCB testing, the EMC had to develop analytical methods that could measure the 13 co-planar PCBs. The purpose of the test program was to develop, evaluate, and implement analytical test methods capable of measuring co-planar PCBs in three matrices: incinerator stack gases, sewage sludge, and scrubber water effluents. The paper summarizes the initial development work that was performed in preparation of analytical test protocols that could measure co-planar PCBs in air, water, and sludge matrices. Following the method development, a MACT emissions test program was conducted at a sewage sludge facility in July 1999 and these data are also summarized in the paper.

Dioxins↗
PubMed2003

Effect of particles on the recovery of cryptosporidium oocysts from source water samples of various turbidities.

Cryptosporidium parvum can be found in both source and drinking water and has been reported to cause serious waterborne outbreaks which threaten public health safety. The U.S. Environmental Protection Agency has developed method 1622 for detection of Cryptosporidium oocysts present in water. Method 1622 involves four key processing steps: filtration, immunomagnetic separation (IMS), fluorescent-antibody (FA) staining, and microscopic evaluation. The individual performance of each of these four steps was evaluated in this study. We found that the levels of recovery of C. parvum oocysts at the IMS-FA and FA staining stages were high, averaging more than 95%. In contrast, the level of recovery declined significantly, to 14.4%, when the filtration step was incorporated with tap water as a spiking medium. This observation suggested that a significant fraction of C. parvum oocysts was lost during the filtration step. When C. parvum oocysts were spiked into reclaimed water, tap water, microfiltration filtrate, and reservoir water, the highest mean level of recovery of (85.0% +/- 5.2% [mean +/- standard deviation]) was obtained for the relatively turbid reservoir water. Further studies indicated that it was the suspended particles present in the reservoir water that contributed to the enhanced C. parvum oocyst recovery. The levels of C. parvum oocyst recovery from spiked reservoir water with different turbidities indicated that particle size and concentration could affect oocyst recovery. Similar observations were also made when silica particles of different sizes and masses were added to seeded tap water. The optimal particle size was determined to be in the range from 5 to 40 micro m, and the corresponding optimal concentration of suspended particles was 1.42 g for 10 liters of tap water.

Animals↗
PubMed1994

A commentary on the NRC report "Science and judgment in risk assessment".

This article provides a brief overview of the report "Science and Judgment in Risk Assessment," prepared by a Committee of the National Research Council/National Academy of Science in response to a U.S. Environmental Protection Agency request mandated by the Clean Air Act Amendments of 1990 (CAAA-1990). The report critiques EPA's current approaches for characterizing human cancer risks from exposure to chemicals and offers recommendations for the conduct of future cancer risk assessments, especially those required in implementing the CAAA-1990 provisions which are concerned with hazardous air pollutants. The report offers specific recommendations that address the role of default options, data needs, methods and models, uncertainty, variability, and the aggregation of data. A cross-cutting theme of the report is the use of an iterative approach in which screening assessments with limited data and, of necessity, default options used in the absence of specific scientific data may be performed initially followed by subsequent assessments, as needed, in which increasing amounts of data are developed and incorporated. In some instances, the specific data on a given chemical or pollutant source will replace conservative default options used in earlier assignments. The report includes two authored appendices that address issues related to the use of default options and their replacement by specific scientific information. One appendix by Finkel advocates a principle of "plausible conservatism" for choosing and altering default options and in making cancer risk estimates. A second appendix by McClellan and North advocates the full use of scientific information in the risk assessment process. This article gives major attention to the key aspects of the NRC/NAS report, especially those dealing with the use and replacement of default options. The default options and the extent to which the options are replaced with specific science have major impact on the final quantitation of cancer risk for exposure to chemicals.

Air Pollution↗
PubMed2001

Harmonization of cancer and noncancer risk assessment: proceedings of a consensus-building workshop.

Significant advancements have been made toward the use of all relevant scientific information in health risk assessments. This principle has been set forth in risk-assessment guidance documents of international agencies including those of the World Health Organization's International Programme on Chemical Safety, the U.S. Environmental Protection Agency, and Health Canada. Improving the scientific basis of risk assessment is a leading strategic goal of the Society of Toxicology. In recent years, there has been a plethora of mechanistic research on modes of chemical toxicity that establishes mechanistic links between noncancer responses to toxic agents and subsequent overt manifestations of toxicity such as cancer. The research suggests that differences in approaches to assessing risk of cancer and noncancer toxicity need to be resolved and a common broad paradigm for dose-response assessments developed for all toxicity endpoints. In November 1999, a workshop entitled "Harmonization of Cancer and Noncancer Risk Assessment" was held to discuss the most critical issues involved in developing a more consistent and unified approach to risk assessment for all endpoints. Invited participants from government, industry, and academia discussed focus questions in the areas of mode of action as the basis for harmonization, common levels of adverse effect across toxicities for use in dose-response assessments, and scaling and uncertainty factors. This report summarizes the results of those discussions. There was broad agreement, albeit not unanimous, that current science supports the development of a harmonized set of principles that guide risk assessments for all toxic endpoints. There was an acceptance among the participants that understanding the mode of action of a chemical is ultimately critical for nondefault risk assessments, that common modes of action for different toxicities can be defined, and that our approach to assessing toxicity should be biologically consistent.

Animals↗
PubMed2001

Toxicant- and response-specific comparisons of statistical methods for estimating effective concentrations.

Standard U.S. Environmental Protection Agency (U.S. EPA) statistical analyses of whole effluent toxicity tests involve the estimation of the concentration associated with a specified level of inhibition relative to control responses. Current U.S. EPA estimation methods (linear interpolation or probit-based methods) are compared to a recently developed parametric regression-based estimator, the relative inhibition concentration estimator RIp. The RIp estimation technique, with level of inhibition p = 25%, is applied to a series of chronic toxicity test data from a U.S. EPA Region 9 database of reference toxicity tests. Tests on marine species are conducted with one reference toxicant, while the freshwater tests are conducted with several reference toxicants. While the U.S. EPA estimators and the RIp estimator are highly correlated for red abalone larval shell development, the degree of correlation for fathead minnow responses varies with reference toxicant tested. The strength of the relationship between the RIp and the standard U.S. EPA estimators varies as a function of the reference toxicant. Correlations range between 0.67 and 0.99. For all biological responses included in this evaluation (fathead minnow growth or survival and red abalone larval development), experiments occurred where the RIp is estimable, while the standard U.S. EPA estimators are not. Nonestimability of the standard EPA methods appears to be related, in part, to the failure of models to account for enhanced responses, such as a hormesis effect prior to toxicity being manifest. The ability to account for such enhanced responses is a strength of the RIp method. Finally, a variance component analysis suggests that lab-to-lab variability is relatively low for the red abalone but relatively high for the fathead minnow.

Animals↗
PubMed2000

Improving cancer dose-response characterization by using physiologically based pharmacokinetic modeling: an analysis of pooled data for acrylonitrile-induced brain tumors to assess cancer potency in the rat.

Historically, U.S. regulators have derived cancer slope factors by using applied dose and tumor response data from a single key bioassay or by averaging the cancer slope factors of several key bioassays. Recent changes in U.S. Environmental Protection Agency (EPA) guidelines for cancer risk assessment have acknowledged the value of better use of mechanistic data and better dose-response characterization. However, agency guidelines may benefit from additional considerations presented in this paper. An exploratory study was conducted by using rat brain tumor data for acrylonitrile (AN) to investigate the use of physiologically based pharmacokinetic (PBPK) modeling along with pooling of dose-response data across routes of exposure as a means for improving carcinogen risk assessment methods. In this study, two contrasting assessments were conducted for AN-induced brain tumors in the rat on the basis of (1) the EPA's approach, the dose-response relationship was characterized by using administered dose/concentration for each of the key studies assessed individually; and (2) an analysis of the pooled data, the dose-response relationship was characterized by using PBPK-derived internal dose measures for a combined database of ten bioassays. The cancer potencies predicted for AN by the contrasting assessments are remarkably different (i.e., risk-specific doses differ by as much as two to four orders of magnitude), with the pooled data assessments yielding lower values. This result suggests that current carcinogen risk assessment practices overestimate AN cancer potency. This methodology should be equally applicable to other data-rich chemicals in identifying (1) a useful dose measure, (2) an appropriate dose-response model, (3) an acceptable point of departure, and (4) an appropriate method of extrapolation from the range of observation to the range of prediction when a chemical's mode of action remains uncertain.

Acrylonitrile↗
PubMed2006

A classification framework and practical guidance for establishing a mode of action for chemical carcinogens.

The recently released U.S. Environmental Protection Agency (U.S. EPA) Supplemental Guidance for Assessing Risk from Early Life Exposure to Carcinogens (SGAC) provides guidance to account for potential increased early life susceptibility to carcinogens that are acting via a mutagenic mode of action. While determination of the mode of carcinogenic action is central to the SGAC procedures and other regulatory risk assessments, little guidance is given as to the approaches, criteria, and nature of the evidence required to define a mutagenic mode of action. The purpose of this paper is to provide a framework along with practical guidance for the process of assigning a mode of action. Strengths, weaknesses, reliability, and choice of a test battery are discussed for select bacterial, cell culture, whole animal and human cell assays. Common confounding factors of induced pathology, cytolethality, and regenerative cell proliferation in rodent cancer bioassays are discussed along with approaches to account for these effects in assigning a mode of action and in risk assessments. Specific examples are given to illustrate the complexity in generating a data set sufficient to move from the default regulatory position of assuming a genotoxic mode of action to actually assigning a nongenotoxic mode of action. A two-part framework is proposed for assigning a mode of action. First, a weight of evidence approach is used to assess mutagenic potential based on results of genetic toxicology test systems. Second, a descriptor is assigned to classify the degree to which mutagenic activity likely played a role in the mode of action of tumor formation. This option provides a more realistic way of describing the mode of action instead of being bound by the strict genotoxic vs. nongenotoxic choices.

Animals↗
PubMed2004

The US EPA reference dose for methylmercury: sources of uncertainty.

The US Environmental Protection Agency (EPA) derived a reference dose for methylmercury in 2001, based on an extensive analysis by the National Research Council (NRC) of the National Academy of Sciences. The NRC performed benchmark dose analysis on a number of endpoints from three longitudinal prospective studies: the Seychelles Islands, the Faroe Islands, and the New Zealand studies. Adverse effects were reported in the latter two studies, but not in the Seychelles study. The NRC also performed an integrative analysis of all three studies. Dose conversion from cord blood or maternal hair mercury concentration was performed by EPA using a one-compartment pharmacokinetic model. A total uncertainty factor of 10 was applied for intrahuman pharmacokinetic and pharmacodynamic variability. There are numerous decisions made by the NRC/EPA that could greatly affect the value of the reference dose (RfD). Some of these include the choice of a linear model for the relationship between mercury body burden and neuropsychological performance, the choice of values of P0 and the benchmark response, the use of the "critical study/critical endpoint" approach in the interpretation of the maternal body burden that corresponds to the RfD, the use of central tendencies in a one-compartment pharmacokinetic model rather than the inclusion of the distributions of variables for the population of reproductive-age women, the assumption of unity for the ratio of fetal cord blood to maternal blood methylmercury concentrations, the choice of a total of 10 as an uncertainty factor, and the lack of dose-response analysis for other health effects such as cardiovascular disease. In addition, it may be argued that derivation of a RfD for methylmercury is inappropriate, given that there does not appear to be a threshold for adverse neuropsychological effects based on available data.

Adult↗
PubMedDate not supplied

A review of US EPA and FDA requirements for electronic records, electronic signatures, and electronic submissions.

Both the United States Environmental Protection Agency (EPA) and the U.S. Food and Drug Administration (FDA) have issued regulatory documents that address the issues and requirements concerning electronic reporting to the Agencies. EPA has published two comprehensive and useful electronic data interchange (EDI) guidelines: 1) the EPA Electronic Data Interchange (EDI) Implementation Guideline, Draft of September 23, 1994 and October 18, 1994 that is available at the following EPA web site address: www.epa.gov/oppeedi1/guidelines/general.pdf and 2) the Interim Final Notice, Filing of Electronic Reports via Electronic Data Interchange, September 4, 1996, Federal Register Notice [FRL-5601-4, Volume 61, Number 172, page 46684], also available at: www.epa.gov/oppeedi1/edipoli.htm. The FDA has published a guidance document titled, "Guidance for Industry, Computerized Systems Used in Clinical Trials, April 1999" that is available at FDA's web site: www.fda.gov/ora/compliance_ref/bimo/ffinalcct.++ +htm. FDA's guidance document addresses a number of issues for electronic records that are applicable to all areas of GLP compliance. Another FDA document presently under development is titled, "Electronic Standards for the Transmission of Regulatory Information (ESTRI) Gateway." The ESTRI document defines strategic plans for electronic submissions to FDA. FDA has published a guidance document in this area titled, "Guidance for Industry: Providing Regulatory Submissions in Electronic Format--General Considerations, January 1999." This guidance document is available at: www.fda.gov/cder/guidance/index.htm. FDA has also published an important final rule applicable to all electronic records and signatures that is part of the U.S. Title 21 Code of Federal Regulations (CFR), Part 11, titled, "FDA's Final Rule, Electronic Records; Electronic Signatures, effective August 20, 1997." This FDA ruling is discussed below and is available at: www.fda.gov/cder/esig/index.htm.

Authorship↗