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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene 1 Introduction Tetrachloroethylene is a volatile chlorinated organic hydrocarbon that is widely used as a solvent in the dry-cleaning and textile-processing industries and as an agent for degreasing metal parts. It is also used as a chemical precursor for synthesis of fluorocarbons. It has the following use pattern: 55% as a chemical intermediate, 25% for metal-cleaning and degreasing, 15% for dry-cleaning and textile-processing, and 5% for other unspecified uses (ATSDR 1997; EPA 2008). Dry-cleaning facilities are an important source of atmospheric emissions of tetrachloroethylene. Tetrachloroethylene becomes a groundwater contaminant as a result of leaks and improper disposal practices; it can persist in groundwater for years because it has little contact with air. The U.S. Environmental Protection Agency (EPA) has classified tetrachloroethylene as a hazardous air pollutant under the Clean Air Act, a toxic pollutant under the Clean Water Act, a contaminant under the Safe Drinking Water Act, a hazardous waste under the Resource Conservation and Recovery Act, and a hazardous substance under the Comprehensive Environmental Response, Compensation, and Liability Act. EPA’s Integrated Risk Information System (IRIS) is a database that provides the agency’s assessments of potential human health effects of exposure to various substances in the environment. IRIS assessments provide quantitative estimates of cancer and noncancer effects that are used to establish air and water quality standards to protect public health and set cleanup standards for hazardous-waste sites. For noncancer effects, EPA establishes an oral reference dose (RfD) and an inhalation reference concentration (RfC), which are estimates (with uncertainty spanning perhaps an order of magnitude) of daily oral exposure and continuous inhalation exposure of the human population (including sensitive subgroups), respectively, that are likely to be without an appreciable risk of deleterious effects during a lifetime. For cancer, the IRIS database provides a characterization of the weight of evidence of human carcinogenicity, oral slope factors, and inhalation unit risks. An oral slope factor is an upper bound, approximating a 95% confidence limit, on the increased cancer risk posed by
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene lifetime exposure to an agent; it is usually expressed in units of proportion (of a population) affected per milligram per kilogram of body weight per day. A unit risk is the upper bound on the excess lifetime cancer risk estimated to result from continuous exposure to an agent at a concentration of 1 μg/L in water or 1 μg/m3 in air. For example, a unit risk of 2 × 10-6 per microgram per liter is interpreted as 2 excess cancer cases (upper-bound estimate) expected to develop per 1,000,000 people if they are exposed to the chemical daily for a lifetime at 1 μg per liter of drinking water. EPA requested that the National Research Council undertake an independent assessment of its draft Toxicological Review of Tetrachloroethylene (Perchloroethylene) (CAS No. 127-18-4) in Support of Summary Information on the Integrated Risk Information System (IRIS), hereafter called the draft IRIS assessment. The draft IRIS assessment proposes an RfC of 1.6 × 10-2 mg/m3, an RfD of 4 × 10-3 mg/kg-day, a range of inhalation unit risks of 2 × 10-6 to 2 × 10-2 per mg/m3, and a range of oral slope factors of 1 × 10-2 to 1 × 10-1 per mg/kg-day. EPA requested a review of those values and their scientific basis in 2006 but delayed public release of the draft IRIS assessment for additional evaluation within the agency. Therefore, the committee’s review did not begin until June 2008, when the draft was released. STATEMENT OF TASK A committee convened by the National Research Council was asked to conduct a scientific review—from toxicologic, epidemiologic, and human clinical perspectives—of EPA’s draft IRIS assessment of tetrachloroethylene that was made available for external review. The committee’s review was to include an evaluation of the adequacy of the assessment and the data and methods used for deriving the RfD and RfC of tetrachloroethylene and its oral and inhalation cancer unit risks. The committee was asked to evaluate whether the key studies underlying the draft IRIS assessment were of requisite quality, reliability, and relevance to support the derivation of the RfD, RfC, and oral and inhalation unit risks; to evaluate whether the scientific uncertainties in EPA's risk assessment were adequately described and, where possible, quantified; and to identify research that could reduce the uncertainties given the current understanding of human health effects associated with tetrachloroethylene exposure. During the study course of the project, EPA submitted specific questions for the committee to address. The final list, submitted in February 2009, included the following questions: General Charge Questions: Does the draft IRIS assessment provide a scientifically sound, balanced, and transparent review and synthesis of the key scientific evidence on chronic noncancer and cancer hazard and risk?
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene Please identify any additional important studies that should be considered in the assessment of the chronic noncancer and cancer health effects of tetrachloroethylene. Specific Charge Questions: Noncancer Assessment Selection of neurotoxicity as the basis for the RfC and RfD for tetrachloroethylene—a number of studies assessing neurobehavioral and other effects in both humans and rodents are available for RfC and RfD analysis. Is EPA’s selection of neurotoxicity, specifically visual dysfunction and cognitive deficits, appropriate for providing a point of departure for derivation of the RfC and RfD? The goal of a reference value is to provide an estimate of exposure of the human population (including susceptible subgroups) that is likely to be without appreciable risk of adverse health effects over a lifetime. Does EPA provide a sound and transparent description of the relevant studies of the neurotoxic effects of tetrachloroethylene? Does the assessment present an appropriate rationale for selection of the study by Altmann et al. (1995) as the critical study? If another study is judged more appropriate for use as the critical study, please provide a critical evaluation of it and of its suitability for meeting the goals of a reference value. Characterization of Uncertainties—the noncancer assessment considers uncertainty on the basis of extrapolation from laboratory animals to humans, variations in response within experimental species, human variation, and database deficiencies; the noncancer RfC and RfD are based on a specific neurotoxicity effect; EPA also presents reference values based on other effects to illustrate the dose dependence of the multiple observed toxicities. Has EPA accurately and clearly characterized the basis of selection of uncertainty factors for the RfC and RfD? Please comment on the rationales underlying the choice of uncertainty factors, such as the database uncertainty factor, which is intended to account for the degree of limitations in both human and animal data. Please comment on EPA’s graphic presentation of noncancer reference values that could have been derived from studies of different neurotoxic effects or toxic effects in other organ systems. Cancer Assessment Weight-of-evidence descriptor—the assessment concludes that tetrachloroethylene is “likely to be carcinogenic to humans” by all routes of exposure
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene within the framework of the Guidelines for Carcinogen Risk Assessment (EPA 2005a). Does EPA provide a clear and cogent weight-of-evidence evaluation? Does the assessment support the conclusion that tetrachloroethylene by oral and inhalation exposure is likely to be carcinogenic in humans (at all levels of exposure)? Mode of action considerations—the mode of action of a carcinogen can inform identification of hazards and approaches used for a dose-response relationship; the assessment concludes that a mode of action of tetrachloroethylene has not been definitively established for any of the site-specific tumor types. Does EPA provide a sound evaluation and characterization of the available data related to mode(s) of action for the carcinogenicity of tetrachloroethylene? Do the available data support EPA’s conclusion that mode(s) of action for tetrachloroethylene-induced carcinogenesis is unknown? Does EPA clearly address why age-dependent adjustment factors for cancer risk are not applied, according to the Guidelines for Carcinogen Risk Assessment (EPA 2005a) and Supplemental Guidance for Assessing Cancer Susceptibility from Early-Life Exposure to Carcinogens (EPA 2005b)? Development of the inhalation unit risk and oral slope factor—EPA’s draft unit-risk estimate relies on choices of tumor type, point of departure, and low-dose extrapolation that aim to provide a “reasonable upper bound estimate” of risk; because the draft assessment judged that there was no strong basis for preferring one physiologically-based pharmacokinetic model over another, a range of tetrachloroethylene unit-risk estimates calculated with three PBPK models is given. Please comment on EPA’s selection of mononuclear-cell leukemia in male rats from the Japanese Industrial Safety Association study for quantitative derivation of the inhalation unit risk and oral slope factor. Note that, consistently with the Guidelines for Carcinogen Risk Assessment (EPA 2005a), the draft IRIS assessment does not infer site concordance of tumors across species. If another study or end point is judged to be more appropriate for the derivation of these risk values, please provide a critical evaluation of the end point and its suitability for supporting a unit risk estimate. Does EPA clearly and objectively describe the low-dose extrapolation approach, that is, linear extrapolation in accordance with default recommendations in the Guidelines for Carcinogen Risk Assessment (EPA 2005a)? Consideration of uncertainties—the cancer assessment considered the contribution of a number of sources of uncertainty; some uncertainties (for example, pertaining to mode of action and human sensitivity and variability) were qualitatively expressed, and in other cases EPA examined the potential quantita-
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene tive impact on the risk estimate; in addition to the unit risk estimate, the assessment provides lower bounds (such as confidence limits) and central estimates. Has EPA identified and described the key sources of uncertainty in assessing cancer risks posed by tetrachloroethylene? Is this analysis transparent and presented at a suitable level of detail for the IRIS assessment? Does the assessment clearly and objectively present the choices made in developing reasonable upper-bound estimates of cancer risk posed by tetrachloroethylene? The assessment includes tabular presentations of point-of-departure- based analyses that use different end points and approaches (see Tables 6-2, 6-3, 6-4, and 6-5). Is the information clearly presented and appropriately characterized? In Section 220.127.116.11, the assessment presents exploratory calculations of potential probabilities of tumor response at low dose by using different functional forms. Is this analysis clearly presented and appropriately characterized? Please discuss research subjects likely to characterize uncertainties better in future tetrachloroethylene cancer risk assessments. Choice of Dose Metrics for Various Toxic Outcomes, PBPK Modeling, and Interspecies Scaling Approaches Exposure to tetrachloroethylene results in the production of several metabolic products. The parent compound is used as the dose metric for neurotoxic effects, and the rate of formation of total metabolites in humans is used for cancer effects. Metabolite formation was modeled by using three PBPK models, which led to a range of cancer risk factors. Please comment on the PBPK application for route-to-route extrapolation in developing an RfD and an oral slope factor from studies of inhalation exposure. Please comment on the sufficiency of the available data to identify whether the parent compound or specific metabolites are responsible for the induction of cancer through tetrachloroethylene exposure. Has EPA clearly and objectively presented Choice of dose metrics for different outcomes and their use in PBPK models? Strengths and weaknesses of different modeling approaches? The approach used in deriving the toxicologically equivalent human dose, including the application of an interspecies scaling factor (BW3/4) to the fraction of the administered rodent dose that is metabolized?
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene Is EPA’s conclusion that there is not a strong basis for preferring any one PBPK model for use in the risk assessment soundly and transparently characterized? COMMITTEE’S APPROACH The committee reviewed the material presented in EPA’s draft IRIS assessment for scientific soundness, balance, and transparency. By the nature of the charge, the focus was on parts of the document that were critical for determining neurotoxicity and cancer end points. The review included evaluation of some of the primary literature cited by EPA, its approaches to evaluating and modeling data, and options for performing qualitative and quantitative assessment of uncertainties. Public comments submitted to EPA and to the committee on the draft assessment were considered. The committee also held public meetings at which it had the opportunity to ask questions of EPA staff, to obtain input from invited speakers who were doing research on tetrachloroethylene or related scientific issues, and to hear from other interested parties. To identify new studies that should be considered in EPA’s IRIS assessment, the committee performed a literature search for papers published from July 2004 (the official cutoff for EPA’s comprehensive literature search) to March 2009. For the purposes of its review, the committee restricted its searches to MEDLINE and EMBASE. MEDLINE is produced by the U.S. National Library of Medicine and covers over 5,200 biomedical journals published in the United States and over 80 foreign countries. EMBASE is produced by Elsevier Science and indexes over 4,800 journals with a focus on the international literature. A simple search for “tetrachloroethylene,” its synonyms, and its Chemical Abstracts Service registry number was performed. Literature retrieval was limited to studies pertinent to the evaluation of adverse health effects, such as toxicology studies (including studies on toxicokinetics and mode of action) and epidemiology studies. Other sources of information that the committee considered included compilations of toxicology and human health information from national and international agencies and organizations, such as the Agency for Toxic Substances and Disease Registry, the International Agency for Research on Cancer, the California Environmental Protection Agency, and the European Union. Relevant publications from the National Research Council and the Institute of Medicine were also consulted. The committee and staff examined the reference lists included in EPA’s draft assessment, major epidemiologic studies, review articles, and major compilations for relevant citations. Smaller targeted literature searches were performed to identify pertinent older literature and papers on specific topics and to gather general background information.
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene CONSIDERATION OF MODE OF ACTION Much of the committee’s task was focused on the mode of action or the toxic and carcinogenic effects of tetrachloroethylene. Because mode of action is considered throughout this report, a brief overview of what it means and of approaches to evaluating it is presented briefly here. The term mode of action is defined in the EPA cancer guidelines as a sequence of key events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomic changes, and resulting in cancer formation. A key event is an empirically observable precursor step that is itself a necessary element of the mode of action or is a biologically based marker of such an element. Mode of action is contrasted with mechanism of action, which implies a more detailed understanding and description of events, often at the molecular level, than is meant by mode of action. The toxicokinetic processes that lead to formation of the active agent or its distribution to the target tissue, although considered in estimating dose, are not part of the mode of action as the term is used in the guidelines. Examples of possible modes of carcinogenic action are also presented in the guidelines, which state that they include mutagenicity, mitogenesis, inhibition of cell death, cytotoxicity with reparative cell proliferation, and immune suppression. Understanding of mode of action is crucial for identifying susceptible life stages and determining appropriate approaches to extrapolation beyond the observable dose-response relationships. As a default, dose-response analysis for chemicals whose modes of action are expected to involve mutation involves linear extrapolation. Other modes of action may be modeled with either linear or nonlinear approaches after a rigorous analysis of available data under the guidance provided in the framework for mode-of-action analysis. In the last decade, a continually evolving framework for considering weight of evidence for hypothesized modes of action and their human relevance has been developed and widely incorporated in guidance and risk assessments for individual chemicals by national and international agencies, including EPA. The framework is relevant to consideration of mechanistic data on both cancer and noncancer effects and sets the stage for informing dose-response relationships through consideration of hypothesized modes of action in the context of key events and their relevance to humans (for example, see Meek 2008). A framework requires delineation of a hypothesis with specified key events and then consideration of the weight of evidence of the hypothesized mode of action in animals in the context of such criteria as consistency, specificity, and biologic plausibility. Human relevance is then taken into account on the basis of consideration of the broader database and such matters as anatomy, physiologic variations, and human disease states. Recent broad-based acceptance of mode of action and human relevance analyses is a function principally of their value in providing a structured approach to articulation of clear hypotheses, to description of the weight of evidence on which conclusions are based in the context of explicitly stated criteria,
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Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene and to delineation of inherent uncertainties. The framework analyses ensure rigor in supporting and communicating the outcome of risk assessment and in facilitating the direction of resources to research to fill critical data gaps. The transparency promoted by framework analyses is expected to contribute to increased consistency in decision-making regarding modes of induction of cancer and later implications for dose-response analysis. Mode-of-action analyses are based on the assumption that tumors in a single tissue are induced by a single mode of action, although in early stages several (seemingly competing) pathways may contribute. Mode of action is increasingly considered to incorporate toxicokinetics because often the critical first key event (which can be rate-limiting in the context of dose-response relationships) is activation to a toxic metabolite. ORGANIZATION OF COMMITTEE’S REPORT In the following chapters, the committee evaluates EPA’s presentation and evaluation of the potential adverse health effects of exposure to tetrachloroethylene. Chapter 2 provides a brief overview of the toxicokinetics of tetrachloroethylene because understanding how the body handles tetrachloroethylene is critical for understanding its effects in the later chapters focused on specific organ systems. Chapter 3 presents an evaluation of the neurotoxic effects of tetrachloroethyelene; such effects were the basis of EPA’s derivation of the RfC and RfD for tetrachloroetheylene, so the review focuses on evaluating the strengths and weaknesses of available studies and their utility in deriving reference values. Chapter 4 reviews EPA’s presentation of the reproductive and developmental toxicity of tetrachloroethylene. That is followed by a chapter on the genotoxicity of tetrachloroethylene, which factors into the consideration of cancers of the liver (Chapter 6), kidney (Chapter 7), hematopoietic system (Chapter 8), and other organs (Chapter 9). Those toxicology reviews are followed by an assessment of EPA’s derivation of the noncancer reference values (Chapter 10) and cancer-risk values (Chapter 11). Chapter 12 provides the committee’s recommendations for future reassessments of tetrachloroethylene.