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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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 precur- sor 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. Environ- mental Protection Agency (EPA) has classified tetrachloroethylene as a hazard- ous air pollutant under the Clean Air Act, a toxic pollutant under the Clean Wa- ter 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 Liabil- ity Act. EPA’s Integrated Risk Information System (IRIS) is a database that pro- vides 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 hazard- ous-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 expo- sure 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 pro- vides 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 16

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17 Introduction 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 inter- preted 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 independ- ent assessment of its draft Toxicological Review of Tetrachloroethylene (Per- chloroethylene) (CAS No. 127-18-4) in Support of Summary Information on the Integrated Risk Information System (IRIS), hereafter called the draft IRIS as- sessment. 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 clini- cal 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 re- search 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, in- cluded the following questions: General Charge Questions: 1. Does the draft IRIS assessment provide a scientifically sound, bal- anced, and transparent review and synthesis of the key scientific evidence on chronic noncancer and cancer hazard and risk?

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18 Review of the EPA’s Draft IRIS Assessment of Tetrachloroethylene 2. Please identify any additional important studies that should be consid- ered in the assessment of the chronic noncancer and cancer health effects of tet- rachloroethylene. Specific Charge Questions: Noncancer Assessment 1. Selection of neurotoxicity as the basis for the RfC and RfD for tetra- chloroethylene—a number of studies assessing neurobehavioral and other ef- fects in both humans and rodents are available for RfC and RfD analysis. a. Is EPA’s selection of neurotoxicity, specifically visual dysfunction and cognitive deficits, appropriate for providing a point of depar- ture for derivation of the RfC and RfD? The goal of a reference value is to provide an estimate of exposure of the human popula- tion (including susceptible subgroups) that is likely to be without appreciable risk of adverse health effects over a lifetime. b. Does EPA provide a sound and transparent description of the rele- vant studies of the neurotoxic effects of tetrachloroethylene? c. Does the assessment present an appropriate rationale for selection of the study by Altmann et al. (1995) as the critical study? If an- other 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. 2. Characterization of Uncertainties—the noncancer assessment consid- ers uncertainty on the basis of extrapolation from laboratory animals to humans, variations in response within experimental species, human variation, and data- base deficiencies; the noncancer RfC and RfD are based on a specific neurotox- icity effect; EPA also presents reference values based on other effects to illus- trate the dose dependence of the multiple observed toxicities. a. 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. b. Please comment on EPA’s graphic presentation of noncancer ref- erence values that could have been derived from studies of differ- ent neurotoxic effects or toxic effects in other organ systems. Cancer Assessment 1. Weight-of-evidence descriptor—the assessment concludes that tetra- chloroethylene is “likely to be carcinogenic to humans” by all routes of exposure

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19 Introduction within the framework of the Guidelines for Carcinogen Risk Assessment (EPA 2005a). a. Does EPA provide a clear and cogent weight-of-evidence evalua- tion? b. Does the assessment support the conclusion that tetrachloroethyl- ene by oral and inhalation exposure is likely to be carcinogenic in humans (at all levels of exposure)? 2. Mode of action considerations—the mode of action of a carcinogen can inform identification of hazards and approaches used for a dose-response rela- tionship; the assessment concludes that a mode of action of tetrachloroethylene has not been definitively established for any of the site-specific tumor types. a. Does EPA provide a sound evaluation and characterization of the available data related to mode(s) of action for the carcinogenicity of tetrachloroethylene? b. Do the available data support EPA’s conclusion that mode(s) of ac- tion for tetrachloroethylene-induced carcinogenesis is unknown? c. 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 Ex- posure to Carcinogens (EPA 2005b)? 3. 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. a. 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. b. Does EPA clearly and objectively describe the low-dose extrapola- tion approach, that is, linear extrapolation in accordance with de- fault recommendations in the Guidelines for Carcinogen Risk As- sessment (EPA 2005a)? 4. Consideration of uncertainties—the cancer assessment considered the contribution of a number of sources of uncertainty; some uncertainties (for ex- ample, 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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20 Review of the EPA’s Draft IRIS Assessment of Tetrachloroethylene tive impact on the risk estimate; in addition to the unit risk estimate, the assess- ment provides lower bounds (such as confidence limits) and central estimates. a. Has EPA identified and described the key sources of uncertainty in assessing cancer risks posed by tetrachloroethylene? b. Is this analysis transparent and presented at a suitable level of de- tail for the IRIS assessment? c. Does the assessment clearly and objectively present the choices made in developing reasonable upper-bound estimates of cancer risk posed by tetrachloroethylene? d. The assessment includes tabular presentations of point-of- departure-based analyses that use different end points and ap- proaches (see Tables 6-2, 6-3, 6-4, and 6-5). Is the information clearly presented and appropriately characterized? e. In Section 6.2.2.2, 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? f. 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 meta- bolic 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 can- cer effects. Metabolite formation was modeled by using three PBPK models, which led to a range of cancer risk factors. 1. Please comment on the PBPK application for route-to-route extrapola- tion in developing an RfD and an oral slope factor from studies of inhalation exposure. 2. 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. 3. Has EPA clearly and objectively presented a. Choice of dose metrics for different outcomes and their use in PBPK models? b. Strengths and weaknesses of different modeling approaches? c. The approach used in deriving the toxicologically equivalent hu- man dose, including the application of an interspecies scaling fac- tor (BW3/4) to the fraction of the administered rodent dose that is metabolized?

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21 Introduction 4. 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 char- acterized? COMMITTEE’S APPROACH The committee reviewed the material presented in EPA’s draft IRIS as- sessment for scientific soundness, balance, and transparency. By the nature of the charge, the focus was on parts of the document that were critical for deter- mining 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 assess- ment of uncertainties. Public comments submitted to EPA and to the committee on the draft assessment were considered. The committee also held public meet- ings at which it had the opportunity to ask questions of EPA staff, to obtain in- put 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 assess- ment, 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 Li- brary 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 litera- ture. A simple search for “tetrachloroethylene,” its synonyms, and its Chemical Abstracts Service registry number was performed. Literature retrieval was lim- ited to studies pertinent to the evaluation of adverse health effects, such as toxi- cology studies (including studies on toxicokinetics and mode of action) and epi- demiology 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 Sub- stances 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 spe- cific topics and to gather general background information.

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22 Review of the EPA’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 ap- proaches 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 em- pirically 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 understand- ing 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 ob- servable 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 guid- ance 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 relation- ships 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 consid- eration of the broader database and such matters as anatomy, physiologic varia- tions, 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 ap- proach to articulation of clear hypotheses, to description of the weight of evi- dence on which conclusions are based in the context of explicitly stated criteria,

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23 Introduction 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 in- creased 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 sin- gle tissue are induced by a single mode of action, although in early stages sev- eral (seemingly competing) pathways may contribute. Mode of action is increas- ingly 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 tetrachloroethyl- ene. Chapter 2 provides a brief overview of the toxicokinetics of tetrachloro- ethylene because understanding how the body handles tetrachloroethylene is critical for understanding its effects in the later chapters focused on specific or- gan systems. Chapter 3 presents an evaluation of the neurotoxic effects of tetra- chloroethyelene; 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 assess- ment of EPA’s derivation of the noncancer reference values (Chapter 10) and cancer-risk values (Chapter 11). Chapter 12 provides the committee’s recom- mendations for future reassessments of tetrachloroethylene.