Tetrachloroethylene: Integrated Risk Information System (IRIS) Draft - PowerPoint PPT Presentation

Tetrachloroethylene: Integrated Risk Information System (IRIS) Draft Toxicological Review Kate Z. Guyton, PhD DABT National Academy of Sciences Tetrachloroethylene Peer Review Panel November 13, 2008 Office of Research and Development National Center for Environmental Assessment

NCEA’s Tetrachloroethylene (Perc) Team Contributors Chemical Managers Nancy Beck Kate Z. Guyton ( since Sept 2007 ) David Bussard Karen A. Hogan ( since Sept 2007 ) Jane C. Caldwell Robert McGaughy ( retired ) Weihsueh Chiu Deborah Rice Other Authors Marc Rigas Stanley Barone, Jr. Bob Sonawane Rebecca C. Brown Paul White Glinda Cooper Nagalakshmi Keshava Leonid Kopylev Susan Makris Jean Parker ( retired ) Cheryl Siegel Scott Ravi Subramaniam Larry Valcovic ( retired ) Office of Research and Development 2 National Center for Environmental Assessment

Presentation Outline: Tetrachloroethylene  Background and assessment history  Key scientific challenges and questions • Metabolism and physiologically based pharmacokinetic (PBPK) modeling • Non-cancer hazard and reference concentration/dose derivation • Carcinogenicity conclusions and dose-response analysis  Summary of EPA’s 2008 assessment findings Office of Research and Development 3 National Center for Environmental Assessment

Tetrachloroethylene Background Information  Most common uses  Fabric dry cleaning (by ~27,000 US dry cleaners) ‏  Metal cleaning and degreasing  Environmental exposures  Indoor air (e.g. in residences adjacent to dry cleaners)  Superfund National Priority List sites  Ground and drinking water Office of Research and Development 4 National Center for Environmental Assessment

Non-Cancer Reference Values: Definition  An estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure (RfC) or daily oral exposure (RfD) to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.  Derived from a NOAEL, LOAEL, or benchmark dose, with uncertainty factors generally applied to reflect limitations of the data used Office of Research and Development 5 National Center for Environmental Assessment

EPA Last Completed an Assessment of Tetrachloroethylene in 1988  Reference dose (RfD) posted on IRIS (1988)  Nominated for reassessment (1998)  Initial draft prepared (2001)  Public, expert panel review of neurotoxicity summary (2003-2004)  Reviews by EPA, Federal Agencies, OMB (2005-2006)  Expanded uncertainty characterization (2006-2008)  Release for public and external peer review (2008) Office of Research and Development 6 National Center for Environmental Assessment

Major Updates Since 1988 IRIS Assessment  Comprehensive literature review (last updated July 2004)  New toxicity values in current draft:  Reference concentration (RfC)  Carcinogenicity assessment  Updated toxicity value (RfD) Office of Research and Development 7 National Center for Environmental Assessment

Overall Goal of Tetrachloroethylene NAS Review EPA seeks NAS input regarding:  EPA’s evaluation of scientific evidence regarding tetrachloroethylene health effects (hazard)  The application of such data in EPA’s quantification of tetrachloroethylene human health risks (dose-response) Office of Research and Development 8 National Center for Environmental Assessment

Assessment overview by chapter 1. Introduction Key scientific challenges 2. Background  Metabolism, PBPK modeling 3. Toxicokinetics  Non-cancer: hazard identification 4. Hazard identification and risk estimation 5. Dose-response  Carcinogenicity assessment and evaluation risk estimation 6. Characterization of hazard and dose- response Office of Research and Development 9 National Center for Environmental Assessment

Metabolism and Considerations for Dose Metrics, PBPK Modeling Dose Metric: Total Metabolism Overview of Metabolic Pathways Liver : T CA contributes, but 1. Oxidation by P450s (CYP2E1) does not fully  Unstable epoxide intermediate explain toxicity  Oxidative metabolites  major metabolite TCA Total Metabolism => excreted in urine Kidney, MCL : No reliable data to 2. Conjugation with GSH develop PBPK  TCVG model  Cysteine conjugate TCVC Blood AUC  N-acetylation => Neurotoxicity : excretion of Parent, mercapturates in urine metabolites contribute Office of Research and Development 10 National Center for Environmental Assessment

Range of Data and PBPK Models Available Chen and Blancato 1987 2.9% Large variation in estimates of PERC metabolism Ward et al. 1988 23% Bois et al. 1990 [1] 23% Bois et al. 1990 [2] 15% Rao and Brown 1993 4.4% Reitz et al. 1996 16% 36% Bois et al. 1996 Loizou 2001 1.9% Clewell et al. 2005 [1] 1.7% Clewell et al. 2005 [2] 2.3% 23% Chiu and Bois 2006 0.0% 20.0% 40.0% 60.0% 80.0% Percent Metabolized at 1 ppb Inhalation Exposure Chiu; WA. (2006) Statistical issues in physiologically based pharmacokinetic modeling. In: Lipscomb, JC; Ohanian, EV; eds., Toxicokinetics and risk assessment, New York: Informa Healthcare, Inc. Office of Research and Development 11 National Center for Environmental Assessment

New PBPK Data/Models? Available after final version of EPA document: • Covington et al. (2007) Regul Toxicol Pharmacol. 47(1):1-18 • Clewell et al. (2005) Crit Rev Toxicol. 35(5):413-33 Percent metabolized at 1 ppb: ~1, 2% Rao and Brown (1996): 4.4% Office of Research and Development 12 National Center for Environmental Assessment

Non-cancer Hazard, Carcinogenicity: Weight-of-Evidence Approach Data sources: laboratory animal, • human and mechanistic studies Considerations: • – Data quality – Study design ( i.e ., strengths, endpoints captured) Guidelines for Carcinogen – Biological significance of Risk Assessment , US EPA, 1986, 1999, 2005 adverse outcomes – Consistency among studies A Review of the Reference Dose – Knowledge gaps and Reference Concentration Processes, US EPA 2002 Office of Research and Development 13 National Center for Environmental Assessment

Non-cancer Hazards Associated with Chronic Exposures Neurotoxicity: Organ systems affected:  Most likely critical effect at  Central nervous system low, chronic exposures  Developing fetus  Effects reported in animal,  Reproductive system human studies  Liver (occupational, residential)  Kidney  Several nervous system domains affected Few mechanistic (mode of  Effects similar to other action, MOA) data solvents regarding these effects  Dose metric unknown   MOA unknown Office of Research and Development 14 National Center for Environmental Assessment

Choice of Critical Study for RfC and RfD Key considerations in study  Altmann et al (1995) Neurobehavioral and selection: neurophysiological outcome of chronic low-  Human data? level tetrachloroethene exposure measured  Standardized measures ( e.g ., in neighborhoods of dry cleaning shops. Environ Res 69:83-9. neurobehavioral battery)?  Mean indoor air exposure: 0.7 ppm  Consistency of effect across for 10.6 years studies?  14 exposed and 23 controls  Environmental ( e.g ., residential) exposures?  Exposed residents demonstrated impaired ability to detect and Neurotoxicity peer review panel respond to visual stimuli (2004):  Similar effects consistently reported  Affirmed endpoint selected in occupational exposure studies  Raised some key science issues ( e.g ., study statistics), which have been clarified in the 2008 draft Office of Research and Development 15 National Center for Environmental Assessment

Reference Values Based on Human Neurotoxicity Principal study: Point of Departure UFs critical effect (POD) LOAEL = 4.8 mg/m 3 RfC Altmann et al. (1995): 300 0.02 neurotoxicity in 10—intraspecies mg/m 3 humans living 10—LOAEL to near dry cleaning NOAEL facilities 3—database RfD Same as above LOAEL = 1.1 mg/kg- Same as above 0.004 day, derived by mg/kg-day route-to-route extrapolation from inhalation exposure Office of Research and Development 16 National Center for Environmental Assessment

New Data/Models to Inform Non- Cancer Hazard or RfC/RfD Estimation? NYC Perc Project • Reviewed in current draft • Study report available on-line (EPA STAR grant) • Draft study report, peer panel review submitted to public docket and available to committee for review Office of Research and Development 17 National Center for Environmental Assessment

Carcinogenicity in Humans and Laboratory Animals Many Epidemiologic Studies 10/10 Positive Rodent Cancer Bioassay Datasets Endpoints identified Lymphoid system Rats: Mice: Esophagus MCL* (males Liver (males and Cervix and females) females) Bladder Kidney (rare) Liver or spleen in males hemangiosarcoma Kidney (males and Lung females) Overall conclusion from rodent data: Overall conclusion from human data: Suggestive, but not conclusive, Multisite, multispecies carcinogen by multiple routes of exposure evidence of cancer hazard *MCL= Mononuclear cell leukemia