Tetrachloroethylene: Integrated Risk Information System (IRIS) Draft Toxicological Review Kate Z. Guyton, PhD DABT

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1 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

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

3 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 3

4 Tetrachloroethylene Background Information Most common uses ( cleaners Fabric dry cleaning (by ~27,000 US dry 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 4

5 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 5

6 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 ( ) Reviews by EPA, Federal Agencies, OMB ( ) Expanded uncertainty characterization ( ) Release for public and external peer review (2008) 6

7 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) 7

8 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) 8

9 Assessment overview by chapter 1. Introduction 2. Background 3. Toxicokinetics 4. Hazard identification 5. Dose-response evaluation 6. Characterization of hazard and doseresponse Key scientific challenges Metabolism, PBPK modeling Non-cancer: hazard identification and risk estimation Carcinogenicity assessment and risk estimation 9

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

11 Range of Data and PBPK Models Available Chen and Blancato 1987 Large variation in estimates of PERC metabolism Ward et al Bois et al [1] Bois et al [2] Rao and Brown 1993 Reitz et al Bois et al Loizou 2001 Clewell et al [1] Clewell et al [2] Chiu and Bois % 4.4% 1.9% 1.7% 2.3% 15% 16% 23% 23% 23% 36% 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. 11

12 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): Percent metabolized at 1 ppb: ~1, 2% Rao and Brown (1996): 4.4% 12

13 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) Biological significance of adverse outcomes Consistency among studies Knowledge gaps Guidelines for Carcinogen Risk Assessment, US EPA, 1986, 1999, 2005 A Review of the Reference Dose and Reference Concentration Processes, US EPA

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

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

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

17 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 17

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

19 Cancer MOA Data Rodent MOAs addressed Genotoxicity PPAR-α Alpha2-u (kidney) Cytotoxicity Immunotoxicity Few human, other mechanistic data (besides limited data regarding genotoxicity of GSH-derived metabolites) to conclusively determine carcinogenicity Overall conclusion: MOA is unknown for any of the rodent tumors 19

20 Weight of Evidence for Potential Human Carcinogenicity Association of human exposure with excess risk of cancers Evidence of carcinogenicity in 10 (of 10) lifetime rodent bioassay datasets Liver cancer (male, female mice) and MCL (male, female rats) in multiple bioassays, oral and inhalation exposures MOA unknown for any tumor type Known hepatocarcinogenicity of two oxidative metabolites Evidence of mutagenicity of certain metabolites, and of tetrachloroethylene under conditions that would generate these metabolites Weight of evidence descriptor: likely to be carcinogenic to humans 20

21 Principal Study for Cancer Risk Estimation Key considerations in study selection: Human data? Standardized measures? Consistency of effect across studies? Environmental exposures? Japan Industrial Safety Association (1993) Carcinogenicity study of tetrachloroethylene by inhalation in rats and mice. F344/DuCrj rats (both sexes) 104 wk inhalation exposure to 0, 50, 200, or 600 ppm Critical effect: MCL in male rats 21

22 Cancer Risk Estimation Considerations: Cancer risk estimates aim to provide reasonable upper bound estimates of risk through choices of tumor type, POD, and low-dose extrapolation approach Endpoint: MCL in male rats Linear low-dose extrapolation (no data to support alternatives) 10-fold range from use of different data sets and methods to estimate metabolism Oral slope factor derived from route-to-route extrapolation Sources of uncertainty: MOA, human sensitivity and variability Statistical uncertainty in estimating POD, extent of human metabolism (including PBPK), choice of rodent tumor dataset How addressed Qualitatively Quantitatively 22

23 Cancer Risk Estimation Principal study: critical effect JISA (1993): mononuclear cell leukemia in male rats Inhalation Unit Risk (per µg/m 3 ) to Oral Slope Factor ( mg/kg-day (per to

24 New Data/Models to Inform Carcinogenicity Assessment? No new rodent studies Public comments concerning human studies (e.g., new analysis of kidney cancer in NYC residents and on Lynge (2006)) submitted to public docket and available to committee for review 24

25 Summary of Tetrachloroethylene Draft Conclusions Adverse non-cancer health effects: Central nervous system Developing fetus Reproductive system Liver Kidney Likely to be carcinogenic to humans Chronic effects most likely to occur at low levels of exposure: Neurotoxicity Cancer 25