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

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

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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

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Office of Research and Development National Center for Environmental Assessment

Tetrachloroethylene: Integrated Risk Information System (IRIS) Draft Toxicological Review

National Academy of Sciences Tetrachloroethylene Peer Review Panel November 13, 2008

Kate Z. Guyton, PhD DABT

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Office of Research and Development National Center for Environmental Assessment

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

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Office of Research and Development 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
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Office of Research and Development 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
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Non-Cancer Reference Values: Definition

  • An estimate (with uncertainty spanning perhaps an
  • rder 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

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Office of Research and Development National Center for Environmental Assessment

EPA Last Completed an Assessment

  • f 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)
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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)
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Office of Research and Development 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)

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Office of Research and Development National Center for Environmental Assessment

Assessment

  • verview by chapter

1. Introduction 2. Background 3. Toxicokinetics 4. Hazard identification 5. Dose-response evaluation 6. Characterization of hazard and dose- response

Key scientific challenges

  • Metabolism, PBPK modeling
  • Non-cancer: hazard identification

and risk estimation

  • Carcinogenicity assessment and

risk estimation

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Office of Research and Development National Center for Environmental Assessment

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

Metabolism and Considerations for Dose Metrics, PBPK Modeling

Kidney, MCL: No reliable data to develop PBPK model Neurotoxicity: Parent, metabolites contribute Dose Metric: Total Metabolism Total Metabolism Blood AUC

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Office of Research and Development National Center for Environmental Assessment

Large variation in estimates of PERC metabolism

2.9% 23% 23% 15% 4.4% 16% 1.9% 1.7% 2.3% 36% 23% 0.0% 20.0% 40.0% 60.0% 80.0%

Percent Metabolized at 1 ppb Inhalation Exposure

Chen and Blancato 1987 Ward et al. 1988 Bois et al. 1990 [1] Bois et al. 1990 [2] Rao and Brown 1993 Reitz et al. 1996 Bois et al. 1996 Loizou 2001 Clewell et al. 2005 [1] Clewell et al. 2005 [2] Chiu and Bois 2006

Range of Data and PBPK Models Available

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.

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Office of Research and Development 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%

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Office of Research and Development 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) – 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 2002

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Office of Research and Development National Center for Environmental Assessment

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
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Office of Research and Development National Center for Environmental Assessment

Choice of Critical Study for RfC and RfD

Key considerations in study selection:

  • Human data?
  • Standardized measures (e.g.,

neurobehavioral battery)?

  • Consistency of effect across

studies?

  • Environmental (e.g., residential)

exposures?

  • Altmann et al (1995) Neurobehavioral and

neurophysiological outcome of chronic low- level 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

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

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Office of Research and Development National Center for Environmental Assessment

Reference Values Based

  • n Human Neurotoxicity

0.02 mg/m3 300 10—intraspecies 10—LOAEL to NOAEL 3—database LOAEL = 4.8 mg/m3 Altmann et al. (1995): neurotoxicity in humans living near dry cleaning facilities 0.004 mg/kg-day Same as above LOAEL = 1.1 mg/kg- day, derived by route-to-route extrapolation from inhalation exposure Same as above RfD RfC UFs Point of Departure (POD) Principal study: critical effect

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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

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Carcinogenicity in Humans and Laboratory Animals

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

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

*MCL= Mononuclear cell leukemia

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Office of Research and Development National Center for Environmental Assessment

Rodent MOAs addressed

Cancer MOA Data

  • Genotoxicity
  • PPAR-α
  • Alpha2-u (kidney)
  • Cytotoxicity
  • Immunotoxicity

Overall conclusion: MOA is unknown for any of the rodent tumors Few human, other mechanistic data (besides limited data regarding genotoxicity of GSH-derived metabolites) to conclusively determine carcinogenicity

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Office of Research and Development National Center for Environmental Assessment

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

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Office of Research and Development National Center for Environmental Assessment

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

Principal Study for Cancer Risk Estimation

Key considerations in study selection:

  • Human data?
  • Standardized measures?
  • Consistency of effect across

studies?

  • Environmental exposures?
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Office of Research and Development National Center for Environmental Assessment

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

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Office of Research and Development National Center for Environmental Assessment

1 × 10-2 to 1 × 10-1 2 × 10-6 to 2 × 10-5 JISA (1993): mononuclear cell leukemia in male rats Oral Slope Factor (per mg/kg-day)‏ Inhalation Unit Risk (per µg/m3) Principal study: critical effect

Cancer Risk Estimation

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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

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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