Office of Research and DevelopmentNational Center for Environmental Assessment

Tetrachloroethylene: Integrated RiskInformation System (IRIS) DraftToxicological Review

National Academy of SciencesTetrachloroethylene Peer Review Panel

November 13, 2008

Kate Z. Guyton, PhD DABT

2Office of Research and DevelopmentNational Center for Environmental Assessment

NCEA’s Tetrachloroethylene (Perc)Team

Chemical ManagersKate Z. Guyton (since Sept 2007)Karen A. Hogan (since Sept 2007)Robert McGaughy (retired)

Other AuthorsStanley Barone, Jr.Rebecca C. BrownGlinda CooperNagalakshmi KeshavaLeonid KopylevSusan MakrisJean Parker (retired)Cheryl Siegel ScottRavi SubramaniamLarry Valcovic (retired)

ContributorsNancy BeckDavid BussardJane C. CaldwellWeihsueh ChiuDeborah RiceMarc RigasBob SonawanePaul White

3Office of Research and DevelopmentNational Center for Environmental Assessment

Presentation Outline: Tetrachloroethylene

Background and assessment historyKey scientific challenges and questions

• Metabolism and physiologically based pharmacokinetic(PBPK) modeling

• Non-cancer hazard and reference concentration/dosederivation

• Carcinogenicity conclusions and dose-responseanalysis

Summary of EPA’s 2008 assessment findings

4Office of Research and DevelopmentNational Center for Environmental Assessment

Tetrachloroethylene BackgroundInformation

Most common usesFabric dry cleaning (by ~27,000 US dry cleaners) ‏Metal cleaning and degreasing

Environmental exposuresIndoor air (e.g. in residences adjacent to drycleaners)

Superfund National Priority List sitesGround and drinking water

5Office of Research and DevelopmentNational Center for Environmental Assessment

Non-Cancer Reference Values:Definition

An estimate (with uncertainty spanning perhaps anorder of magnitude) of a continuous inhalationexposure (RfC) or daily oral exposure (RfD) to thehuman population (including sensitive subgroups) thatis likely to be without an appreciable risk of deleteriouseffects during a lifetime.

Derived from a NOAEL, LOAEL, or benchmark dose,with uncertainty factors generally applied to reflectlimitations of the data used

6Office of Research and DevelopmentNational Center for Environmental Assessment

EPA Last Completed an Assessmentof 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)

7Office of Research and DevelopmentNational Center for Environmental Assessment

Major Updates Since 1988 IRISAssessment

Comprehensive literature review (last updated July 2004)New toxicity values in current draft:Reference concentration (RfC)Carcinogenicity assessment

Updated toxicity value (RfD)

8Office of Research and DevelopmentNational Center for Environmental Assessment

Overall Goal of TetrachloroethyleneNAS Review

EPA seeks NAS input regarding:

EPA’s evaluation of scientific evidence regardingtetrachloroethylene health effects (hazard)

The application of such data in EPA’squantification of tetrachloroethylene human healthrisks (dose-response)

9Office of Research and DevelopmentNational Center for Environmental Assessment

Assessmentoverview by chapter

1. Introduction2. Background3. Toxicokinetics4. Hazard identification5. Dose-response

evaluation6. Characterization of

hazard and dose-response

Key scientific challengesMetabolism, PBPK modelingNon-cancer: hazard identificationand risk estimationCarcinogenicity assessment andrisk estimation

10Office of Research and DevelopmentNational Center for Environmental Assessment

Overview of Metabolic Pathways1. Oxidation by P450s (CYP2E1)

Unstable epoxideintermediate Oxidative metabolites

major metabolite TCA=> excreted in urine

2. Conjugation with GSH TCVG

Cysteine conjugate TCVC N-acetylation =>

excretion ofmercapturates in urine

Liver: TCAcontributes, butdoes not fullyexplain toxicity

Metabolism and Considerationsfor Dose Metrics, PBPK Modeling

Kidney, MCL: Noreliable data todevelop PBPKmodel

Neurotoxicity:Parent,metabolitescontribute

Dose Metric:Total Metabolism

Total Metabolism

Blood AUC

11Office of Research and DevelopmentNational Center for Environmental Assessment

Large variation in estimates of PERC metabolism2.9%

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 ModelsAvailable

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.

12Office of Research and DevelopmentNational 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%

13Office of Research and DevelopmentNational 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 CarcinogenRisk Assessment,US EPA, 1986, 1999, 2005

A Review of the Reference Doseand Reference ConcentrationProcesses, US EPA 2002

14Office of Research and DevelopmentNational Center for Environmental Assessment

Non-cancer Hazards Associated withChronic Exposures

Organ systems affected: Central nervous system Developing fetus Reproductive system Liver Kidney

Few mechanistic (mode ofaction, MOA) dataregarding these effects

Neurotoxicity: Most likely critical effect at

low, chronic exposures Effects reported in animal,

human studies(occupational, residential)

Several nervous systemdomains affected

Effects similar to othersolvents

Dose metric unknown MOA unknown

15Office of Research and DevelopmentNational Center for Environmental Assessment

Choice of Critical Study for RfC and RfDKey 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 andneurophysiological outcome of chronic low-level tetrachloroethene exposure measuredin neighborhoods of dry cleaning shops.Environ Res 69:83-9.Mean indoor air exposure: 0.7 ppm

for 10.6 years14 exposed and 23 controlsExposed residents demonstrated

impaired ability to detect andrespond to visual stimuli

Similar effects consistently reportedin occupational exposure studies

Neurotoxicity peer review panel(2004):

Affirmed endpoint selected Raised some key science issues

(e.g., study statistics), which havebeen clarified in the 2008 draft

16Office of Research and DevelopmentNational Center for Environmental Assessment

Reference Values Basedon Human Neurotoxicity

0.02mg/m3

300 10—intraspecies 10—LOAEL to NOAEL 3—database

LOAEL = 4.8 mg/m3Altmann et al. (1995):neurotoxicity inhumans livingnear dry cleaningfacilities

0.004mg/kg-day

Same as aboveLOAEL = 1.1 mg/kg-day, derived byroute-to-routeextrapolationfrom inhalationexposure

Same as aboveRfD

RfC

UFsPoint of Departure(POD)

Principal study: critical effect

17Office of Research and DevelopmentNational 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 submittedto public docket and available to committee forreview

Carcinogenicity in Humans andLaboratory Animals

10/10 Positive Rodent CancerBioassay Datasets

Rats:MCL* (males

and females)Kidney (rare)

in males

Mice:Liver (males and

females)Liver or spleen

hemangiosarcoma(males andfemales)

Overall conclusion from rodent data:Multisite, multispecies carcinogen by

multiple routes of exposure

Many Epidemiologic StudiesEndpoints identifiedLymphoid systemEsophagusCervixBladderKidneyLung

Overall conclusion from human data:Suggestive, but not conclusive,evidence of cancer hazard

*MCL= Mononuclear cell leukemia

19Office of Research and DevelopmentNational Center for Environmental Assessment

Rodent MOAs addressed

Cancer MOA Data

GenotoxicityPPAR-αAlpha2-u (kidney)CytotoxicityImmunotoxicity

Overall conclusion:MOA is unknown for any ofthe rodent tumors

Few human, other mechanisticdata (besides limited dataregarding genotoxicity ofGSH-derived metabolites) toconclusively determinecarcinogenicity

20Office of Research and DevelopmentNational Center for Environmental Assessment

Weight of Evidence for Potential HumanCarcinogenicity

Association of human exposure with excess risk of cancersEvidence of carcinogenicity in 10 (of 10) lifetime rodent bioassay datasetsLiver cancer (male, female mice) and MCL (male, female rats) in multiple

bioassays, oral and inhalation exposuresMOA unknown for any tumor typeKnown hepatocarcinogenicity of two oxidative metabolitesEvidence of mutagenicity of certain metabolites, and of

tetrachloroethylene under conditions that would generate thesemetabolites

Weight of evidence descriptor: likely to be carcinogenic to humans

21Office of Research and DevelopmentNational Center for Environmental Assessment

Japan Industrial Safety Association(1993) Carcinogenicity study oftetrachloroethylene by inhalation inrats and mice.

F344/DuCrj rats (both sexes)104 wk inhalation exposure to

0, 50, 200, or 600 ppmCritical effect: MCL in male

rats

Principal Study for Cancer RiskEstimation

Key considerations in studyselection: Human data? Standardized measures? Consistency of effect across

studies? Environmental exposures?

22Office of Research and DevelopmentNational Center for Environmental Assessment

Cancer Risk Estimation

Considerations:Cancer risk estimates aim to

provide reasonable upper boundestimates of risk through choices oftumor type, POD, and low-doseextrapolation approach

Endpoint: MCL in male ratsLinear low-dose extrapolation

(no data to support alternatives)10-fold range from use of

different data sets and methodsto estimate metabolism

Oral slope factor derived fromroute-to-route extrapolation

Sources of uncertainty:MOA, human sensitivity and variabilityStatistical uncertainty in estimating POD,

extent of human metabolism (includingPBPK), choice of rodent tumor dataset

How addressedQualitatively Quantitatively

23Office of Research and DevelopmentNational Center for Environmental Assessment

1 × 10-2 to 1 × 10-12 × 10-6 to 2 × 10-5JISA (1993):mononuclear cellleukemia in male rats

Oral Slope Factor(per mg/kg-day) ‏

Inhalation UnitRisk

(per µg/m3)Principal study: critical effect

Cancer Risk Estimation

24Office of Research and DevelopmentNational Center for Environmental Assessment

New Data/Models to InformCarcinogenicity Assessment?

•No new rodent studies•Public comments concerning human studies(e.g., new analysis of kidney cancer in NYCresidents and on Lynge (2006)) submitted topublic docket and available to committee forreview

25Office of Research and DevelopmentNational Center for Environmental Assessment

Summary of TetrachloroethyleneDraft Conclusions

• Adverse non-cancer health effects:Central nervous systemDeveloping fetusReproductive systemLiverKidney

• Likely to be carcinogenic to humans• Chronic effects most likely to occur at low levels of exposure:

NeurotoxicityCancer