Post on 15-Mar-2020
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
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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
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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
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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
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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
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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)
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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)
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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)
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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
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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
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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.
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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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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
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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
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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
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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
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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 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
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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
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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
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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?
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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
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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
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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
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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