# Presentation: 181571

## EPA Presentation: What are the Key Difficult Scientific Issues in the Assessment of TCE Health Risks ?

***EPA Presentation: ******What are the Key Difficult Scientific Issues ******in the Assessment of ******TCE Health Risks ?***

- Presentation to the
- National Research Council’s Committee
*Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues*
- Peter W. Preuss, Ph.D., Director
- Weihsueh A. Chiu, Ph.D., TCE Chemical Manager
- National Center for Environmental Assessment
*Research & Development*
- United States Environmental Protection Agency

## Outline

***Outline***

- Background
- Summary of TCE Science
- Overview of Key Issues Discussed in EPA Issue Papers
*Issues in TCE pharmacokinetics*
*Interactions of TCE, its metabolites, and other chemical exposures*
*Role of peroxisome proliferation-activated receptor in TCE toxicity*
*Issues in TCE cancer epidemiology*
- Concluding Remarks

## EPA Last Completed an Assessment of TCE in 1985

***EPA Last Completed an ******Assessment of TCE in 1985***

- 1985 EPA “Health Assessment Document for TCE”
- 1987 EPA External Review Draft Addendum “Updated Carcinogenicity Assessment for TCE”
- EPA SAB advice suggested that cancer classification between Group B “probable human carcinogen” and Group C “possible human carcinogen.”
- Quantitative risk estimates removed from IRIS in 1989 and there are no current IRIS values.

## Outreach Effort Preceeded Release of 2001 Draft Assessment

***Outreach Effort Preceeded ******Release of 2001 Draft Assessment***

- EPA’s goal was to solicit a wide range of perspectives on scientific issues by
*Reaching out to many different groups and individuals*
*Encouraging diversity by not seeking consensus*
- EPA employed a number of outreach mechanisms
*“**External Involvement Group”*
*“**Williamsburg” meetings (1993, 1995)*
*“**State-of-the-Science” papers (2000)*
- External review draft assessment released in 2001 contained EPA’s synthesis and characterization

## External Review of EPA’s 2001 Draft Assessment

***External Review of ******EPA’s 2001 Draft Assessment***

- Public submitted over 800 pages of comments on 2001 draft assessment.
*Federal and state agencies*
*Industry, trade, and public interest groups.*
*Individuals*
- Independent panel formed by EPA Science Advisory Board conducted peer review.
*Peer review report released in December 2002*

## Major Conclusions of EPA’s 2001 Draft Assessment

***Major Conclusions of ******EPA’s 2001 Draft Assessment***

- Noncancer Effects:
*Significant toxicity shown in animal and human data (Central Nervous System, Immune System, Endocrine System, Liver, Kidney, Developmental)*
*Noncancer RfD and RfC calculated*
- Cancer:
*Overall characterization as “Highly likely to be carcinogenic in humans” / “Probable human carcinogen,” based on animal and human data, supported by mechanistic studies*
*Range of cancer slope factors calculated, reflecting uncertainty*
- Risk may be modulated by other factors
*Disease (e.g., diabetes), lifestyle (e.g., alcohol), concurrent exposures, children*
*Lack of data to quantify effects*

## Significant UnderlyingScience Issues

***Significant Underlying******Science Issues***

- Many issues identified in draft assessment, SAB report, and public comments
- SAB commended EPA for tackling important new issues, suggested need for more transparency
- Substantial new scientific literature
*Hundreds of relevant articles published since 2000*
*EPA held public symposium on new TCE science in February 2004 *
*DOE held symposium on TCE research projects funded by DOE in October 2004*
- Key subset of issues detailed in EPA issue papers

## Challenges In Assessing TCE

***Challenges In Assessing TCE***

- TCE is inherently complex toxicologically, with multiple metabolites and multiple potential modes of action.
- There is a large database of information on TCE, but there are also significant gaps in knowledge.

## TCE Metabolism is Complex

***TCE Metabolism is Complex***

- Rapid absorption via inhalation and ingestion, with distribution to blood-rich organs and storage in fat
- Metabolized by two competing pathways
*P450-mediated oxidative pathway*
*Metabolites CH, TCA, DCA*
*Glutathione-S-transferase conjugative pathway*
*Metabolites DCVG, DCVC*
- Toxicity generally attributed to metabolites rather than parent compound.

## TCE Metabolism Scheme

***TCE Metabolism Scheme***

**TCE**

- Liver cancer may be attributed to TCA and/or DCA

- Kidney cancer may be attributed to thioketene/ other GST metabolites

*Source:*   Dobrev, Andersen, and Yang 2002, with modifications based on Lash et al. 2000a.

- Oxidation

- Conjugation

- Conjugation

- 10

## TCE is Associated with Toxicity in Multiple Organs/Systems

***TCE is Associated with Toxicity in Multiple Organs/Systems***

- Toxicity includes cancer and non-cancer endpoints
*Neurotoxicity well established, similar to other organic solvents*
*Effects in liver, kidney, immune/lympho-hematopoietic, lung*
*Cervical and prostate cancers suggested in epidemiological studies*
*Endocrine system, reproductive system, and developing fetus (e.g., cardiac effects)*
- Multiple hypothesized modes of action with varying support
*Most information on liver and kidney carcinogenicity*

## Large Epidemiological Database Assessing Carcinogenicity

***Large Epidemiological Database Assessing Carcinogenicity***

- Over 80 studies and reports assessing possible association between TCE exposure and cancer
*EPA’s draft assessment concluded strongest evidence for carcinogenicity for liver, lymphomas, and kidney. *
*Sparse human MOA data (e.g., VHL mutations and kidney cancer)*
*Several important studies published since EPA’s draft assessment.*
- Wartenberg et al. (2000) analysis of epidemiologic evidence supported EPA’s cancer conclusions
*Joint analysis of cohort studies and a systematic review of case-control and community studies*
*Joint analysis focused on study grouping by specificity of exposure characterization to reduce heterogeneity.*
*“**Overall, our analysis is consistent with that of IARC (1995) and Weiss (1996) but suggests more strongly an association of TCE exposure with kidney and liver cancers and some support for Hodgkin’s disease and NHL.”*

- 12

## Additional Data on Pharmacokinetics and Susceptibility for TCE

***Additional Data on Pharmacokinetics and Susceptibility for TCE***

- Extensive database on pharmacokinetics in rodents and humans
*Multiple PBPK models based on differing datasets and parameter estimation methods, with some dose metric predictions differing by ~10-fold*
*Potential uses of PBPK models include species and route extrapolation and analysis of uncertainty and variability*
- Data on differential susceptibility suggest metabolism, genetic differences, co-exposures can effect toxicity, but in many cases do not have specific data to quantify potential effects.

## EPA’s TCE Issue Papers Focus on Subset of Key Scientific Issues

***EPA’s TCE Issue Papers Focus on Subset of Key Scientific Issues***

- Issues in TCE pharmacokinetics
- Interactions of TCE, its metabolites and other co-exposures
- Role of PPAR agonism and cell signaling in TCE toxicity
- Issues in TCE cancer epidemiology

## Issues in TCE Pharmacokinetics

***Issues in TCE Pharmacokinetics***

- Uncertainties due to complex metabolism and multiple models/parameters impact ability to quantify pharmacokinetics.
- Key questions are:
*Adequacy of the existing data to support quantitative pharmacokinetic analyses *
*Suggestions as to additional relevant data or improved methods/approaches*
*The reasonableness of EPA’s planned approach to evaluate and characterize pharmacokinetic uncertainty and variability*

## Recent Collaborative Work Was Done on TCE PBPK

***Recent Collaborative Work Was Done on TCE PBPK***

- The USAF funded a contract to develop a harmonized PBPK model with significant scientist involvement by USEPA.
- Team members for that work included:  Eric Hack and Dr. Jay Zhao, TERA; Dr. David Mattie, U.S. Air Force; Harvey Clewell, CIIT; Dr. Jeff Fisher, University of Georgia; and Drs. Jerry Blancato, Weihsueh Chiu and John Lipscomb, U.S. Environmental Protection Agency.
- Additional scientific input from USAF-funded peer consultation with outside experts.
- The written reports on this work and the source code are available online at _[www.tera.org/news](http://www.tera.org/news)_
- EPA and the Air Force request the opportunity to discuss this work with the NRC in more detail.

## Characterization of uncertainty and variability in PBPK models in general remains area of active research
A number of TCE PBPK model structural features as well as additional in vivo datasets need evaluation
Uncertainties in TCE metabolite dosimetry persist
Remaining inconsistencies in parameters for oxidative metabolism – variability or model misspecification?
GST pathway and kidney dosimetry
Chloral and lung dosimetry
DCA and liver dosimetry
EPA’s PBPK issue paper describes EPA’s proposed approach to addressing these issues.

- A number of TCE PBPK model structural features as well as additional in vivo datasets need evaluation
- Uncertainties in TCE metabolite dosimetry persist
*Remaining inconsistencies in parameters for oxidative metabolism – variability or model misspecification?*
*GST pathway and kidney dosimetry*
*Chloral and lung dosimetry*
*DCA and liver dosimetry*
- EPA’s PBPK issue paper describes EPA’s proposed approach to addressing these issues.

***EPA Plans to Build on This Work, Evaluating and Addressing a Number of Remaining Issues***

## Interactions of TCE, its Metabolites and Other Co-Exposures

***Interactions of TCE, its Metabolites ******and Other Co-Exposures***

- Mixture of metabolites complicates assessment of toxicity and MOA.
- Potential impact of co-exposures with similar metabolites/toxicity needs to be evaluated.
- Key questions are:
*What TCE metabolites (or combinations of metabolites) are involved in TCE toxicity?*
*What chemical co-exposures may modulate TCE toxicity?*

## Recent data on TCE metabolites

***Recent data on TCE metabolites***

- DCA and TCA data (e.g., tumor phenotypes) may be useful for comparison with TCE to help inform source(s) of liver toxicity
- CH data (e.g., recent bioassays) as compared to TCE may help elucidate importance of metabolites/pathways
- DCVC data may help elucidate kidney MOA
- TCOH data inform hypothesis that formic acid is related to kidney toxicity

## Co-Exposures

***Co-Exposures***

- Co-contaminants not uncommon
*TCA, DCA, chloroform, other solvents*
*Possible interactions include metabolic inhibition/ induction, common MOAs and target tissues.*
- Potential effects from ethanol consumption
*Changes in blood flow*
*Induction of metabolism (P450s, ALDH)*
*Effects on regulatory processes and hepatotoxicity*

## Role of PPAR Agonism and Cell Signalingin TCE Toxicity

***Role of PPAR Agonism and Cell Signaling******in TCE Toxicity***

- Human health risks posed by PPAR alpha (PPAR) agonists is controversial, both in the case of TCE and in general.
- Key questions, given the current state-of-the-science, are:
*The involvement of PPAR in TCE toxicity*
*The relative sensitivity of humans to the PPAR-related mechanisms involved in TCE toxicity*

## Perspectives on TCE, PPAR Agonism, and Tumor Induction

***Perspectives on TCE, PPAR************ Agonism, and Tumor Induction***

- TCE, TCA, and DCA are weak peroxisome proliferators
*Evolution of hypotheses with respect to the PPAR**** MOA for tumor induction*
*Is peroxisome proliferation related to tumors?*
*PPAR**** is activated in humans*
*Different perspectives on human sensitivity and events causally related to tumorogenesis.*
- Substantial new literature on PPAR since 2001.

## Recent Studies on TCE and PPAR Agonism

***Recent Studies on TCE and ******PPAR************ Agonism***

- Suggestion that peroxisome proliferation is not a key step in TCE-induced liver tumorogenesis (Bull et al. 2004)
- TCA and DCA-induce hypomethylation (Pereira et al., 2004; Tau et al., 2000, 2004)
- TCE, TCA, and DCA in PPAR knockout mice examining liver weights, gene expression changes (Laughter et al., 2004)

## Role of New Literature on PPAR Agonism

***Role of New Literature on ******PPAR********** Agonism***

- Understanding the full range effects from PPAR agonism can inform assessment of TCE for MOAs involving extra-peroxisomal events
- Substantial recent literature in following areas:
*Pleiotropic effects of PPAR**** agonism.*
*Role of non-parenchymal cells in liver effects.*
*Adequacy of PPAR**** knockout mouse model for inferences of down-stream effects*
*Factors affecting risk of PPAR**** agonists (e.g., sex, life-stage)*

## Recent Epidemiologic Studies Evaluating TCE Exposure and Potential Carcinogenicity

***Recent Epidemiologic Studies Evaluating TCE Exposure and Potential Carcinogenicity***

- Two recent cohort incidence studies provide more evidence for increased NHL risk among TCE-exposed workers (Hansen et al., 2001; Raaschou-Nielsen et al., 2003).
*Exposure-response patterns in Raaschou-Nielsen et al. (2003) (too few cases in Hansen et al. 2001 to assess exposure-response patterns)*
*Authors considered socio-economic status not likely confounder since cohorts are “blue-collar”*
- Elevated esophageal cancer risks among TCE-exposed workers in Raaschou-Nielsen et al. (2003) replicates observations of Hansen et al. (2001) for this cancer site.
- Two case-control studies assess renal cell carcinoma and occupational TCE exposure (Pesche et al., 2000; Bruning et al. 2003)
- Several new community studies assess drinking water exposure to TCE
*Childhood leukemia case-control study (Costas et al., 2002)*
*Ecological study (Morgan and Cassady, 2002)*
*Mortality odds ratio study of liver cancer (Lee et al., 2003)*

- 25

## Issues in TCE Cancer Epidemiology

***Issues in TCE Cancer Epidemiology***

- Epidemiology is a key element of the hazard characterization of TCE.
- Key questions are:
*What approaches can best inform causal inference?*
*What are the strengths and limitation of the epidemiologic body of evidence? *
*Which studies carry greater weight upon consideration of their strengths and limitations?*
*What factors are important to consider for interpreting observations of NHL?*
*Are meta-analysis methods appropriate to synthesize the TCE epidemiologic evidence?*

## Approaches to Synthesizing Evidence for Causal Inference

***Approaches to Synthesizing Evidence ******for Causal Inference***

- Narrative reviews “tally” or count positive/non-positive findings
- Systematic reviews perform qualitative evaluation based on criteria/standards, such as “Hill” criteria
- Meta-analysis approaches develop quantitative syntheses of study results
*Multiple methods – fixed-/random- effects, regression, pooled analyses.*
*One key issue is whether studies grouped together are heterogeneous*

## Concluding Remarks

***Concluding Remarks***

- TCE is a challenging chemical for assessment of human health risks.
- We look forward to your advice as to how to best address the critical scientific issues, many of which we have highlighted today.
*Where there is consensus, guidance on implementing your advice would help to expedite development of our revised risk assessment.*
*For those areas where conclusive answers are not possible given the current state-of-the-science, identifying and characterizing alternatives and research needs will be helpful.*

## Acknowledgements

***Acknowledgements***

- _NCEA Leadership:_
- 	Peter Preuss, Director NCEA
- 	David Bussard, Director NCEA-W
- 	Paul White, Chief, QRMG
- _EPA TCE Risk Assessment _
- _Team:_
- 	Jerry Blancato, NERL
- 	Jane Caldwell, NCEA
- 	Chao Chen, NCEA

- _EPA TCE Risk Assessment Team (cont.)_
- 	Weihsueh Chiu, NCEA
- (chemical manager)
- 	Marina Evans, NHEERL
- 	Jennifer Jinot, NCEA
- 	Nagu Keshava, NCEA
- 	John Lipscomb, NCEA
- 	Miles Okino, NERL
- 	Fred Power, NERL
- 	John Schaum, NCEA
- 	Cheryl Siegel Scott, NCEA