# Presentation: 332987

## Charge to the National Academy of Science’s Committee for “Assessing the Human Health Risks of Trichloroethylene : Key Scientific Issues” 

- Interagency Working Group on TCE
- Richard Canady, PhD DABT
- March 23, 2005

## Agencies on the TCE IWG

**Department of Agriculture**
**Department of Defense**
**Department of Energy**
**Department of Health and Human Services**
**Department of State **
**Environmental Protection Agency**
**National Aeronautics and Space Administration**
**Coordinated through the Executive Office of the President**

**Notes:**
Representatives from these agencies are available for any questions the committee may have. OSTP can help facilitate the interaction through the IWG so that the committee gets what it wants. 

## Activities of the IWG

**Information sharing **
**Develop common language for science and science policy across agencies and programs regarding TCE**
**Identify gaps and needs**
**Coordinate Risk Management Strategies**

## “Issues statements” by agencies

**This talk is the consensus view of the agencies regarding the charge and context of the effort**
**There are differences of opinion on how to interpret and even frame the science  underlying the assessment of TCE **
**Individual agencies have asked to present information to you in issues papers and presentations**
_***These individual presentations should not be construed as modification to the charge***_

## Context of the NAS Review

**Good estimates of TCE toxicity are important for many reasons**
**There are potential public health impacts due to TCE.**
**Imperative that risk-based TCE cleanup levels are accurately set that are protective to human health and the environment**
**There are economic costs to regulatory controls and site cleanups**
**Limited resources should be directed where best  returns can be gained in improved public health**

## Good science

**Is essential to determine the quantity of a chemical that a person can be exposed to without causing adverse health effects, and should be  **
**Based on sound scientific research**
**Supported by the scientific community**
**Obtained from human studies where possible, and appropriately extrapolated from animals otherwise**
**Based on realistic assumptions**
**i.e., not overly conservative**

## TCE common at hazardous waste sites

**At approximately 1320 nonfederal RCRA and CERCLA sites**
**At approximately 183 federal RCRA and CERCLA sites**
**Also other contaminants at those sites**
**States are applying EPA’s 2001 Draft Health Risk Assessment at sites with multiple contaminants making TCE the primary risk driver and requiring cleanup levels that some consider impractically low**

## Time-consuming to remediate

**Removal of TCE from ground water can be slow, similar to other dense non-aqueous phase liquids**
**TCE sinks through an aquifer, pooling in cracks, soil interstices, or bedrock**
**It slowly enters adjacent ground water, limited by its low solubility in water**
**TCE can be slow to remediate because of this behavior, and very difficult to remediate completely**

## Air as well as drinking water exposures

**TCE contamination in ground water can release TCE vapors to the subsurface**
**At many sites these vapors may then enter buildings from below, similar to radon**
**Indoor air concerns may lead to cleanup of groundwater not considered a current or potential drinking water source (e.g., water table aquifers), and therefore not subject to drinking water regulations**
**There is no single regulatory standard set by rulemaking for TCE in air**

## Large Potentially Exposed Population

**Average ambient outdoor air concentrations have leveled out at ~ 0.3 microgram/m****3**** since 1996**
**9-34% of public drinking water sources may contain some TCE**
**Water at the tap from public drinking water sources is almost always below the existing MCL**
**About 10% of Americans have blood concentrations of TCE above 0.01 microgram/L**
**Based on NHANES III**

## Ongoing Efforts to Remediate

**Technologies employed at most sites include pump and treat, excavation, air sparging, soil vapor extraction, and monitored natural attenuation**
**New technologies being investigated include biostimulation/bioremediation, chemical oxidation, surfactant/cosolvent flushing, thermal desorption and destruction, phytoremediation, and permeable reactive barriers**

## Charge from the IWG

**Developed in consideration of scientific and risk management issues of IWG agencies**
**Asks for advice on science interpretation that would then feed into an objective, realistic, and scientifically-balanced TCE health risk assessment**
**Not asking for the risk assessment**

**Please do not provide a risk assessment **

## Scientific focus issues

**Hazard characterization and mode of action**
**Carcinogenicity: production and importance of metabolites**
**For liver and kidney tumors**
**Strength and weight of evidence for other cancer sites and non-cancer effects in humans**
**Including positive, negative, and inconclusive toxicity studies**

## Discussion of modes of action should include where possible

**Identification of key events, including precursors to adverse effects**
**Adversity of effects, such as degree  of structural or functional changes**
**Potential for contributions from multiple modes of action**
**Differences in modes of action due to dose-dependence or other factors**

## Approaches to epidemiological data

**Use of meta-analysis or other techniques **
**Strengths and limitations of the body of epidemiological evidence with respect to kidney cancer**
**Strength and weight of evidence provided by reported molecular information on associations with mutations in the von Hippel-Lindau tumor suppressor gene**
**Identification and evaluation of epidemiologic studies for informing overall conclusions on the potential carcinogenicity of TCE**
**Advice on the application of Hill’s criteria for causality**

## Susceptibility 

**Internal dose effects of  **
**Altered metabolism, whether by intrinsic or acquired factors **
**Cumulative exposures**
**Pharmacodynamic factors **
**genetic polymorphism**
**disease states**
**developmental windows**
**Degree to which differential susceptibility can be quantified**

## Mixtures

**The NAS panel shall provide its views and advice on how to best evaluate and interpret the evidence for effects from TCE exposures alone compared with that for effects from mixtures of chemicals that include TCE.**

**Notes:**
Mention dose additivity as the focus – not effects additivity

## Physiologically-Based Pharmacokinetic Modeling

***Approaches ***
**Relative strengths and limitations of model structures and parameterizations**
**tradeoff between model complexity/ completeness and uncertainty**
**b.****	****Evaluation of model uncertainties, including the use of Markov-Chain or other Monte Carlo methods**

## Physiologically-Based Pharmacokinetic Modeling

***Uses for risk assessment***
***	***
***Dose-metrics for developing human equivalent doses, route-to-route extrapolations, or use in biologically-based dose-response modeling***
***	******e.g., TCA AUC, DCA AUC in blood and/or tissues******	***
***Analyzing and addressing uncertainties associated with PBPK-based dose-metrics***
***	******non-PBPK-based scaling approaches?***
***Impact on internal doses from environmental exposures of ***
***human variation ***
***e.g., enzyme polymorphism, enzyme induction****** ***
***chemical mixtures***

**Give consideration to the recently harmonized TCE physiologically-based pharmacokinetic (PBPK) model**
**Developed in collaboration between EPA and DoD**

**Notes:**
Ask for the opportunity to present

## Dose-Response Assessment

**Key scientific issues for quantitative assessment of risks**
**Strengths/limitations of key studies**
**Selection of studies for quantification**
**Approaches/methods to quantify risk**
**Approaches/methods to characterize uncertainty and inter-individual variability**

## 

Thanks in advance

**Thanks in advance**

## White Papers

**DoD**
**Trichloroethylene Dose Response Assessment: Additional Issues Relevant for a Scientifically Credible Approach**
**Does Drinking Water Contaminated with Trichloroethylene Contribute to an Increased Risk of Congenital Heart Defects? A Critical Analysis of the Current Literature**
**Occupational TCE Exposure and Non-Hodgkin’s Lymphoma in Humans: A Review and Meta-Analysis of Epidemiologic Studies**
**EPA**
**Issues in Trichloroethylene Pharmacokinetics**
**Interactions of Trichloroethylene, Its Metabolites, and Other Chemical Exposures**
**Role of Peroxisome Proliferator-Activated Receptor Agonism and Cell Signaling in Trichloroethylene Toxicity**
**Issues in Trichloroethylene Cancer Epidemiology**
**DOE**
**Trichloroethylene, The Scientific Basis of Risk Assessment **