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Project Title:
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Review of EPA's Toxicological Assessment of Tetrachloroethylene
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PIN:
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BEST-K-06-03-A
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Major Unit:
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Division on Earth and Life Studies
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Sub Unit:
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Board on Environmental Studies & Toxicology
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RSO:
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Martel, Susan
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Subject/Focus Area:
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Environment and Environmental Studies; Policy for Science and Technology
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Project Scope
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A committee of the National Academies will conduct a scientific review of the U.S. Environmental Protection Agency's external review draft "Toxicological Review of Tetrachloroethylene (Perchloroethylene) CAS No. 127-18-4 in Support of Information on the Integrated Risk Information System" from a toxicologic, epidemiologic, and human clinical perspective. The review will include an evaluation of the adequacy of the assessment and the data and methodology used for deriving the reference dose (RfD), reference concentration (RfC), and oral and inhalation cancer unit risks for tetrachloroethylene. The committee will evaluate whether the key studies underlying EPA's draft health risk assessment are of requisite quality, reliability, and relevance to support the derivation of the RfD, RfC, and oral and inhalation cancer unit risks. The committee will evaluate whether the scientific uncertainties in EPA's risk assessment have been adequately described and, where possible, quantified. The committee will also identify research that could reduce the uncertainty in the current understanding of human health effects associated with tetrachloroethylene exposure.
Specifically, the committee will answer the following questions about EPA's external review document:
1. Does the hazard characterization of tetrachloroethylene provide a scientifically-balanced, objective, and complete description that synthesizes the animal, clinical, and epidemiologic evidence for toxicity?
a. Has the scientific database on cancer and non-cancer hazards from oral and inhalation exposure been adequately characterized and synthesized?
b. Has the scientific evidence regarding potential susceptible populations and vulnerable life stages been identified and appropriately discussed?
c. Is the weight of evidence evaluation clear and cogent?
d. Is the conclusion that tetrachloroethylene is likely to be carcinogenic to humans via the oral and inhalation routes of exposure consistent with EPA's 2005 Guidelines for Carcinogen Risk Assessment?
2. Do the available data support the hypothesis that multiple modes of action may contribute to carcinogenesis following exposure to tetrachloroethylene?
a. Has the information on the modes of action been adequately evaluated in accordance with EPA's 2005 Guidelines for Carcinogen Risk Assessment?
b. Are the available data sufficient to identify whether tetrachloroethylene and/or specific metabolites are responsible for the induction of cancer?
c. Has the available modes of action information been appropriately interpreted to support use of a linear dose-response model to estimate cancer risk in humans in the EPA draft document?
d. Is it clear why an age-dependent adjustment factor is not applied to the cancer risk?
e. Is it clear that the mode of action is independent of exposure route?
3. Have the choice of dose metrics for various toxic outcomes and the procedures for physiologically-based pharmacokinetic (PBPK) modeling been clearly and scientifically articulated?
a. Are the selection of dose metrics for different outcomes appropriately justified?
b. Have the dose metrics for different outcomes been used appropriately in PBPK models?
c. Have the strengths and weaknesses of the different modeling approaches been adequately described and justified?
d. Have the rationale and scientific basis for adjusted dose metrics using PBPK modeling and cross-species scaling been clearly articulated?
e. Is there a basis for preferring any one of the PBPK models, or other available models, to derive an equivalent human dose for cancer effects?
f. Comment on the use of route extrapolation for developing an oral RfD based on inhalation data.
4. Has the selection of neurotoxicity as the basis for the RfC and RfD been scientifically justified and appropriately handled?
a. Were the right studies selected to determine the most sensitive end point?
b. Was the selection of the specific neurotoxicity outcomes of visual dysfunction and cognitive deficits as the basis for the RfC/RfD appropriate? If not, what end point and studies should be used?
5. Have the scientific uncertainties in the database been identified and clearly articulated?
a. Are the critical data gaps and uncertainties adequately characterized?
b. Has the basis for the selection of uncertainty factors used in the non-cancer risk assessments been adequately explained, and specifically has it been done clearly with respect to the database uncertainty factor?
c. Are the uncertainties related to critical gaps in the toxicity database, mode of action for different outcomes, PBPK modeling of different dose metrics, and available data for low dose extrapolation scientifically appropriate and articulated well?
d. What approaches are available for reducing these uncertainties in the future? A distinction should be made between approaches that are more appropriately addressed through short-term analyses and approaches that will require the conduct of medium- or long-term research projects.
e. Have the uncertainties in the final risk assessment been adequately characterized and, where possible, quantified?
The committee will not develop its own risk characterization, nor will it address any risk management issues.
The project is sponsored by the U.S. Environmental Protection Agency.
The original start date for the project was 06/01/2006. The start has since been postponed until EPA releases the draft risk assessment.
A report will be issued at the end of the project.
Note: The project duration has been extended. The report is expected to be issued in late 2009.
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Project Duration:
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15 months
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