Review of the Environmental Protection Agency's Draft IRIS Assessment of Tetrachloroethylene (2010) / Chapter Skim
Currently Skimming:
Summary
Summary
Pages 1-15
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 1... ...
Review of the Environmental Protection Agency's Draft IRIS Assessment of Tetrachloroethylene
|
From page 3... ...
At the request of EPA, the National Research Council convened a committee to conduct an independent scientific review of the draft IRIS assessment of tetrachloroethylene from toxicologic, epidemiologic, and human clinical perspectives. The committee was asked to evaluate the adequacy of the EPA assessment, the data and methods used for deriving the noncancer values for inhalation and oral exposures and the oral and inhalation cancer unit risks posed by tetrachloroethylene; to evaluate whether the key studies underlying the draft IRIS assessment are of requisite quality, reliability, and relevance to support the derivation of the reference values and cancer risks; to evaluate whether the uncertainties in EPA's risk assessment were adequately described and, where possible, quantified; and to identify research that could reduce the uncertainty in the current understanding of human health effects associated with tetrachloroethylene exposure.
|
From page 4... ...
of a continuous inhalation exposure and a daily oral exposure of the human population (including sensitive subgroups) , respectively, that are likely to be without appreciable risk of deleterious effects during a lifetime.
|
From page 5... ...
. Derivation of Reference Values EPA derived sample inhalation reference values by using results from several supporting neurotoxicity studies for comparison with its principal study by Altmann et al.
|
From page 6... ...
Reference values derived from neurotoxicity data are presented, as are values based on other noncancer effects to illustrate dose dependence of multiple forms of observed toxicity. Overall, the committee supports the approach of presenting the evidence in this visual format.
|
From page 7... ...
FIGURE S-1 Distribution of sample reference values. Each horizontal bar represents a single study.
|
From page 8... ...
Tetrachloroethylene was one of five chemicals of 500 tested by NTP that showed statistically significant increases in MCL in both male and female rats despite the high background rates. The publication advocated that such statistical evidence be supported with a weight-ofevidence analysis of biologic data before conclusions were drawn.
|
From page 9... ...
Hepatic Cancer Statistically significant increases in hepatic tumors were observed in male and female mice after oral or inhalation exposure. As in the case of MCL, the biologic significance of the increases was debated by the committee because B6C3F1 mice have a high background incidence of hepatic cancer.
|
From page 10... ...
were too great to support using MCL data rather than data on hepatic or renal cancer for determining quantitative estimates of risk. Those members judged that the use of the MCL data could be justified only if it is EPA's policy to choose the most conservative unit risk when considering options but that such justification should be distinguished as a policy decision, not a scientific one.
|
From page 11... ...
The imposed linearity explains the similarity among the slopes of the models and among the unit risks derived from the models. In the case of hepatocellular adenoma and carcinoma in male mice and MCL in female rats, EPA considered the fitted models acceptable solely on the grounds that statistical tests for goodness of fit had nonsignificant results (p > 0.10)
|
From page 12... ...
Two other pathways involve the GSH conjugation pathway that produces metabolites that are further metabolized by the β-lyase pathway or the β-lyase-independent pathway, each of which produce metabolites that have been associated with renal cancer. To take those metabolic factors into account, EPA used three PBPK
|
From page 13... ...
The modeling exercise would be useful in identifying data gaps that prevent successful modeling, which can be used to guide research that will allow more comprehensive PBPK models to be developed in support of the next IRIS reassessment of tetrachloroethylene. Uncertainty Analysis EPA has clearly identified key sources of uncertainty as part of its process of assessing the cancer risk posed by exposure to tetrachloroethylene, including human population variation, low-dose extrapolation, dose metrics, extrapolation from animals to humans, and the use of PBPK models for route-to-route extrapolation.
|
From page 14... ...
The committee supports EPA's quantitative assessments of uncertainty with regard to choice of dose-response models, the use of PBPK models, and variation between studies. In particular, the committee found EPA's consideration of uncertainty due to different forms of dose-response models to be valuable, and it recommends that such quantitative evaluations be extended to all candidate datasets so that a fuller array of uncertainties can be assessed.
|
From page 15... ...
EPA's uncertainty analysis remained typically focused on individual sources of uncertainty, and the analysis was often qualitative without presenting a full range of the uncertainty. Without an in-depth illustration of the propagation and cumulative effect of the uncertainties on the final risk estimate, quantification of the overarching uncertainty surrounding the final risk assessment is not possible.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.