Review of the Environmental Protection Agency's Draft IRIS Assessment of Tetrachloroethylene (2010) / Chapter Skim
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11 Cancer Risk Estimates for Tetrachloroethylene
11 Cancer Risk Estimates for Tetrachloroethylene
Pages 98-113
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From page 98... ...
This chapter discusses how those cancer risk estimates were determined by EPA. CANCER CLASSIFICATION EPA asked for an evaluation of whether conclusions it has drawn in the draft IRIS assessment are consistent with its cancer guidelines (EPA 2005a)
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From page 99... ...
association between human exposure and cancer or evidence that the agent or an im portant metabolite causes events generally known to be associated with tumor formation (such as DNA reactivity or effects on cell growth control) likely to be related to the tumor response in this case.
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From page 100... ...
Hepatic Cancer Evidence for a statistically significant increase in hepatic tumors was observed in male and female mice after oral or inhalation exposure. Like MCL, the biological significance of these increases was debated by the committee because B6C3F1 mice have a high background incidence of hepatic cancer (about 20%)
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From page 101... ...
These members judged that the use of the MCL data could only be justified if it is EPA's policy to choose the most conservative unit risk when considering a range of options, but that such justification should be distinguished as a policy decision and not a scientific one. They believe that a more scientifically defensible approach would be to use the data set with the least uncertainty, rather than the data set that yields the most conservative estimate of risk.
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From page 102... ...
Chapters 6 and 7 provide more specific guidance on how to improve the presentation of the MOA evidence on tetrachloroethylene-induced hepatic and renal cancer. In general, the committee observes that discussion of MOA1 analy 1 There was some disagreement among the committee members on what constitutes "modes of action" and "key events." In Section 4.4.4 of the draft IRIS assessment, EPA discusses several "topics" relevant to the MOA for hepatic toxicity, including metabolism, receptor activation, genotoxic effects, and nongenotoxic effects.
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From page 103... ...
Other data relevant to the evaluation of hypothesized MOAs should be included. The advantage of such a presentation is that it makes explicit the consideration of the timeline of key events in the context of dose, concordance or lack of concordance between early and late events, and the relative contribution of chemical-specific data compared with generic information on categories of chemicals.
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From page 104... ...
Then the associated extra cancer risk is divided by the POD to yield a unit risk or a slope factor. In the draft IRIS assessment, EPA illustrates low-dose extrapolation with six datasets, hepatocellular adenoma or carcinoma in male and female mice (JISA 1993)
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From page 105... ...
The committee also notes that the polynomial order used in the multistage doseresponse models is limited by the number of dose groups in each experiment; only lower-order multistage models can be fitted, and they are forced to be nearly linear in the low dose range. Therefore, the similarity between the slope of the models and the unit risk taken from the models reflects more on the nearly linear model imposed on the data than the true shape of the dose-response curve.
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From page 106... ...
The full range of variation and uncertainty in relation to model choice is not presented, in part because EPA did not consider the possibility of other forms of nonlinear dose-response models, including supralinear, for all candidate datasets. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS, DOSE METRICS, AND INTERSPECIES SCALING The draft IRIS assessment appears to do a thorough job of reviewing the pertinent scientific literature on the toxicokinetics of tetrachloroethylene.
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From page 107... ...
There is inadequate justification for the selection of dose metrics for tetrachloroethylene metabolism, particularly in the use of total metabolites as the overall dose metric for cancer. The risk assessment would be improved if more effort were devoted to estimating the fraction of an absorbed tetrachloroethylene dose that enters the GSH pathway and the fraction entering the cytochrome P-450 pathway, which leads to the formation of trichloroacetic acid (TCA)
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From page 108... ...
If modeling the GSH pathway is determined to be infeasible, total metabolism can be used as a reasonably conservative dose metric. The PBPK model could then be built and tested around a combination of blood tetrachloroethylene and TCA concentrations, in vitro metabolism data, and urinary-excretion data for various metabolites (such as TCA, N-Ac-TCVC)
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From page 109... ...
The approach used by the different PBPK models to estimate metabolism and specifically estimation of the key metabolic parameters Vmax and Km varies substantially. Estimation of total metabolite formation in humans with the Reitz model relies primarily on in vitro hepatic metabolism data (microsomal metabolism, hence only the P-450 pathway)
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From page 110... ...
Human (nm/mg per hour) Substrate Concentrations ♂-TCVG (hepatic cytosol)
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From page 111... ...
The three PBPK models used by EPA were specifically formulated and validated against inhalation exposures. There was no attempt to validate model predictions against blood tetrachloroethylene concentrations after oral dosing.
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From page 112... ...
, and the use of PBPK models for route-to-route extrapolation. EPA's investigation of the effects of uncertainties on risk estimates is qualitative except in dealing with such issues as the choice of dose-response models, the use of PBPK models, and, to a small degree, variation between studies.
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From page 113... ...
. The capability to quantify the full range of overarching uncertainties associated with risk estimates facilitates separation of the science of risk assessment from risk-management decision-making.
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