In a few respects, the committee disagrees with EPA’s presentation on uncertainties. For example, EPA notes narrow variation between cancer risks derived from four dose-response models. However, in its comparison, EPA used only data on male rats, and all four models were linear or nearly linear at lower doses. Failure to consider a wider array of feasible dose-response models, including multistage models of various orders, could lead to inadequate quantification of uncertainty associated with the choice of dose-response model.

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.

The committee found several parts of the draft IRIS assessment that could be improved on in the future. Such changes are not necessary for completing the current assessment but should be considered when tetrachloroethylene is reevaluated in the future. They include improving transparency in selection and analysis of data, particularly with regard to uncertainty analysis. The committee encourages EPA to consider the most recent guidance from the National Research Council report Science and Decisions.

There is a vast amount of literature on tetrachloroethylene, and the draft IRIS assessment was hampered by having to manage the sheer volume of information on the chemical. Any new reassessment should begin with problem formulation and issue identification, consideration of whether to rely on previous reviews, determination of the focus of the new effort, and identification of the specific issues on which the reassessment is likely to focus. That would help to identify where multidisciplinary input at early stages of reanalysis should be sought, such as in data selection and mode-of-action evaluations in the context of risk-assessment practices. The process would include a delineation of criteria for selecting studies, approaches for conducting a weight-of-evidence evaluation, and options for dose-response assessment and the characterization of uncertainties. EPA should also consider ways to reorganize the document to streamline presentation of the data and analyses.