Review of EPA's Updated Problem Formulation and Protocol for the Inorganic Arsenic IRIS Assessment (2019)

• at EPA. On the second issue, no information was presented for the committee to understand how dose-response analyses will be performed if there are sufficient data on early life exposure to iAs and adult health outcomes. Thus, it was not possible for the committee to make a determination about whether early life exposure will be adequately addressed in EPA’s iAs IRIS assessment.

• Mode-of-action (MOA) information to inform dose-response analyses: Because EPA will rely on epidemiological data and will be performing dose-response analyses within the range of observation, the majority of the committee agreed that MOA data were unnecessary for determining the shape of the dose-response curve unless EPA finds it necessary to extrapolate to lower levels. One member felt that MOA data are still required for performing the dose-response assessment.
• Hierarchical, Bayesian meta-analysis approach: EPA has implemented a sophisticated methodology that will allow it to use data from multiple epidemiological studies to determine the shape of the dose-response curve in the observed range. The majority of the committee supports this approach, and recommended clarifications on some of the procedures. One member felt that statistical approaches are inferior to using MOA data to determine the shape of the dose-response curve.
• Common intake approach: The committee agrees with EPA’s conversion of a variety of exposure metrics to a common intake value to facilitate including as many studies as possible in the dose-response analysis for each health end point considered. The physiologically based pharmacokinetic (PBPK) model was developed and appropriately validated to be generalizable for converting urinary arsenic measures to water arsenic concentrations.
• Modeling approaches: The majority of the committee agrees with EPA’s approach for dose-response investigations for cancer and noncancer end points. EPA intends on using a logistic regression model with fractional polynomials, which will accommodate a variety of curve shapes. The committee has suggested additional steps that EPA could take to strengthen its approach, including the performance of sensitivity analyses to address uncertainties, as well as other statistical options that could be informative. One member disagrees that statistical approaches alone should be used to evaluate the shapes of dose-response curves (his arguments are presented in a dissenting statement in Appendix A, along with the committee rebuttal).

BACKGROUND

EPA’s IRIS program has developed an Updated Problem Formulation and Protocol for the Inorganic Arsenic IRIS Assessment (EPA 2019a). The document outlines the approaches that are being used to conduct the IRIS assessment, including methods that were implemented in response to recommendations from previous committees of the National Academies about performing toxicological assessments of iAs (NRC 2013) and improving the methods used in IRIS assessments in general (NRC 2014; NASEM 2018). At the request of EPA, the National Academies convened another ad hoc committee (see Appendix B for biographical information on the members) to evaluate the updated plans for completing the iAs IRIS assessment. The committee’s charge was to