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Suggested Citation:"BACKGROUND." National Academies of Sciences, Engineering, and Medicine. 2019. Review of EPA's Updated Problem Formulation and Protocol for the Inorganic Arsenic IRIS Assessment. Washington, DC: The National Academies Press. doi: 10.17226/25558.
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  • 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

evaluate the revised scope of the assessment and determine whether the proposed methods address recommendations made in a 2013 NRC [National Research Council] report and are appropriate to synthesize the scientific evidence and quantitate estimates of toxicity. The committee will comment on

  • The approach to prioritizing health outcomes,
  • The clarity and appropriateness of the systematic review methods,
  • Whether potential health effects from early life exposures are adequately addressed,
  • The feasibility of using mode-of-action information to inform dose-response analyses,
  • The hierarchical, Bayesian meta-regression approach to develop point estimates and confidence intervals,
  • The use of common intake values to support inclusion of more studies in the dose-response analysis,
Suggested Citation:"BACKGROUND." National Academies of Sciences, Engineering, and Medicine. 2019. Review of EPA's Updated Problem Formulation and Protocol for the Inorganic Arsenic IRIS Assessment. Washington, DC: The National Academies Press. doi: 10.17226/25558.
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The Integrated Risk Information System (IRIS) is a program within the US Environmental Protection Agency (EPA) that is responsible for developing toxicologic assessments of environmental contaminants. An IRIS assessment contains hazard identifications and dose-response assessments of various chemicals related to cancer and noncancer outcomes. Although the program was created to increase consistency among toxicologic assessments within the agency, federal, state, and international agencies and other organizations have come to rely on IRIS assessments for setting regulatory standards, establishing exposure guidelines, and estimating risks to exposed populations.

The EPA has been working on its IRIS assessment of inorganic arsenic (iAs) for many years, and recently released its plans for completing it in the Updated Problem Formulation and Protocol for the Inorganic Arsenic IRIS Assessment. Much of the update was made in response to recommendations in a 2013 report made by the National Academies of Sciences, Engineering, and Medicine. The National Academies recently convened another evaluation of whether the various elements of the IRIS iAs assessment plan are appropriate to synthesize the scientific evidence and quantitate estimates of iAs toxicity. Review of EPA’s IRIS Assessment Plan for Inorganic Arsenic explores the EPA’s approach to prioritizing health outcomes, EPA’s systematic review methods, EPA’s consideration of potential health effects from early life exposures, mode-of-action information to inform dose-response analyses, and various approaches to investigate dose-response relationships.

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