1

Introduction

The US Environmental Protection Agency (EPA) asked the National Research Council to help its Integrated Risk Information System (IRIS) program in developing a scientifically credible toxicologic review of inorganic arsenic. IRIS assessments include the hazard identification and dose–response assessment steps of risk assessment. The two other risk-assessment steps of exposure assessment and risk characterization are conducted separate from the IRIS assessment to support risk management decisions. In develoing the IRIS assessment for inorganic arsenic, the agency is faced with the challenge of evaluating a large body of scientific information on arsenic, addressing recommendations for improving aspects of its past analyses of arsenic (e.g., NRC 1999, 2001; EPA SAB 2007, 2011), and incorporating recommendations for generally improving hazard identification and dose–response analysis (e.g., NRC 2009, 2011). EPA has worked on updating its assessment of inorganic arsenic for many years and released an updated draft cancer assessment of inorganic arsenic in 2010. However, in 2011, Congress mandated an independent peer review of the toxicologic assessment of inorganic arsenic by the National Research Council before EPA takes any action to make its IRIS assessment final. In response to the mandate, EPA withdrew its draft cancer assessment and announced plans to redo the toxicologic assessment to include cancer and noncancer effects. The agency has asked the National Research Council to provide guidance in the early stages of developing the IRIS assessment and to review the draft document after the agency has considered the committee’s recommendations and input from stakeholders. The statement of task for the project is presented in Box 3.

The National Research Council convened the Committee on Inorganic Arsenic, which comprises experts in epidemiology, toxicology, carcinogenesis, mechanisms, biologic modeling, environmental medicine, biostatistics, and risk assessment (see Appendix A for biographic information on the members). The committee held a workshop on April 4, 2013, to obtain input from arsenic researchers, risk-assessment professionals, and stakeholders on important aspects of hazard identification and dose–response analysis for inorganic arsenic (see Appendix B for workshop agenda). Information from the workshop was supplemented by materials provided by EPA, including a summary report of an internal EPA partner workshop, a summary report of a public stakeholder workshop held in January 2013, a planning and scoping summary for the toxicologic review of inorganic arsenic, EPA’s draft plans for performing the review, and draft supporting documents that provide examples of how EPA has begun it hazard assessment. The committee also considered written and oral statements provided by stakeholders over the course of the study. A preliminary review of the arsenic literature was also used in conjunction with these materials to inform the committee’s evaluations. The conduct of more comprehensive or systematic reviews of the literature was not part of the committee’s charge.

This interim report addresses the first phase of the project by providing recommendations on key aspects of and controversies related to the performance of the hazard identification and dose–response analyses for inorganic arsenic. The committee’s recommendations are specific to inorganic arsenic and may not be applicable for other chemical assessments. The committee considered materials describing EPA’s continuing efforts to improve the development of IRIS assessments (EPA 2013a,b). It was outside the scope of the committee’s task to comment on those materials.1

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1Another National Research Council committee is reviewing EPA’s initiatives to improve the overall process and quality of IRIS assessments. That committee expects to release its report in 2014.



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1 Introduction The US Environmental Protection Agency (EPA) asked the National Research Council to help its In- tegrated Risk Information System (IRIS) program in developing a scientifically credible toxicologic review of inorganic arsenic. IRIS assessments include the hazard identification and dose-response assessment steps of risk assessment. The two other risk-assessment steps of exposure assessment and risk characterization are conducted separate from the IRIS assessment to support risk management decisions. In develoing the IRIS assessment for inorganic arsenic, the agency is faced with the challenge of evaluating a large body of scien- tific information on arsenic, addressing recommendations for improving aspects of its past analyses of arse- nic (e.g., NRC 1999, 2001; EPA SAB 2007, 2011), and incorporating recommendations for generally im- proving hazard identification and dose–response analysis (e.g., NRC 2009, 2011). EPA has worked on updating its assessment of inorganic arsenic for many years and released an updated draft cancer assessment of inorganic arsenic in 2010. However, in 2011, Congress mandated an independent peer review of the toxi- cologic assessment of inorganic arsenic by the National Research Council before EPA takes any action to make its IRIS assessment final. In response to the mandate, EPA withdrew its draft cancer assessment and announced plans to redo the toxicologic assessment to include cancer and noncancer effects. The agency has asked the National Research Council to provide guidance in the early stages of developing the IRIS assess- ment and to review the draft document after the agency has considered the committee’s recommendations and input from stakeholders. The statement of task for the project is presented in Box 3. The National Research Council convened the Committee on Inorganic Arsenic, which comprises ex- perts in epidemiology, toxicology, carcinogenesis, mechanisms, biologic modeling, environmental medi- cine, biostatistics, and risk assessment (see Appendix A for biographic information on the members). The committee held a workshop on April 4, 2013, to obtain input from arsenic researchers, risk-assessment pro- fessionals, and stakeholders on important aspects of hazard identification and dose–response analysis for inorganic arsenic (see Appendix B for workshop agenda). Information from the workshop was supplement- ed by materials provided by EPA, including a summary report of an internal EPA partner workshop, a summary report of a public stakeholder workshop held in January 2013, a planning and scoping summary for the toxicologic review of inorganic arsenic, EPA’s draft plans for performing the review, and draft sup- porting documents that provide examples of how EPA has begun it hazard assessment. The committee also considered written and oral statements provided by stakeholders over the course of the study. A preliminary review of the arsenic literature was also used in conjunction with these materials to inform the committee’s evaluations. The conduct of more comprehensive or systematic reviews of the literature was not part of the committee’s charge. This interim report addresses the first phase of the project by providing recommendations on key as- pects of and controversies related to the performance of the hazard identification and dose–response anal- yses for inorganic arsenic. The committee’s recommendations are specific to inorganic arsenic and may not be applicable for other chemical assessments. The committee considered materials describing EPA’s con- tinuing efforts to improve the development of IRIS assessments (EPA 2013a,b). It was outside the scope of the committee’s task to comment on those materials.1 1 Another National Research Council committee is reviewing EPA’s initiatives to improve the overall process and quality of IRIS assessments. That committee expects to release its report in 2014. 8

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Introduction 9 BOX 3 Statement of Task An ad hoc committee will plan and conduct a public workshop to evaluate critical scientific issues in assessing cancer and noncancer effects from oral exposure to inorganic arsenic. The workshop will enable the committee to gather a variety of perspectives from stakeholders and others on the issues. Informed by the workshop, the committee will prepare an interim report providing recommendations on how those issues can be addressed in EPA's IRIS assessment. After EPA has revised the IRIS assessment, the committee will review it to determine whether the scientific literature on inorganic arsenic was adequately evaluated, whether appropriate methods were used to derive cancer risk estimates and noncancer reference values, and whether dose–response relationships between inorganic arsenic and cancer and noncancer effects were appropriately estimated and characterized. As requested by Congress, the committee will also determine whether the arsenic document reflects recommendations made in Chapter 7 of the 2011 NRC report on formaldehyde for improving descriptions of methods and criteria for selecting studies, approaches to evaluating critical studies, weight-of-evidence analyses, and justification of modeling approaches in IRIS assessments. RECOMMENDATIONS FROM PREVIOUS NATIONAL RESEARCH COUNCIL COMMITTEES EPA has made clear that two National Research Council reports will influence how it conducts its assessment of inorganic arsenic. The more recent one was an evaluation of EPA’s draft IRIS assessment of formaldehyde (NRC 2011). Chapter 7 of that report outlined a “roadmap to revision” for future IRIS documents, and Congress has directed EPA to address the recommendations in its toxicologic assessment of inorganic arsenic. The recommendations are in four broad categories: improving (1) descriptions of methods and criteria for selecting studies, (2) approaches to evaluating critical studies, (3) weight-of- evidence analyses, and (4) justification of modeling approaches. Important elements in achieving im- provements in those categories include standardization of the presentation of evidence, standardization of review and evaluation approaches (for literature review, hazard identification, dose–response modeling, and weight-of-evidence evaluation), guidelines for study selection, description and justification of as- sumptions and models used, and assessment of the sensitivity of derived risk estimates to model assump- tions and end points selected. EPA also plans to incorporate more general recommendations about assessment approaches outlined in Science and Decisions (NRC 2009), the second of the two reports mentioned above. A major recom- mendation of that report was that more attention be focused on designing the risk assessment in the form- ative stages, specifically in planning and scoping and in problem formulation. EPA was encouraged to involve risk managers, risk assessors, and stakeholders early in the process to help determine which major factors to consider, the decision-making context, and the timeline and depth needed to conduct the as- sessment. The report recommended that dose–response assessments be conducted similarly for cancer and noncancer effects so that risk-specific doses can be developed for both types of effects. Background expo- sures and disease processes, susceptible populations, and modes of action that may affect human dose– response relationships should be factored into the dose–response analysis. Suggestions were also made for planning the characterization of uncertainty and variability early in the process so that it can be devel- oped to meet the needs of comparative evaluation of risk-management options. The National Research Council also conducted two evaluations of EPA’s drinking-water standard for inorganic arsenic (NRC 1999, 2001). Those reports were used by EPA to set a maximum contaminant level of 10 µg/L for arsenic (66 Fed. Reg. 6975 [2001]). The database on arsenic has expanded substan- tially since those reports were published and will have to be considered along with the guidance of the other National Research Council reports (NRC 2009, 2011).

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10 Critical Aspects of EPA’s IRIS Assessment of Inorganic Arsenic THE ENVIRONMENTAL PROTECTION AGENCY’S DRAFT PLANS EPA provided the committee with its draft planning documents for future IRIS assessments (EPA 2013a,b) and for inorganic arsenic in particular (EPA 2013c,d), which clearly reflect the agency’s intent to address the recommendations of previous National Research Council committees (NRC 2009, 2011). The draft planning and scoping summary reflects input collected from program and regional offices of EPA and other stakeholders and provides a general description of the EPA plans to approach the toxico- logic assessment. Important elements of the plan include  Literature search and evaluation—Systematic review principles will be used to evaluate the scien- tific literature on inorganic arsenic, and studies will be judged according to defined criteria and such fac- tors as bias and study quality.  Temporal and exposure considerations—Factors will include subchronic and chronic exposures, exposures during different life stages, and evaluation of risks posed by oral, inhalation, and dermal expo- sures. Aggregate exposures will be considered only in the context of how they might affect exposure es- timates in dose–response analysis. Exposure to metabolites will be considered only in mode-of-action analyses.  Scope of hazard identification—The toxicologic assessment will include cancer and noncancer effects of exposure to inorganic arsenic. In addition to the temporal and exposure considerations de- scribed above, factors that might increase susceptibility to inorganic arsenic will be considered, and un- certainties associated with the hazard identification will be characterized.  Scope of dose–response analysis—The dose–response analyses will examine potential health risks over a range of exposures, and probabilistic, linear, and nonlinear low-dose extrapolation will be included to the extent possible. Aggregate exposures, bioavailability, and speciation will be considered only in the context of how they might affect dose estimates in dose–response analysis. Uncertainties asso- ciated with those considerations and other aspects of the dose–response analysis will be considered quali- tatively and quantitatively. Mode-of-action analyses will be conducted for health effects associated with direct exposure to inorganic arsenic.  Communication and public outreach—EPA will seek public input from stakeholders throughout the development of the toxicologic assessment through formal workshops and meetings, webinars, and a public Web site. STRUCTURE OF THE REPORT Specific aspects of EPA’s plans for the inorganic-arsenic assessment are reviewed in the remaining chapters of this report. Chapter 2 describes exposure issues that will be important to consider in the IRIS assessment, including sources and biomarkers of exposure to inorganic arsenic and the chemical’s toxico- kinetics; Chapter 3 provides guidance for performing systematic reviews and meta-analyses for the as- sessment. In Chapter 4, the committee provides an overview of relevant evidence on most of the major health effects that will be the focus of EPA’s hazard identification process. The committee did not per- form a comprehensive or systematic review of the literature but focused on identifying studies and issues that will be useful in guiding mode-of-action assessments and dose–response analyses. Chapter 5 discuss- es factors that increase susceptibility to the adverse effects of inorganic arsenic and their implications for the IRIS assessment. The committee’s recommendations regarding the performance of dose–response assessments of inorganic arsenic are presented in Chapter 6.