EPA/630/R-14/101

November 2015

www.epa.gov/iris

Assessment Development Plan for the 

Integrated Risk Information System (IRIS) 

Toxicological Review of Inorganic Arsenic 

[CASRN 7440-38-2]

November 2015 

NOTICE:

This is a draft comprising development materials. This information is distributed solely for the 

purpose of pre-dissemination review under applicable information quality guidelines. It has not 

been formally disseminated by EPA. It does not represent and should not be construed to represent 

any Agency determination or policy. 

U. S. Environmental Protection Agency

Office of Research and Development

National Center for Environmental Assessment

Washington, D.C.
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 ii

1 Disclaimer

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This information is distributed solely for the purpose of pre-dissemination review under 

applicable information quality guidelines. It has not been formally disseminated by EPA. It does not 

represent and should not be construed to represent any Agency determination or policy. Mention of 

trade names or commercial products does not constitute endorsement or recommendation for use. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 iii

CONTENTS

PREFACE ...................................................................................................................................................................................... v

EXECUTIVE SUMMARY .........................................................................................................................................................vi

1. BACKGROUND............................................................................................................................................................... 1-1

1.1.Previous EPA Assessments of Inorganic Arsenic and NRC Evaluations ....................................... 1-1

1.2.Congressional Directive for EPA Toxicological Review of Inorganic Arsenic............................. 1-2

1.3.The NRC Interim Report, Critical Aspects of EPA’s IRIS Assessment of Inorganic 

Arsenic ...................................................................................................................................................................... 1-2

1.4.June 2014 IRIS Public Science Meeting on Inorganic Arsenic........................................................... 1-4

2. KEY CHARACTERISTICS OF THE ASSESSMENT DEVELOPMENT PLAN............................................... 2-1

2.1.Goals of the Assessment Development Plan............................................................................................. 2-1

2.2.Agency Partners and Public Stakeholder Engagement........................................................................ 2-1

2.3.Transparency......................................................................................................................................................... 2-2

2.4.Timeline for Completion................................................................................................................................... 2-2

2.5.Overall Conceptual Model................................................................................................................................ 2-2

3. ANALYSIS PLAN FOR THE TOXICOLOGICAL REVIEW................................................................................. 3-1

3.1.Literature Search ................................................................................................................................................. 3-1

Literature Identification ........................................................................................................................................... 3-1

Risk-of-Bias Analysis.................................................................................................................................................. 3-4

Evidence Tables............................................................................................................................................................ 3-6

3.2.Health Hazard Identification........................................................................................................................... 3-6

Evidence Synthesis...................................................................................................................................................... 3-7

Evaluate Adverse Outcome Pathway or Network Data for Hazard Identification ........................... 3-7

Evaluate Susceptibility Factors.............................................................................................................................. 3-8

Evidence Integration and Causal Determinations ......................................................................................... 3-8

3.3.Dose-response Analyses ................................................................................................................................... 3-9

Data Selection for Dose-response Analyses...................................................................................................... 3-9

Variability and Uncertainty in Dose-response Analyses........................................................................... 3-11

Dose-response Modeling Approaches............................................................................................................... 3-11

Extrapolation for Dose-response Analyses..................................................................................................... 3-12

4. REFERENCES................................................................................................................................................................. 4-1

Appendix A. Evidence Integration................................................................................................................................ A-1
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

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TABLES

Table 3-1. Example risk-of-bias considerations ..................................................................................................... 3-5

Table 3-2. General risk-of-bias ratings ....................................................................................................................... 3-5

Table 3-3. Summary of proposed inorganic arsenic dose-response analysis tiers................................3-13

FIGURES 

Figure 2-1. Overall conceptual model for IRIS Toxicological Review of Inorganic Arsenic. ................... 2-3

Figure 3-1. Overview of the analysis plan for IRIS Toxicological Review of Inorganic 

Arsenic. ............................................................................................................................................................. 3-2

Figure 3-2. Process for identifying, sorting, and evaluating susceptibility, mechanistic, 

and health effect studies for the IRIS Toxicological Review of Inorganic 

Arsenic. Studies reporting health effect data often also include susceptibility 

and mechanistic data; targeted searches or cluster analyses enable 

identification of these data to support planned susceptibility factor 

evaluations and AOP/N analyses. (Colors depict data streams for each type 

of literature searched.).............................................................................................................................. 3-3

Figure 3-3. Overview of hazard identification for arsenic.................................................................................. 3-6

BOXES

Box 1-1. History.................................................................................................................................................................... 1-1

Box 1-2. Hierarchy of Health Endpoints of Concern for Inorganic Arsenic................................................. 1-3

Box 2-1. Key Messages....................................................................................................................................................... 2-1

Box 3-1. Key Messages....................................................................................................................................................... 3-1

Box 3-2. Adverse Health Effects under Consideration......................................................................................... 3-7
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

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2 PREFACE 

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For the Integrated Risk Information System (IRIS) Program, the National Center for 

Environmental Assessment (NCEA) at the U.S. Environmental Protection Agency (EPA) is 

developing a state-of-the-science Toxicological Review of Inorganic Arsenic. The approaches NCEA is 

applying to assess the hazard and dose-response of inorganic arsenic, and the associated 

uncertainty, are based on evolving practices in the IRIS Program and are guided by National 

Research Council recommendations (2014, 2013, 2011, 2009). Many of these approaches have yet 

to be used extensively in environmental health assessment. Inorganic arsenic provides an 

opportunity to explore these approaches because numerous human observational studies of 

environmental exposures are available. IRIS Toxicological Reviews are incorporating several new 

elements as part of this evolving process: comprehensive problem formulation and planning 

involving stakeholders, specific questions to guide risk-of-bias evaluations, and explicit quantitative 

consideration of sensitive subpopulation risks and risk modifiers. The reviews also integrate 

thorough analyses of adverse outcome pathways and networks to inform causal determinations 

and dose-response model choices, Bayesian regression meta-analyses of studies to examine doseresponse, and Bayesian analyses of uncertainties. The results of these evaluations will enable EPA 

to refine these new approaches and consider their utility for application to other types of 

assessments. Of note is that the data required for many of these approaches are usually unavailable 

for most chemicals the IRIS Program evaluates. Moreover, these approaches might not be fit for 

purpose for other assessments. Consequently, the use of these approaches in developing the 

Toxicological Review of Inorganic Arsenic does not necessarily signal a change from current 

assessment approaches for other NCEA products. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

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EXECUTIVE SUMMARY 

For the Integrated Risk Information System (IRIS) Program, the National Center for 

Environmental Assessment (NCEA) at the U.S. Environmental Protection Agency (EPA) is 

developing a state-of-the-science Toxicological Review of Inorganic Arsenic. This Assessment 

Development Plan presents an overview of the types of scientific information and technical 

approaches EPA will consider when developing the draft Toxicological Review. Additional 

supporting materials are available on the IRIS inorganic arsenic webpage.

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The scientific information considered and the approaches proposed were informed by the 

National Research Council’s (NRC, 2013) Interim Report, Critical Aspects of EPA’s IRIS Assessment of 

Inorganic Arsenic,

2 and several other NRC reports NRC (2014); (2011, 2009). EPA Program and 

Regional Offices, other federal agencies, and public stakeholders have actively participated in the 

scoping and planning for the Toxicological Review and in the review of draft preliminary materials. 

Based on their recommendations, the Toxicological Review will examine the cancer and noncancer 

effects from oral, inhalation, and potentially dermal exposure to inorganic arsenic. Adverse 

outcome pathway and network analyses and susceptible populations also will be considered, as 

feasible. 

The key messages in this Assessment Development Plan are:

• The IRIS Toxicological Review for arsenic will evaluate the efficacy of several NRCrecommended innovations. Based on these evaluations, approaches will be refined and 

their utility for broader application determined. Approaches ultimately used in the 

Toxicological Review of Inorganic Arsenic do not necessarily signal a change from 

current assessment approaches used for other NCEA products. 

• This plan represents the fruition of an extensive problem formulation and planning 

effort with substantial NRC and stakeholder involvement. 

• A formal, systematic review of the literature has been conducted, informed by the 

National Toxicology Program’s (NTP) Office of Health Assessment and Translation 

approach. Results should not be interpreted as a checklist to exclude or include studies 

automatically, but rather as an investigation of one approach to literature evaluation. 

• For hazard identification, the Toxicological Review will, as feasible: 

° Consider all endpoints identified by NRC (2013) in their Interim Report. 

° Identify susceptible subpopulations and risk modifiers. 

 

1 http://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm?substance_nmbr=278&forceAssessmentTab=true. 2 http://www.nap.edu/catalog/18594/critical-aspects-of-epas-iris-assessment-of-inorganic-arsenic-interim. 
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1 ° Develop adverse outcome pathway or network analyses for endpoints considered to 

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be causally or likely causally associated with specific adverse outcomes, or having 

ambiguous causal determinations based on epidemiologic data only. 

° Identify and present characteristics and results for all studies considered for hazard 

identification and dose-response in evidence tables. 

° Base causal determination on integration of these data and expert judgment. 

• For dose-response analyses, the following will be completed, as warranted and feasible:

° Estimate noncancer and cancer risks for causal or likely causal endpoints, including 

risk-specific doses. 

° Consider non-U.S. and U.S. information on dietary contributions to total exposure

and use available data and pharmacokinetic models to characterize urinary 

biomarkers of exposure compared to exposure.

° Explicitly consider observational data at U.S. exposure levels down to background 

exposure (total urinary arsenic ~ 1–5 μg/L). 

° Evaluate susceptible subpopulations and risk modifiers (such as different 

phenotypes and smokers). 

° Apply various dose-response models and present the results. 

° Conduct meta-analyses of epidemiologic data. 

° Use adverse outcome pathway or network analyses, and human variability and 

susceptibility data, to inform extrapolations below the observed range of doseresponse. 

° Possibly conduct additional adverse outcome pathway or network analyses for a 

subset of causal and likely causal endpoints for which dose-response models 

significantly diverge in the low-dose range.

° Conduct Bayesian analyses to account for prior information and characterize 

uncertainties more fully (e.g., study selection, model choice).

° Treat more complex analyses as limited in application (e.g., subset of endpoints) or

as illustrative only, depending on outcomes. 

• EPA will continue to take advantage of opportunities to engage Agency Program and 

Regional Offices, other federal agencies, the Executive Office of the President, and public 

stakeholders.
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

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1 1. BACKGROUND

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This section summarizes major activities completed since publication of the 1988 IRIS 

Toxicological Review of Inorganic Arsenic. 

Box 1-1. History 

• 1988: EPA published the IRIS Health Hazard Assessment for Inorganic Arsenic.

• 1999: The National Research Council (NRC), at EPA’s request, published Arsenic in Drinking Water.

• 2003: EPA began updating the 1988 IRIS Toxicological Review.

• 2005: EPA released the draft IRIS Toxicological Review of Inorganic Arsenic for public comment

and peer review.

• 2007: An expert panel convened by EPA’s Science Advisory Board completed a review of key

scientific issues included in the draft Toxicological Review and published comments in an advisory

report.

• 2010: EPA released the revised draft IRIS Toxicological Review of Inorganic Arsenic for public

comment and peer review.

• 2010: SAB completed its review of the draft Toxicological Review.

• 2011: Congress directed EPA to contract with the NRC to review the draft Toxicological Review.

• 2013 (January): EPA held a public scoping and problem formulation meeting for development of a

new IRIS Toxicological Review of Inorganic Arsenic.

• 2013 (March–July): EPA held eight science issues public webinars.

• 2013 (May): EPA submitted a draft Assessment Development Plan and preliminary assessment

materials to NRC for review.

• 2013 (November): NRC released the interim report, Critical Aspects of EPA’s IRIS Assessment of

Inorganic Arsenic and provided recommendations; NRC supported EPA’s plan.

• 2014 (June): EPA held a public science meeting to present and encourage comments on the

Assessment Development Plan, preliminary assessment materials, and key science issues.

4 1.1. Previous EPA Assessments of Inorganic Arsenic and NRC 

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Evaluations

EPA completed and published a final IRIS Health Hazard Assessment for Inorganic Arsenic in 

1988 (see Box 1-1). In 1996, EPA asked NRC to evaluate the inorganic arsenic database and 

recommend revisions to the 1988 Health Hazard Assessment. In response, NRC published Arsenic in 

Drinking Water (NRC, 1999) and an update in 2001. In 2003, EPA began incorporating

recommendations from the 1999 and 2001 NRC reports into a new, draft IRIS Toxicological Review 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

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1 of Inorganic Arsenic. EPA also divided the Toxicological Review to focus on cancer outcomes and 

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noncancer outcomes separately. In 2005, EPA released a draft IRIS Toxicological Review of Inorganic 

Arsenic of cancer health effects following oral exposure and requested comments from the public 

and review by EPA’s Science Advisory Board (SAB). The SAB provided recommendations to EPA in 

2007 (SAB, 2007), which EPA subsequently incorporated into the Toxicological Review. The revised 

draft IRIS Toxicological Review of cancer health effects following oral exposure to inorganic arsenic 

was released for public comment and SAB review in 2010 (U.S. EPA, 2010). The SAB provided their 

comments and recommendations the following year (SAB, 2011). 

1.2. Congressional Directive for EPA Toxicological Review of Inorganic 

Arsenic

In December 2011, Congress directed EPA (U.S. Congress, 2011) to contract with NRC to 

review EPA’s draft inorganic arsenic Toxicological Review. Congress asked NRC to conduct a twophase review of the Toxicological Review, considering both cancer and noncancer hazards from 

oral exposure to inorganic arsenic. For the first phase, NRC was directed to review the scope and 

key science issues and provide recommendations to EPA for developing a draft Toxicological 

Review. For the second phase, NRC was directed to provide EPA with a critical scientific peer 

review of the draft. 

1.3. The NRC Interim Report, Critical Aspects of EPA’s IRIS Assessment of 

Inorganic Arsenic

NRC conducted the first phase of its review between July 2012 and November 2013. A 

special committee convened by the NRC collected and reviewed information on hazard 

identification and dose-response analysis of inorganic arsenic during an NRC-sponsored workshop 

in April 2013.

3 The committee evaluated and commented on draft materials that EPA provided 

related to the ongoing IRIS Toxicological Review, including planning and scoping documents, 

reports from workshops EPA conducted, and a draft plan for completion. That draft plan, a 

predecessor to this Assessment Development Plan, described EPA’s proposed technical approaches 

for literature searches and evaluation, hazard identification, and dose-response and uncertainty

analyses. NRC presented the results of the first phase of its review in the 2013 Interim Report, 

Critical Aspects of EPA’s IRIS Assessment of Inorganic Arsenic (NRC, 2013). The report comments on 

key aspects of inorganic arsenic toxicology and provides specific recommendations to EPA for 

conducting the IRIS Toxicological Review. 

The NRC stated that the scoping materials submitted for review clearly demonstrated that 

EPA is incorporating previous NRC recommendations (NRC, 2011, 2009) to involve risk managers, 

risk assessors, and stakeholders early in the development process. Regarding EPA’s analysis plans, 

3 http://www2.epa.gov/iris/inorganic-arsenic-workshop. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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1 NRC observed that the draft approach for searching and evaluating the literature likely would 

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capture the salient information from epidemiologic studies but suggested that collecting animal and 

in vitro data also could be important for adverse outcome pathway and network (AOP/N) analyses.

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NRC acknowledged that the outlined approaches to incorporate systematic review in EPA’s plan 

also reflect NRC recommendations (NRC, 2011, 2009). 

For hazard identification, EPA proposed 

evaluating the relationship between inorganic arsenic

exposure and human health effects using a causal 

determination framework as previously described (U.S. 

EPA, 2013a, c, 2005). NRC supported this approach as 

well as the proposal to consider animal and mechanistic 

data as supporting evidence for determining causality. 

NRC prioritized specific health endpoints to evaluate for 

hazard identification (see Box 1-2) and stated that EPA 

will refine these categorizations after it conducts a more 

comprehensive analysis. They also supported EPA’s use of 

evidence tables to present information and stressed the 

importance of explaining causal determination judgments 

in the synthesis text. NRC supported EPA’s proposal to 

perform AOP/N analyses on health endpoints considered 

“causal” or “likely causal.” They recommended 

considering “suggestive” endpoints for AOP/N 

development to inform causal determination. The 

committee agreed with EPA’s proposal to conduct doseresponse analysis for “causal” or “likely causal” 

relationships even if an AOP/N cannot be determined. 

The AOP/N process “will be used to organize mechanistic 

information to determine how mechanistic information 

supports low-dose extrapolation and to inform how dose-response analyses account for the 

 

4 The NRC and stakeholders use the terms “adverse outcome pathway” and “mode of action” to describe 

conceptual models of underlying mechanisms of adverse health outcome. While the terms are similar, 

adverse outcome pathway models are adverse outcome specific rather than chemical specific (but can be 

informed by chemical-specific information), whereas, mode of action models are generally chemical specific. 

EPA and other Organization for Economic Co-operation and Development members are moving toward use of 

adverse outcome pathways or networks to describe mechanistic conceptual models; hence, the terms adverse 

outcome pathway or networks are used throughout this document unless quoting another source where 

mode of action is used. Specifically, an AOP is defined as a “conceptual framework that organizes existing 

knowledge concerning biologically plausible, and empirically supported, links between molecular-level 

perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory 

relevance” (Villeneuve et al., 2015). Multiple, interconnected AOPs related to the same disease, and which 

more broadly capture underlying events, are termed adverse outcome networks (AONs). 

Box 1-2. Hierarchy of Health 

Endpoints of Concern for 

Inorganic Arsenic 

Tier 1: Evidence of a causal 

association determined by other 

agencies or in published systematic 

reviews

• Lung, skin, and bladder cancer

• Ischemic heart disease

• Skin lesions

Tier 2: Other priority outcomes

• Prostate and renal cancer

• Diabetes

• Nonmalignant respiratory disease

• Pregnancy outcomes

• Neurodevelopmental toxicity

• Immune effects

Tier 3: Other endpoints 

• Liver and pancreatic cancer

• Renal disease

• Hypertension

• Stroke

• Pregnancy outcomes (fetal loss, 

stillbirth, and neonatal mortality)

(Reproduced from NRC 2013) 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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1 uncertainty associated with susceptibility” (NRC, 2013). Applications of AOP/N analyses are 

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discussed in Section 3.

NRC made several recommendations for the dose-response analysis. They stated that EPA 

should develop risk estimates across the array of health effects having adequate epidemiologic 

evidence. They recommended performing the analyses with data in the range of epidemiologic 

observations. When those data are not available, they recommended using AOP/N analyses to 

inform dose-response model choices when extrapolating below the range of observed data. They

cautioned, however, that extrapolations become increasingly uncertain the farther below the 

observed range they are made. They also stated (1) extrapolations should be limited to within an 

order of magnitude; and (2) although they do not assume that background concentrations are with 

or without health effects, assessing health risk could be facilitated by characterizing dose-response 

relationships down to background concentrations. NRC recommended that EPA derive risk-specific 

doses, which would facilitate subsequent efforts to evaluate cumulative risk, conduct risk-benefit 

evaluations, and perform comparative analyses.

NRC agreed with EPA’s proposal to use probabilistic approaches when considering

variability and uncertainty associated with susceptibility factors. Susceptibility due to preexisting 

disease, early-life exposure, and sex differences in metabolism were among several factors NRC 

recommended for consideration. Based on available evidence, the committee suggested considering 

whether dose-response analyses should focus on the population as a whole or involve separate 

approaches for the general population and susceptible groups. 

1.4. June 2014 IRIS Public Science Meeting on Inorganic Arsenic

Following the publication of the NRC (2013) interim report, EPA compiled preliminary 

materials for the IRIS Toxicological Review of Inorganic Arsenic for public review. Materials included 

an updated Toxicological Review Development Plan, a description of the literature search strategy 

and systematic review methods, summaries of relevant epidemiologic and animal toxicity studies 

identified to date and key evidence from those studies, and information on AOP/N and

susceptibility. EPA solicited public input on these preliminary materials, and comments received 

are available in the inorganic arsenic docket (EPA-HQ-ORD-2012-08305). EPA also invited the 

public to make presentations on key science issues at a public science meeting6 held June 2014. 

5 http://www. regulations.gov/#!searchResults;rpp=25;po=0;s=EPA-HQ-ORD-2012-0830;fp=true;ns=true. 6 http://www2.epa.gov/iris/iris-bimonthly-public-meeting-jun-2014. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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2. KEY CHARACTERISTICS OF THE ASSESSMENT

DEVELOPMENT PLAN

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3 This section describes overall objectives and features of this Assessment Development Plan. 

Box 2-1. Key Messages

• The goal for the Assessment Development Plan is to highlight the fundamental considerations and

potential approaches for the IRIS Toxicological Review of Inorganic Arsenic, communicate these

topics, and facilitate discussion on them.

• EPA will continue to seek and take advantage of opportunities to engage Agency Program and

Regional Offices, other federal agencies, the Executive Office of the President, and public

stakeholders in the discussions of the Toxicological Review.

• This Assessment Development Plan and additional supporting materials are available on the IRIS

arsenic webpage to facilitate transparent understanding of the data and methods to be used.

• Included in this Assessment Development Plan is an analysis plan for hazard identification and

dose-response assessment.

4 2.1. Goals of the Assessment Development Plan

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The goals for the Assessment Development Plan are to highlight the basic considerations 

and potential approaches to be used in the IRIS Toxicological Review of Inorganic Arsenic, 

communicate EPA’s intentions regarding these to stakeholders, and facilitate discussion on these 

topics. The Assessment Development Plan reflects the problem formulation and planning efforts 

EPA has completed to date. This plan and other materials are available on the IRIS inorganic arsenic 

webpage.

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2.2. Agency Partners and Public Stakeholder Engagement

EPA is committed to engaging EPA Program and Regional Offices, other federal agencies, the 

Executive Office of the President, and public stakeholders throughout the development of this

Toxicological Review. Agency partners and public stakeholders (e.g., nongovernmental 

organizations, industry groups, citizens, academia) have been active participants in planning and 

scoping meetings, identifying their needs for the IRIS Toxicological Review of Inorganic Arsenic, and 

making scientific recommendations. Of note is that the IRIS Toxicological Review for Inorganic 

7 http://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm?substance_nmbr=278&forceAssessmentTab=true. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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and Drug Administration. 

2.3. Transparency

EPA is committed to making certain the Toxicological Review proceeds transparently. 

Preliminary materials being used to develop the Toxicological Review are available to the public on 

the IRIS inorganic arsenic webpage8 and the HERO project page for inorganic arsenic.

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2.4. Timeline for Completion

The comments received at the June 2014 IRIS Public Science Meeting and the plan described 

here inform the development of the draft Toxicological Review. The draft Toxicological Review will 

undergo internal EPA review, review by other federal agencies, and the Executive Office of the 

President. It will be made publicly available for comment before it is released for external peer 

review, which NRC will perform. Following revisions and additional review by EPA, other federal 

Agencies, and the Executive Office of the President, EPA anticipates posting the final IRIS 

Toxicological Review of Inorganic Arsenic to the IRIS database in 2017. 

2.5. Overall Conceptual Model

The conceptual model EPA has developed for the Toxicological Review is illustrated in 

Figure 2-1. In Figure 2-1, black lines and darker blue boxes indicate relationships and elements that 

EPA will consider in the Toxicological Review; gray lines and lighter blue boxes indicate aspects of 

inorganic arsenic exposure that are outside the scope of this Toxicological Review. Additional 

discussion of the conceptual model is found in Draft Development Materials for the Integrated Risk 

Information System (IRIS) Toxicological Review of Inorganic Arsenic on the IRIS website.

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8 http://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm?substance_nmbr=278&forceAssessmentTab=true.

9 http://hero.epa.gov/index.cfm/project/page/project_id/2211. 10http://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=524796#_ga=1.136360240.1891222957.14444057

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Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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Source: Adapted from NRC (2009). 

Figure 2-1. Overall conceptual model for IRIS Toxicological Review of Inorganic 

Arsenic. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 3-1

3. ANALYSIS PLAN FOR THE TOXICOLOGICAL 

REVIEW

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This section describes the analysis plan. Figure 3-1 illustrates the technical activities as a 

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Box 3-1. Key Messages

• The analysis plan describes how the Toxicological Review will be implemented.

• A systematic literature search and review process identifies and selects studies, evaluates study 

methods based on clearly defined criteria, and transparently documents the selection outcome. 

• The analysis plan and additional material on the Web describe approaches to hazard identification 

and dose-response analysis, including systematic review, adverse outcome pathway or network 

analyses, and uncertainty analyses.

• The analysis plan is flexible and can be modified as the Toxicological Review is developed, 

depending on data and analytical requirements.

• This plan has been revised in response to NRC recommendations in the interim report Critical 

Aspects of EPA’s IRIS Assessment of Inorganic Arsenic (NRC, 2013); public input from the June 2014 

IRIS Public Science Meeting on Inorganic Arsenic; and recommendations in the NRC report, Review 

of EPA's Integrated Risk Information System (IRIS) Process (NRC, 2014).

ies of generally sequential steps. 

3.1. Literature Search

This section describes the approach used for identifying relevant literature and evaluating 

risk of bias. EPA systematically reviewed and evaluated the available literature on inorganic arsenic 

to guide expert judgment, as NRC recommended in its report, Review of EPA's Integrated Risk 

Information System (IRIS) Process (NRC, 2014). The review process formulates specific strategies to 

identify and select studies, evaluates methods used in the studies based on clearly defined criteria, 

and transparently documents the process and its outcomes. 

12 Literature Identification

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The initial literature search process for the Toxicological Review included selecting 

databases of references, defining search terms, documenting search strategies, and selecting a 

stopping date for literature searches. EPA conducted searches using the HERO interface, updated 

through July 2014. The resulting literature search products are publicly available on the HERO 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 3-2

project page for inorganic arsenic.

11 1 The outcome of the literature search process was a 

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comprehensive list of the available scientific literature on inorganic arsenic. 

4 Figure 3-1. Overview of the analysis plan for IRIS Toxicological Review of 

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Inorganic Arsenic. 

Figure 3-2 outlines the literature search strategy for information on health effects and 

mechanistic data for the IRIS Toxicological Review of Inorganic Arsenic. PubMed, Web of Science, 

and TOXLINE were searched using the chemical name and CAS (Chemical Abstracts Service) 

number. The results from the three databases were combined, and duplicate records were

removed. The gray lines in Figure 3-2 indicate literature set aside during the literature search 

process; the dark lines indicate the progression of literature being considered during development 

of the Toxicological Review. Although not explicitly depicted in this figure, pharmacokinetic 

information is also captured in the “Mechanistic Data Cluster.” 

Non-peer-reviewed articles, abstracts, posters, and review articles were separated in the 

initial screening of the comprehensive list of references. The Agency uses only peer-reviewed 

articles in IRIS Toxicological Reviews. Posters are often not publicly available or peer reviewed, and 

although abstracts and review articles were considered potential sources for identifying additional 

 

11 http://hero.epa.gov/index.cfm/project/page/project_id/2211. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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DRAFT – November 2015 3-3

1 peer-reviewed references, the Toxicological Review relies on data from primary source material. As 

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shown in Figure 3-2, the remaining references in the considered list were grouped using natural 

language processing. A computer algorithm was initially used to group references into “clusters” 

based on text similarities in the titles and abstracts. The clustering process is a tool to organize the 

arsenic literature database.

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Figure 3-2. Process for identifying, sorting, and evaluating susceptibility, 

mechanistic, and health effect studies for the IRIS Toxicological Review of 

Inorganic Arsenic. Studies reporting health effect data often also include 

susceptibility and mechanistic data; targeted searches or cluster analyses 

enable identification of these data to support planned susceptibility factor 

evaluations and AOP/N analyses. (Colors depict data streams for each type of 

literature searched.)
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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DRAFT – November 2015 3-4

1 Following the screening by title and abstract, the full text of all epidemiologic and toxicology 

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studies identified was further reviewed to identify characteristics of the study design and the health 

effects reported in the study to determine if the study would inform the hazard identification for 

inorganic arsenic. All screening process results are captured in the publicly available HERO project 

page for inorganic arsenic.

12 

Risk-of-Bias Analysis 

Epidemiologic and toxicology studies considered relevant for hazard identification were

subject to risk-of-bias evaluations. Risk-of-bias evaluations assess some aspects of internal validity 

of study findings based on study design, conduct, and reporting. Risk-of-bias evaluations identify

potential issues associated with chance, bias, or confounding so these can be considered in hazard 

identification (see Section 3.2). The risk-of-bias evaluation should not be considered a checklist or 

inclusion/exclusion criteria but rather a way to characterize potential strengths and weaknesses of 

individual studies more transparently. Risk of bias for each study was evaluated using the questions 

and considerations proposed in the Office of Health Assessment and Translation (OHAT) approach 

(NTP, 2013). The OHAT approach was developed initially from clinical and animal toxicology 

experience and has not previously been extensively evaluated using epidemiologic studies. 

Application to the arsenic database helps evaluate the approach’s efficacy for application to

epidemiologic data. The OHAT approach will not necessarily be applied for other IRIS Toxicological 

Reviews, nor does this change necessarily signal a departure from current assessment approaches 

used for other NCEA products. Note that each study was evaluated in isolation; if clarification of a 

risk-of-bias issue is reported in another paper, this was not considered.

Individual studies were evaluated using series of questions regarding potential sources of 

bias (Table 3-1). Risk of bias was assessed for each study question using a four-point scale

developed by OHAT that includes ratings of definitely low bias, probably low bias, probably high 

bias, and definitely high bias (Table 3-2). The supporting rationale for each rating applied was 

documented by the reviewer. In cases where the rationale for one of the bias domains might differ 

for different health effects presented in one study, those differences were noted. Risk-of-bias 

evaluations necessarily require subjective conclusions by an expert scientist. Each study was

evaluated independently by two scientists who referred to the draft OHAT approach for systematic 

review (NTP, 2013) and arsenic-specific clarifications developed for each question. After 

independently reviewing a study, the two reviewers discussed differences and resolved any

discrepancies between their ratings and rationales. The same risk-of-bias questions were applied 

across all epidemiologic studies or animal toxicology studies using different rating guidelines and 

arsenic-specific clarifications for each discipline. The OHAT approach does not produce an “overall” 

risk-of-bias rating for each study, and no overall risk-of-bias ratings or other descriptors were 

developed for the arsenic studies at the study level. 

 

12 http://hero.epa.gov/index.cfm/project/page/project_id/2211. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 3-5

1 Table 3-1. Example risk-of-bias considerations 

Category Risk-of-bias questions1

Selection 1. Was administered dose or exposure level adequately randomized?

2. Was allocation to study groups adequately concealed?

3. Were the comparison groups appropriate?

4. Did the study design or analysis account for important confounding and modifying

variables?

5. Did researchers adjust or control for other exposures that are anticipated to bias results?

Performance 6. Were experimental conditions identical across study groups?

7. Did researchers adhere to the study protocol?

8. Were the research personnel and human subjects blinded to the study group during the

study?

Attrition 9. Were outcome data complete without attrition or exclusion from analysis?

Detection 10. Were the outcome assessors blinded to study group or exposure level?

11. Were confounding variables assessed consistently across groups using valid and reliable

measures?

12. Can we be confident in the exposure characterization?

13. Can we be confident in the outcome assessment?

Selective reporting 

bias

14. Were all measured outcomes reported?

Other 15. Were there no potential threats to internal validity (e.g., statistical methods were

appropriate)?

1 2 In consultation with OHAT, the wording of Questions 7, 9, and 15 included in the 2013 draft (NTP, 2013) was 

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changed so that answering “yes” would consistently indicate lower risk of bias, while answering “no” would 

indicate higher risk of bias.

Table 3-2. General risk-of-bias ratings

Rating Description

(++) Definitely low 

risk of bias

There is direct evidence of low risk-of-bias practices (direct evidence is an explicit 

statement(s), generally in the study report or through contacting the authors).

(+) Probably low 

risk of bias

There is indirect evidence of low risk-of-bias practices OR it is deemed by the risk-of-bias

evaluator that deviations from low risk-of-bias practices for these criteria during the study 

would not appreciably bias results, including consideration of direction and magnitude of 

bias (indirect evidence provides information to address the risk-of-bias question but falls 

short of direct evidence).

(-) Probably high 

risk of bias

There is indirect evidence of high risk-of-bias practices OR there is insufficient information 

provided about relevant risk-of-bias practices.

(- -) Definitely high 

risk of bias

There is direct evidence of high risk-of-bias practices (could include specific examples of 

relevant high risk-of-bias practices).
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 3-6

1 Evidence Tables

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All studies identified as potentially relevant for a specific endpoint, including key studies 

upon which hazard identification conclusions might be based and additional studies that might be 

used as supporting evidence as warranted, were included in the evidence tables. The hazard 

identification sections for each health outcome will further discuss strengths and weaknesses of 

studies included in the evidence tables. Evidence tables include information for comparing key 

features such as study design, exposure metrics, and dose-response information. In addition, EPA 

has searched for and specifically identified studies that partially or fully meet the following criteria 

NRC recommended: individual measures of arsenic exposure, measurements of arsenic that 

precede outcome, and low-to-moderate exposure to inorganic arsenic (≤100 μg/L drinking water). 

These latter studies will be specifically considered in the dose-response analysis, with the aim of 

better informing responses at lower doses. Although the studies that meet these criteria will be 

specifically evaluated, neither the hazard identification nor the dose-response analyses will be 

restricted to only studies meeting these criteria. This comprehensive approach is judged the best 

method for evaluating the full set of data available for this Toxicological Review. Adopting this 

approach does not necessarily signal a departure from current assessment approaches for other 

NCEA products.

3.2. Health Hazard Identification

For the hazard identification process for inorganic arsenic, the relevant evidence of health 

effects identified through the literature search will be summarized and then integrated as described

in the Cancer Guidelines (U.S. EPA, 2005) and the Integrated Science Assessments for lead and 

ozone (U.S. EPA, 2013a, b), as supported by NRC (2013). These documents describe the Agency’s 

process for integrating evidence and making judgments about causality for both cancer and 

noncancer endpoints. The process is depicted in Figure 3-3 and described in more detail in the 

following sections. Application of the Integrated Science Assessment framework for assessing 

causality to noncancer examinations within the IRIS Program is currently unique to arsenic.

28 

Assess 

Causality

Integrate information based on 

the modified Bradford Hill 

causality framework and 

consideration of the potential 

for chance, bias, and 

confounding in the overall 

database

Make Causality 

Determination

• Causal

• Likely to be causal

• Suggestive

• Inadequate

• Not likely to be

causal

Synthesize 

Evidence

Synthesize:

• Epidemiologic data

• Toxicological data

• Human mechanistic data

• Animal mechanistic data

Evaluate susceptibility factors 

and variability

Figure 3-3. Overview of hazard identification for arsenic. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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DRAFT – November 2015 3-7

1 Evidence Synthesis

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Epidemiologic studies, animal toxicology studies, 

and mechanistic studies can all inform the evaluation of

health effects associated with inorganic arsenic exposure. 

These studies will be synthesized in hazard identification 

sections. These sections are not intended to provide 

detailed summaries of individual studies but rather to

highlight the most informative evidence for considering 

causality. Hazard identification for inorganic arsenic will 

focus on studies conducted using relevant pollutant 

exposures. As NRC (2014) recommended, evidence will be 

integrated using expert judgment informed by the results 

of the risk-of-bias evaluations. Mechanistic data could provide additional information pertaining to 

causal determinations, human relevance of animal data, and insights into model choices for lowexposure extrapolation in the absence of observational data in the range of U.S. exposure levels. 

(Relevance to dose-response characterization is discussed below.) Evidence for susceptibility and 

population variability in responses also will be ascertained. Finally, the health effect synthesis 

sections will describe strengths and weaknesses in the available database and data gaps that limit

the utility of the available data to inform hazard identification. Adverse health effects under 

consideration are shown in Box 3-2. Other effects identified in the hazard identification process will 

also be considered.

Evaluate Adverse Outcome Pathway or Network Data for Hazard Identification

As NRC (2013) noted, mode of action analyses “permit the integration of data to advance 

understanding of the coherence, biological plausibility, and human relevance of findings throughout 

the exposure-response continuum, and provide a transparent means of synthesizing the data.” As 

part of the evidence synthesis for hazard identification, EPA will collect and analyze AOP/N

information for each health endpoint of significant concern. For this Toxicological Review, EPA 

plans to consider both disease- and chemical-specific information in building conceptual models of 

mechanisms and link initial molecular-initiating events to population-level responses, as feasible. In 

addition to influencing hazard identification, AOP/N analyses might inform the shape of the doseresponse curve beyond the range of the observational data. (See the description of dose-response 

model selection in Section 3.3 for more discussion.) The analyses also could be used to inform

susceptibility and variability features, integrate mechanistically related outcomes, and help 

evaluate multiple risk modifiers (e.g., preexisting disease backgrounds, differences in genetic 

susceptibilities, smoking, alcohol consumption, diet). EPA plans to follow the NRC-recommended 

steps for mechanistic analyses and the Organization for Economic Co-operation and Development 

guidance on AOP development (OECD, 2013), to the extent feasible; however, early analyses 

Box 3-2. Adverse Health 

Effects under Consideration

• Lung, skin, bladder, prostate, renal,

liver, and pancreatic cancer

• Cardiovascular disease

• Skin lesions

• Diabetes

• Nonmalignant respiratory disease

• Pregnancy outcomes

• Neurodevelopmental toxicity

• Immune effects

• Renal disease
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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DRAFT – November 2015 3-8

1 suggest that data might not be available to execute the NRC vision fully. Tables and diagrams will be 

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created in the AOP/N analysis section to summarize the available information considered during 

evaluation of underlying mechanisms for adverse effects. 

Evaluate Susceptibility Factors

Several factors could modify the association between exposure to inorganic arsenic and 

health outcomes among potentially susceptible populations. To identify susceptibility factors, the 

synthesis sections on health effects will evaluate the available evidence on factors such as life stage

and early-life exposures, intrinsic variability (e.g., genetic makeup), and influence of environmental 

factors using an evidence-of-susceptibility framework (see Chapter 5 in U.S. EPA (2013a) for 

additional discussion). The evaluation process will focus on studies identified through a literature 

search within the overall arsenic literature database. The susceptibility analysis will focus primarily 

on human susceptibility, and to a lesser extent on animal susceptibility. Similarly, mechanistic data 

might be used to inform the observations from human and animal data. 

The evaluation of susceptibility factors will focus primarily on studies with stratified 

analyses (i.e., epidemiologic) that compare populations or life stages exposed to similar inorganic 

arsenic concentrations within the same study design. Animal toxicology studies also might provide 

evidence of susceptibility factors that influence human responses to inorganic arsenic exposure as 

observed in epidemiologic studies. For instance, animal studies that examine developmental 

outcomes or use animal models with genetic polymorphisms can aid in understanding how life

stage or the presence of genetic polymorphisms affect response. These data, in turn, support 

assertions of coherence between toxicologic and epidemiologic findings and the biological

plausibility of the health effect. The results will be used to determine whether a particular factor 

alters the occurrence of effects from inorganic arsenic exposure and to inform the exposureoutcome relationship, as feasible. Tables will be created to summarize the available information 

considered during evaluation of potential populations of concern for the IRIS Toxicological Review 

of Inorganic Arsenic. 

Evidence Integration and Causal Determinations

The process of evidence integration and causal determinations will be based on information 

presented in the hazard identification synthesis (see Figure 3-3). Appendix A of this document 

provides more discussion, and additional information on the process of evidence integration is 

provided in the draft development materials for this Toxicological Review (U.S. EPA, 2014) and 

EPA’s guidelines for carcinogen risk assessment (U.S. EPA, 2005). Aspects of an association that 

suggest causality are drawn from Hill (1965), elaborated by Rothman and Greenland (1998), and 

referenced in other risk assessment documents (HHS, 2014; U.S. EPA, 2013a; IOM, 2008; IARC, 

2006; U.S. EPA, 2005; HHS, 2004). Additionally, recommendations from the NRC review (NRC, 

2014) influence this process.
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 3-9

1 3.3. Dose-response Analyses

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Dose-response analyses will be developed for cancer and noncancer health endpoints for 

which inorganic arsenic exposure is “causal” or “likely causal.” Consistent with NRC (2013)

recommendations, one focus of the dose-response analyses will be epidemiologic observations for 

exposures ranging from background levels in drinking water to 100 μg/L in drinking water, which 

would encompass exposures commonly found in the United States. (Background levels of exposure 

would result in concentrations of 1–5 μg/L or less in urine, summing inorganic, monomethyl, and 

dimethyl arsenic forms.) Other, higher exposure levels also will be considered informative. As noted

above, AOP/N information will be evaluated for the potential to inform dose-response analyses for 

endpoints that have inadequate epidemiologic data for characterizing dose-response at lower 

exposures. Additionally, AOP/N analyses could help characterize human variability and 

susceptibility. Variability and uncertainty will be characterized, including variability and 

uncertainty within and across models (and associated with model choices), among studies, and 

between individuals. 

Where appropriate, EPA will consider approaches for evaluating changes in continuous 

effects (e.g., impact on IQ or blood pressure) in addition to dichotomous endpoints (binary 

outcomes, such as whether cancer has occurred). Possible approaches include assessing potential 

changes in distributions compared to background distributions and estimating changes in incidence 

above clinical or other thresholds (e.g., changes in blood pressure that lead to hypertension). 

Outputs for cancer and noncancer evaluations will be equations describing the doseresponse relationships. Accompanying these equations will be tables and plots that express risks 

associated with various exposures (e.g., in ppm), doses (e.g., in mg/kg-day), or biomarker (e.g., 

urinary) levels of inorganic arsenic (e.g., exposures, doses, or concentrations associated with 

estimated lifetime cancer risk of 1 in one million, 1 in one hundred thousand, 1 in ten thousand). 

These risks will be presented with confidence bounds that account for identified sources of 

variability and uncertainty to the extent the data can support such analyses. 

Data Selection for Dose-response Analyses

For inorganic arsenic, dose-response analyses will be performed for health effects for which 

inorganic arsenic is determined “causal” or “likely causal.” These analyses likely will be performed 

using epidemiologic data. 

Meta-analyses that use data from multiple studies will be performed if at least three studies 

are available having exposures corresponding to intakes of drinking water with inorganic arsenic

concentrations less than or equal to 100 μg/L (or comparable equivalent) and exposure metrics 

that are suitable for combined analyses. In addition, other studies that do not meet these criteria 

but contribute to our understanding of potential health effects and exposure-response relationships

will be analyzed, including data with “sufficient” or “adequate” evidence of susceptibility. These 

dose-response analyses will inform the potential dose-response differences in susceptible 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 3-10

1 populations. Other factors influencing selection of studies for dose-response analyses of individual 

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studies and meta-analyses include elements that potentially bias study results (e.g., methods of 

endpoint evaluation, controlling for confounders, studies with and without individual data, 

exposure misclassification). 

Although an exposure assessment is beyond the scope of the Toxicological Review, aspects 

of exposure characterization are relevant to the use of such data in dose-response analyses. For 

estimating total daily exposure, NRC indicated that delineation of exposure sources (i.e., drinking 

water, diet, air) should be characterized, preferably using probabilistic approaches (NRC, 2013). In 

response to this recommendation, EPA will qualitatively and, where possible, quantitatively 

delineate between sources of exposure and consider information provided by biomarkers of 

exposure. Studies conducted on U.S. populations and other populations (e.g., Taiwanese, 

Bangladeshi) will be evaluated for hazard identification and a determination made on whether an 

adjustment in estimated dose-response behavior in the U.S. population is warranted. 

A critical aspect of exposure pathway considerations is capability to estimate intake or 

internal dose, or both, based on available data. EPA will evaluate the feasibility for qualitative and 

quantitative analyses based on the available data and physiologically based pharmacokinetic 

model(s). 

EPA also will consider exposure uncertainty in collecting data for dose-response analyses. 

For example, studies might report arsenic concentrations for a particular route of exposure (e.g., 

drinking water), but not consider contribution from other sources such as dietary or inhalation 

exposure; or studies might report arsenic exposure concentrations from a particular source (e.g., a 

community water supply) rather than individual exposure levels. Furthermore, these source 

concentrations might be estimated from samples taken over a limited period or a single time point 

and extrapolated to lifetime exposures. Therefore, studies with exposure data for individuals are 

assumed to introduce less uncertainty to associations between health effects and inorganic arsenic. 

To complement the conceptual model described in this document and to inform hazard 

identification and dose-response analyses, EPA will evaluate arsenic exposures and exposure 

pathway considerations. Based on NRC’s recommendation, urinary arsenic concentrations of 1–5 

μg/L (summing inorganic, monomethyl, and dimethyl arsenic forms) will be assumed a reasonable 

estimate of background for the U.S. population. If necessary, descriptions of background might be 

generated for non-U.S. populations, based on available data. Supplementary materials for exposure 

pathway considerations will include: 

• evaluation of the applicability of a physiologically based pharmacokinetic model(s) to

estimate biomarkers of exposures such as inorganic arsenic or its metabolite levels in

urine;

• use of physiologically based pharmacokinetic model(s) for the forward estimation of

biomarkers of exposures (e.g., urine levels) and reverse calculations of total ingested

inorganic arsenic levels related to risk-estimated biomarkers; and
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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DRAFT – November 2015 3-11

1 • consideration of dosimetry and pharmacokinetic issues concerning analyses of

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developmental effects. 

If the AOP/N analysis suggests a direct and quantifiable relationship between a key event 

and an adverse outcome, the key event could be selected for dose-response analyses. Otherwise, 

human or animal toxicology or in vitro data might provide a mechanistic understanding and 

interpretation of low-dose effects observed in epidemiologic studies. Specifically, these data could

be used to inform variability and uncertainty in the dose-response analysis and selection of doseresponse modeling approaches.

Variability and Uncertainty in Dose-response Analyses

Variability and uncertainty are important components of risk characterization. Variability 

represents the diversity or heterogeneity of a factor that can influence the response within an 

individual or across a population. Uncertainty represents unavailable or incomplete information on 

a specific variable that can influence the analyses. Regarding variability, many factors are 

instrumental in determining an individual’s risk from exposure, including concurrent background 

exposures to other chemicals and the individual’s biological susceptibility due to genetic, lifestyle, 

health, and other factors. In turn, population responses to chemical exposures depend on the 

distribution of these varying individual determinants in the population. The IRIS Toxicological 

Review of Inorganic Arsenic will use observational and mechanistic data, as feasible, to inform the 

variability and uncertainty characterizations. In addition, EPA will develop sensitivity analyses for 

life stage and potentially other factors that influence dose-response analyses for inorganic arsenic. 

Dose-response Modeling Approaches

Dose-response analyses will be performed on endpoints for which inorganic arsenic is 

determined “causal” or “likely causal.” NRC and others have recommended using approaches that 

result in a probabilistic characterization of risk as a function of dose, while incorporating issues of

susceptibility. The use of probabilistic approaches to incorporate information on uncertainty and 

variability into the derivation of human health toxicity values for cancer and noncancer endpoints 

will lead to an improved use of the available scientific information and promotion of research to 

characterize these factors. The approaches used in the IRIS Toxicological Review of Inorganic Arsenic

are specific to inorganic arsenic at this time; adopting such an approach does not necessarily signal 

a change from current assessment approaches for other NCEA products.

The general approach EPA plans to take for this Toxicological Review is described as three 

tiers of increasing complexity: Tier 1 represents a standard approach to be applied to most

endpoints, and Tiers 2 and 3 represent methods to be applied if warranted for selected endpoints. 

Generally, Tier 1 dose-response will be restricted to a relatively small set of simple models, 

and risk estimates will be derived based on the units of exposure or intake the authors report. No 

attempts will be made to incorporate multiple sources of arsenic or to compare studies based on 

different dose metrics. Outputs of Tier 1 analyses could include estimates of low-dose points of 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

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DRAFT – November 2015 3-12

1 departure (such as benchmark doses and lower limits of benchmark doses) that have been used in 

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EPA’s traditional approach for deriving cancer slope factors and noncancer reference doses. A goal 

of Tier 1 is to help generate screening-level risk estimates to support approximate comparisons of 

risk across studies, and to guide the selection of data sets for higher-tier analyses. 

As illustrated in Table 3-3, Tiers 2 and 3 differ from the more simplified Tier 1 analyses 

regarding the types of study data analyzed (individual instead of grouped data), the numbers of 

studies evaluated (the higher tiers accommodate pooled and meta-analyses where feasible), and 

dosimetric methods to be employed. Also, the range of model forms is wider in Tiers 2 and 3, which 

both incorporate model averaging where feasible. The higher tiers also will use more advanced 

approaches, including explicitly probabilistic models, to evaluate uncertainty and variability in 

dose-response. Bayesian analyses of single data sets, or meta-regression based on data from 

multiple studies, might be used to derive fully probabilistic risk estimates in either Tier 2 or Tier 3. 

A distinguishing feature of a Tier 3 approach is application of Bayesian (Markov Chain Monte Carlo) 

approaches to generate distributional outputs based on the data and the assumed prior 

probabilities for models and distributions of model parameters. Depending on data availability, EPA 

might also use empirical data or physiologically based pharmacokinetic models to compare studies 

that present risks as a function of exposure with those that present risks versus biomarkers, such as 

urinary arsenic. The range of model forms also is more extensive in the higher tiers, with 

approaches “fine-tuned” to specific data sets as appropriate. As feasible, mechanistic data will 

inform model selection and evaluation in the higher tiers. 

Extrapolation for Dose-response Analyses

NRC recommended using observed data to characterize dose-response relationships. They 

also recommended limited extrapolation, to within an order of magnitude of observed data, using 

the modeled shape of the dose-response relationship to provide data-informed estimates of the 

potential dose-response relationship below the range of observation. Model choices will allow for 

nonlinear or threshold phenomena, as supported by the data. NRC further recommended 

characterizing dose-response relationships down to (but not necessarily at exposures below) 

background levels, which they estimated to be 1–5 μg/L inorganic arsenic in urine for U.S.

populations. NRC indicated that the risks below background concentrations should be 

characterized to the extent feasible but also assumed the needs of risk assessors would be met if 

risk can be characterized down to background concentrations. Extrapolations in the Toxicological 

Review will be informed by these recommendations. As feasible, EPA will consider statistical 

methods and measures such as confidence or prediction limits that might help develop these 

extrapolations; details will be provided in the supplementary materials for EPA’s dose-response 

analyses. Biological considerations also will inform model choice and extrapolation, as feasible. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 3-13

1 Table 3-3. Summary of proposed inorganic arsenic dose-response analysis 

2 tiers

Dose-Response 

Element Approach Tier 1 Tier 2 Tier 3

Type of study data Grouped exposure or outcome, or both   

Individual exposure, outcome, covariates  

Number of studies 

evaluated

One at a time   

Multiple studies (meta-analysis and similar)  

Dosimetry Exposure or intake metrics as reported by authors 

Intake metrics including exposures from multiple sources  

Biomarker data   

Intraconversion of intake/biomarker metrics based on 

empirical data, physiologically based pharmacokinetic models

 

Dose-Response 

Model Forms

Standard parametric models (Poisson regression, 

benchmark-dose type models, etc.) 



Complex parametric and nonparametric models (random 

effects, etc.)

 

Dose-Response 

Modeling Methods

Conventional (primarily maximum likelihood estimate)  

Bayesian (Markov Chain Monte Carlo) 

Model averaging  

Output Risk Metrics Points of departure, reference doses, low-dose slope factors, 

or equivalent



Model-based risk estimates  

Fully probabilistic risk estimates 

Uncertainty and

Variability Analyses

Primarily qualitative, evaluation of risk differences across 

models, studies



Risk for subpopulations based on quantitative estimates of 

sensitivity (absorption, distribution, metabolism, excretion, 

etc.) 

 

Probabilistic modeling of exposure, pharmacokinetic, and 

prior distribution uncertainty as supported by data



Low-Dose 

Extrapolation

Within range of study data only 

Statistical confidence limits on predicted risks  

Quantitative consideration of adverse outcome pathway

information, individual variability 


Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 4-1

1 4. REFERENCES 

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HHS (U.S. Department of Health and Human Services). (2004). The health consequences of smoking: 

A report of the Surgeon General. Washington, DC. 

http://www.cdc.gov/tobacco/data_statistics/sgr/2004/complete_report/index.htm. 

HHS (U.S. Department of Health and Human Services). (2014). The health consequences of 

smoking—50 years of progress: a report of the surgeon general. In Reports of the Surgeon 

General. Atlanta (GA): Centers for Disease Control and Prevention (US).

Hill, AB. (1965). The environment and disease: Association or causation? Proc R Soc Med 58: 295-

300. 

IARC (International Agency for Research on Cancer). (2006). Preamble to the IARC monographs. 

Lyon, France. http://monographs.iarc.fr/ENG/Preamble/. 

IOM (Institute of Medicine). (2008). Improving the presumptive disability decision-making process 

for veterans. In JM Samet; CC Bodurow (Eds.). Washington, DC: National Academies Press. 

http://www.nap.edu/openbook.php?record_id=11908. 

NRC (National Research Council). (1999). Arsenic in drinking water. Washington, DC: National 

Academy Press. http://www.nap.edu/catalog/6444.html. 

NRC (National Research Council). (2009). Science and decisions: Advancing risk assessment. 

Washington, DC: National Academies Press. http://www.nap.edu/catalog/12209.html. 

NRC (National Research Council). (2011). Review of the Environmental Protection Agency's draft 

IRIS assessment of formaldehyde. Washington, DC: National Academies Press. 

http://www.nap.edu/catalog/13142.html. 

NRC (National Research Council). (2013). Critical aspects of EPA's IRIS assessment of inorganic 

arsenic: Interim report. Washington, D.C: The National Academies Press.

NRC (National Research Council). (2014). Review of EPA's Integrated Risk Information System 

(IRIS) process. Washington, DC: The National Academies Press. 

http://www.nap.edu/catalog.php?record_id=18764. 

NTP (National Toxicology Program). (2013). Draft OHAT approach for systematic review and 

evidence integration for literature-based health assessments – February 2013. National 

Institute of Environmental Health Sciences, National Institutes of Health. 

http://ntp.niehs.nih.gov/ntp/ohat/evaluationprocess/draftohatapproach_february2013.pd

f. 

OECD (Organisation for Economic Co-operation and Development). (2013). Guidance document on 

developing and assessing adverse outcome pathways. (ENV/JM/MONO(2013)6). Paris, FR: 

Organisation for Economic Co-operations and Development. 

http://search.oecd.org/officialdocuments/displaydocumentpdf/?cote=env/jm/mono(2013

)6&doclanguage=en. 

Rothman, KJ; Greenland, S. (1998). Modern epidemiology (2nd ed.). Philadelphia, PA: Lippincott, 

Williams, & Wilkins. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

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1 SAB (Science Advisory Board). (2007). Advisory on EPA’s assessments of carcinogenic effects of 

2 

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organic and inorganic arsenic: A report of the US EPA Science Advisory Board. (EPA-SAB07-008). Washington, D.C.: U.S. Environmental Protection Agency. 

http://cfpub.epa.gov/ncea/iris_drafts/recordisplay.cfm?deid=219111. 

SAB (Science Advisory Board). (2011). Review Comments on EPA’s Responsiveness to SAB 2007 

Recommendations for the Revision of Cancer Assessment of Inorganic Arsenic. (EPA-SAB11-003). Washington, D.C.: U.S. Environmental Protection Agency. 

http://yosemite.epa.gov/sab/sabproduct.nsf/9FCEE4E20ABD6EB48525784600791AC2/$

File/EPA-SAB-11-003-unsigned.pdf. 

U.S. Congress. (2011). Consolidated Appropriations Act, 2012. (Pub. L. No. 112-74; 125 STAT. 786). 

112th U.S. Congress. http://www.gpo.gov/fdsys/pkg/PLAW-112publ74/pdf/PLAW112publ74.pdf. 

U.S. EPA (U.S. Environmental Protection Agency). (2005). Guidelines for carcinogen risk 

assessment. (EPA/630/P-03/001F). Washington, DC: U.S. Environmental Protection 

Agency, Risk Assessment Forum. http://www.epa.gov/cancerguidelines/. 

U.S. EPA (U.S. Environmental Protection Agency). (2010). IRIS Toxicological review of inorganic 

arsenic (cancer) - external review draft. (EPA/635/R-10/001). Washington, DC. 

http://cfpub.epa.gov/ncea/iris_drafts/recordisplay.cfm?deid=219111. 

U.S. EPA (U.S. Environmental Protection Agency). (2013a). Integrated science assessment for lead 

[EPA Report]. (EPA/600/R-10/075F). Research Triangle Park, NC. 

http://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=514513. 

U.S. EPA (U.S. Environmental Protection Agency). (2013b). Integrated science assessment for ozone 

and related photochemical oxidants. (EPA/600/R-10/076F). Research Triangle Park, NC: 

U.S. Environmental Protection Agency, National Center for Environmental Assessment. 

http://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=247492. 

U.S. EPA (U.S. Environmental Protection Agency). (2013c). Integrated science assessment for ozone 

and related photochemical oxidants (final report) [EPA Report]. (EPA/600/R-10/076F). 

Washington, DC: U.S. Environmental Protection Agency, National Center for Environmental 

Assessment. http://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=247492. 

U.S. EPA. (2014). Draft development materials for the Integrated Risk Information System (IRIS) 

toxicological review of inorganic arsenic. (EPA/630/R-14/101). Washington, D.C.: Office of 

Research and Development, Biomonthly Public Meeting: June 2014. 

http://www.epa.gov/iris/publicmeeting/iris_bimonthly-jun2014/iApreliminary_draft_materials.pdf. 

Villeneuve, PJ; Weichenthal, SA; Crouse, D; Miller, AB; To, T; Martin, RV; van Donkelaar, A; Wall, C; 

Burnett, RT. (2015). Long-term exposure to fine particulate matter air pollution and 

mortality among Canadian women. Epidemiology 26: 536-545. 

http://dx.doi.org/10.1097/EDE.0000000000000294. 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

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1 Appendix A. Evidence Integration

2 The Evidence-Integration Process

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The objective of hazard identification is to answer systematic review questions of the form: 

“What does the evidence indicate about the relationship between [the agent] and [a specific health 

outcome] in humans?” Evidence integration is a process that answers such questions by combining 

inferences from different lines of evidence: human, animal, and mechanistic. IRIS assessments 

integrate evidence through a structured process that involves scientific judgment.

The evidence-integration process considers the human and animal evidence and then 

evaluates whether the animal evidence supports, does not support, or is irrelevant to a conclusion 

of a health hazard to humans. Mechanistic evidence, if available, can have two distinct uses in 

hazard identification: to evaluate the relevance of animal evidence to humans or to augment the 

evidence in humans or animals by establishing the occurrence of precursor events that are 

attributable to the agent.

State-of-the-art approaches to evidence integration apply a standardized approach for 

grading the strength of the evidence and use clear and consistent summative language (NRC, 2011). 

As the IRIS Program evaluates multiple health outcomes of many chemical agents, the terms used in 

these conclusions should be consistent across health outcomes. The goal is clear and consistent 

communication of hazard conclusions, maintaining the rigor and transparency that systematic 

review brings to the early steps of an assessment.

Aligning Different Lines of Evidence

In IRIS assessments, each major class of health outcome (e.g., cancer, reproductive toxicity, 

neurotoxicity, respiratory-tract toxicity, liver toxicity) can be the subject of a separate exercise in 

evidence integration. In practice, drawing inferences at a finer level of specificity of effect (e.g., 

learning and memory, pregnancy outcomes) and then using these inferences to draw conclusions 

about the major health outcomes often makes sense. Human studies often enable the synthesis of 

evidence for specific health outcomes (e.g., separately for breast cancer and colorectal cancer, or for 

fetal cardiac defects and low birth weight).

The question of site concordance between animal species or between animals and humans, 

however, complicates the process of evidence integration. For example, liver tumors in one animal 

species can be predictive of carcinogenic potential in other species, but not necessarily in the liver. 

Similarly, malformations at one anatomical site in animals suggest the potential for developmental 

toxicity that could appear in another form in humans. In such cases, site-specific human inferences 

would be integrated with animal inferences across multiple sites (e.g., cancer observed at any site 

in animals overall could support an inference of breast cancer observed in humans). Even so, for 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 A-2

1 some health outcomes, toxicological understanding might be sufficient to justify the integration of 

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human and animal evidence at a site-specific level.

A similar complication can arise if the human and animal studies investigate related agents. 

For example, human studies could involve exposure only to mixtures of related compounds, while 

the animal and mechanistic studies investigate the compounds individually. In this case, mixturerelated human findings would be integrated with compound-specific animal and mechanistic 

findings (e.g., adverse effects observed in animals for nickel sulfate and nickel oxide could support 

an inference in humans for nickel compounds overall).

Synergy can occur through the synthesis of inferences from different disciplines. Initial 

views of one type of evidence can change when other lines of evidence are considered. For example:

• When the human evidence has alternative explanations, animal or mechanistic evidence 

can strengthen or diminish the plausibility of some explanations of the human evidence.

• When uncertainty exists as to whether a response in animals or humans is dose related, 

information on the occurrence of precursor events can add to or subtract from the 

plausibility of the response.

• When the animal response is strong, evidence establishing that the mechanisms 

underlying the animal response does not operate in humans can support the view that 

the animal response is irrelevant to humans. In this case, the animal response provides 

neither an argument for nor an argument against a conclusion of hazard to humans.

• Similarly, when general knowledge in the field indicates that animals are not a suitable 

model for a specific human disease (e.g., no animal model is accepted for human 

prostate cancer), the animal evidence is irrelevant and provides neither an argument 

for, nor an argument against, a conclusion of hazard to humans (e.g., negative results for 

prostate cancer in animals is not an argument against the possibility of prostate cancer 

in humans).

• When the evidence across different animal species or human populations seems 

inconsistent, evidence that different mechanisms or metabolites operate in different 

species can provide coherence to the overall results (e.g., evidence showing that positive 

results occur in, and only in, species that form a particular metabolite can explain a mix 

of positive and null results in different species).

The Evidence-Integration Narrative

The evidence-integration narrative presents the reasoning behind the evidence-integration 

process. The evidence-integration narrative assembles the major findings from human studies, 

animal studies, and mechanistic studies for each major class of health outcome. The evidenceintegration narrative: 

• presents the conclusions from each line of evidence, 

• explains the reasoning that led to these conclusions, 
Assessment Development Plan for the IRIS Toxicological Review of Inorganic Arsenic

This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT – November 2015 A-3

1 • cites the studies that were pivotal to these conclusions, 

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• identifies the key issues and how they were resolved, and

• integrates all lines of evidence to characterize the agent’s association with each health 

outcome. 

The evidence-integration narrative should cite the major items of evidence that argue for a 

hazard within each evidence stream versus the major items of evidence that argue against the 

hazard. Subsequent discussion should attempt to resolve apparent inconsistencies; finding 

coherence across results would increase confidence in the overall conclusion. For example, a mix of 

positive (i.e., increased incidence of endpoint) and null (i.e., no increased incidence of endpoint) 

could result from differences in internal dose of a key metabolite. Conversely, unexplained 

inconsistency would indicate gaps in knowledge.