EPA/6 30/R

- 14/101 November 2015 www.epa.gov/iris



## Assessment Development Plan **for the Integrated Risk Information System (IRIS)**  **Toxicological Review of Inorganic A**  **rsenic**

[CASRN 7440

- 38

- 2]

**November 201**  **5**
**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 **Disclaimer** 

### 1
2 3 4 5 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 sh o ul d 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 

# C ONTENTS

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 Inorgan ic 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 Engage ment

........................................................................ 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 Var i ability 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-1Assessment 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 iv 

# 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 Inorg anic 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


# B OXES

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

......................................................................................... 3-7Assessment 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 v 

### 1 

# PREFACE 2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 For the Integrated Risk Information System (IRIS) Program, the National Center for Enviro nmental Assessment (NCEA) at the U.S. Environmental Protection Agency (EPA) is dev elo ping a state

- of

- the

- sci e nce Toxicological Review of Inorganic Arsenic . The approaches NCEA is applying to assess the h azard and dose

- response of inorganic arsenic, and the associated uncertainty, are based on evolving practices in the IRIS Program and are gui d ed by National Research Council recommendations ( 201 4 , 2013 , 2011 , 2009 ). Many of these approaches have yet to be used extensively in environmental health assessment. I norganic arsenic provides an opportunity to explore these approaches b ecaus e n umerous human observational studies of environmental exposures are avai l able

. IRIS Toxicological Reviews are incorporating several new elements as part of thi s e volving process : comprehensive problem formulation and planning involving stakeholders, specific questions to guide risk

- of

- b i as evaluations , and explicit quantitative consideration of sensitive subpopulation risks and risk modifiers . The r ev iews also integrate thorough analys es of adverse outcome pathway s and network s to infor m causal determinations and dose

- response model choices , Bay e sian regression meta

- analyses of studies to examine dose

response, and Bayesian analyses of uncertainties. The results of these evaluations will enable EPA to refine these new approaches and cons ider t heir utility for application to other types of
assessment s . Of no t e 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 To x icological Review of Inorganic Arsenic doe s n ot 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. DRAFT – November 2015 vi 

### 1

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 

# 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

- sci e nce Toxicological Review of Inorganic Arsenic

. Thi s Assessment Development Plan presents an o ve rview of the types of scientific information and technical approaches EPA will consider when developing the draft Toxicological Review . Additional supporting material s are avai lab le on the IRIS inorganic arsenic webpage

. 1 The scientific information considered and the appro aches proposed were informed by the National Research Council’s ( NRC , 2 013 ) 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 active ly particip ated in the scoping and planning for the T o xicological Review and in the review of draft preliminary materials

. Based on their recommendations, the Toxicological R evi ew will examine the cancer and noncancer effects from oral, inhalation, and pote n t ially dermal exposure to inorganic arsenic . Adverse outcome p athw ay a nd n etwork analyses and susceptible populations also will be considered, as feasible. The k ey messages in this Assessment Development Plan are:

• T he IRIS To x icological Review for arsenic will evaluate the efficacy of several NRC

recommended innovations

. Based o n these evaluations , approaches will be refined and their utility for bro a der application determined. A pproaches ultimately used in the Toxicological Review of Inorganic Arsenic do n o t necessarily signal a change from current assessment approaches used for o ther NCEA products.

• This plan represents the fruition of an extensive pr ob lem formulation and planning effort with su bs tantial NRC and stakeholder involvement

.

• A f ormal, systemati c r e view of the literature has been conducted , informed by the National Toxicology Program’s (NTP) Office of Health Assessment and Translation approach . R e su l ts should not be interpreted as a checklist to exclude or include studies automatically, but r a the r as an investigation of one approach to literature evaluation

.

• For hazard identification , t he To xicological Review will, as feasible :

° Consider a ll e ndpoints identified by NRC (2013) in their Interim Report

.
° Identify s usce ptible 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

.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 vii ° Develop a dve rse outcome pathway or n etwork analyses for e ndpoints considered to 

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 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 stu di es considered for hazard identification and dose

- res p onse in e vidence tables

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

.

• Fo r dose

- re sp onse analyses , the following will be completed , as warranted and feasible:

° Estimat e n o ncancer and cancer risks for causal or likely causal endpoints , including risk

- specific doses

.
° Consider n on -U

. S. and U .S. information on dietary contributions to total exposure and use available data and pharmacokinetic models to characterize urinary biom arkers of exposure compared to exposure.

° Explicitly consider o bs er vati onal data at U .S. exposure levels down to background exposure (total urinary arsenic ~ 1

– 5 μg/L ).

° Evaluate s usc e ptible subpopulations and risk modifiers (such as different phenotypes and smok e rs)

.
° Apply v ar io us dose

- response model s and present the results

.
° Conduct m eta

- a n alyses of epidemiologic data

.
° Use adverse outcome pathway or network analyses , a nd human variability and susceptibility data, t o i nform e xtrapolat ions below the observed range of dose

response
.
° Possibly conduct additional adver se outcome pathway or network analyses for a subset of c ausal an d likely causal endpoints for which dose

- response models significantly diverge in the low

- dos e r ange.

° Conduct Bay es ian analyses to acco unt for prior information and characterize uncertainties mor e fully (e.g. , stud y selection, model choice).

° Treat m or e compl ex analyses as limited in application (e.g. , subset of endpoints) or
as illustrative only , dep en ding on outcomes

.

• EPA will continue to take advantage of opportunities to engage Agency Program and Reg i onal Offices, other federal agencies, the Ex e cutive 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. DRAFT – November 2015 1-1 

# 1. BACKGROUND 1

2 3 This section summarizes major activities completed since public ation of the 1988 IRIS Toxicological Revie w of Inorga n ic 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 re view 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 (Jan uary ): EPA held a public scoping and problem formulation meeting for development of a n ew IRIS Toxicological Review of Inorganic Arsenic

.


### • 2013 (Mar ch

– July): EPA held eight science issues public webinars.



### • 2013 (May): EPA submitted a draft Assessment Development Plan and p reliminary assessment materials to NRC for review.



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

Inorganic Arsenic and provided recommendations; NRC support ed 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.



## 1.1. **Previous EPA Assessments o f**  **Inorganic A rsenic**  **and NRC** 4 5 6 7 8 9 10 

## Evaluations EPA completed and published a final IRIS Health Hazard Assessment for Inorganic Arsenic in 1988 ( see Box 1-1 ) . In 1 996, EPA asked NRC to evaluate the inorganic arsenic database and recommend revis i ons to the 1 9 88 Health Hazard Assessment . In response, NRC published Arsenic in Drinking Water ( NRC, 199 9 ) and a n update in 2001

. In 2003, EPA began incorporating recommendations from the 1999 and 2001 NRC reports into a new, draft IRIS Toxicological ReviewAssessment 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 1-2 of I norganic A rsenic

. EPA also divided the Toxicological Review to focus on cancer outcomes and 

### 1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16 17

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 noncancer outcomes separately . In 2005, EPA released a draft IRIS Toxicological Review of Inorganic Ar senic of cancer health effects following oral exposure and req uested comment s from the public and review by EPA’s Science Advisory Board (SAB). T he 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 i n 2010 ( U.S. EPA, 2010 ) . T he SAB provided their comments and recommendations the following year ( SAB, 2011 )

. 

## 1.2. **Congressional Directive**  **for EPA Toxicological Review of Inorganic**  **A rsenic** 

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 two

phase review of the To x icological Review , considering both cancer and noncancer hazards from oral exposure to inorganic arsenic

. For t h e first phase, NRC was directed to review the scope and key science issues and pr o vide recommendations to EPA for developing a draft Toxicological Review. For the s e cond 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 A rsenic

NRC conducted t he first phase of its review between July 2012 and November 2013. A special committee conven e d by the NRC collected and reviewed information on hazard identification and dose

- respo n se analysis of inorganic arsenic during an NRC

- sponsored workshop in April 2013

. 3 T he committee evaluated and comment ed on draft materials that EPA provided related to the ongoing IRIS Toxicological Review , includ ing planning and scoping documents , reports from workshops EPA condu ct ed , and a draft plan for completi on . That draft plan, a predecessor to this A ssessme n t D evelopment P lan, described EPA’s proposed technical approaches for literature searches and ev aluati o n, hazard identification, and dose

- response and uncertainty analyses

. NRC presented t he re s ults of the first phase of its review in the 2013 Interim R eport , Critical Aspects of EPA’s IRIS Assessment of Inorganic Arseni c ( NRC, 2013 )

. Th e report comments on key aspects of inorganic arsenic toxicolo gy and provides specific recommendations to EPA for conducting the IRIS Toxico l ogical Review

. The NRC stated that the scoping materials submitted for review clearly demonstrated that EPA is incorporating previous NRC recommendations ( NRC, 2 0 11 , 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/inorgani c- arsenic

- workshop

.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 1-3 NRC observed that the draft approach for search ing and evaluati ng the literature likely would 

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 capture the salient informatio n 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

. 4 NRC acknowledged that the outlined approaches to incorporate systematic review in EPA’s plan also reflect NRC recommendations ( NRC, 2 0 11 , 2009 )

. For hazard identification, EPA proposed evaluating the relationship between inorganic arsen ic exposure and human health effects using a causal determination framework as pre v iously des cribed ( U.S. EPA, 2013a , c , 2005 )

. NRC support ed this approach a s well as the proposal to consider animal and mechanistic data as supporting evidence for d eterminin g causality. NRC prioritized spe c ific health endpoints to evaluate for hazard identification (see Box 1-2 ) and stated that EPA will refine these categ o rizations after it conducts a more comprehensive analysis. They a l so supported EPA’s use of evidence tables to present information and s tres s ed th e importance of explaining causal determination judgments in the synthesis text. N RC s up ported EPA’s proposal to perform AOP/ N analy s es on health endpoints considered “causal” or “likely causal.” They reco m mended consider ing “sug g estive” endpoints for AOP/ N development to info r m causal determination. The committee agreed w i th EPA’s proposal to conduc t dose

response analysis for “causa l ” or “likely causal” relationships even if a n AOP/ N cannot be determined

. The AOP/ N pro ce ss “ will be used to organize mechanistic information to d et ermine how mechanistic information supports low

- dose ex t rapolation 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 ad verse 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 mo ving 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, a n 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 AOP s related to the same disease , and which more broadly capture underlying events , are termed a dverse o utcome n et works (AONs). 

### Box **1-2**

**. Hierarchy of Health**  **End p**  **oints of Concern for Inorganic Arsenic**  Tier 1: Evidence of a causal association determined by other agencies or in published syste matic 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) (R eproduced from NRC 2013 )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 1-4 uncertainty associated with susceptibility ” ( NRC, 2013 ). Applications of AO P/ N analyses are 

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

21 22 23 24 25 26 27 28 29 discussed in S ection 3

. NRC m ade se v eral recommendations for the dose

- response analysis. They stated that EPA should develop risk estimates across the array of health effects having adeq u ate epidemiologic evidence. They r e commended performing the analyses with data in the range of epidemiologic observations. Whe n th o se data are not available, they recommended using AOP /N analyses to inform dose

- resp o nse model choice s when extrapolating below the range of observ ed data . T hey cautioned , how ev er, that extrapolations become increasingly uncertain the farther below th e observed range they are made

. They also stated ( 1) extrapolations should be limited to within an order of magnitude; and ( 2) a l though they do not assume that background concentrations are with or without health effects, asse s sing health risk could be facilitated by characterizing dose

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

- speci f ic doses, which would facilitate subsequent eff o rts to evaluate cumulative risk, conduct risk

- benefit evaluations, an d pe r form comparative analyses. NRC agreed with EPA’s proposal to use probabilistic approaches when consi d er ing variability and u ncertainty associated with susceptibility factors. Susceptibility due to preexisting disease, early

- life exp o sure, and sex diff erences in metabolism were among several factors NRC recommended for consideration. Based on avai lab le evidence, the committee suggested considering whether dose

- resp o nse analyses should focus on the population as a whole or involve separate approaches for the g en eral 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 I norganic A rsenic for public review. Materials included an updated Toxi co logical Review D evelopment P lan, 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

su sceptibility. EPA so l i cited p ublic i nput on these preliminary materials , and comments received are available in the inorganic arsenic docket (EPA

- HQ

- ORD

- 2012

- 0830 5 )

. EPA also invited the public to make presentations on key science issues at a public science meeting 6 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

This document is a draft for review purposes only and does not constitute Agency policy. DRAFT – November 2015 2-1 

# 2. KEY CHARACTERISTICS OF THE ASSESSMENT DEVELOP MENT PLAN 1

2

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.



### • I ncluded in this Assessment Development Plan is an analysis plan for hazard identification and

dose

- response assessment.



## 2.1. **Goal s**  **of the Assessment Development Plan** 4 5 6 7 8 9 10

11 12 13 14 15 16 17 The goal s for the Assessment Development Plan are to highlight the basic considerations and potential approaches to be used in th e IRIS Toxicologic al Review of Inorganic Arsenic , communicate EPA’s intentions regar d ing these to stakeholders , and facilitate discussion on these topics

. Th e Assess m ent Development Plan reflects the problem formulation and planning efforts EPA has completed to date

. Th i s plan and other materials are available on the IRIS inorganic arsenic webpage

. 7


## 2.2. **Agency Partner s**  **and Public Stakeholder Engagement** EPA is committed to engaging EPA Program and Regional O ffices , other federal agencies, the Executive Office of the President, and public stakeholders throughout the development of this Toxicological Review

. Agency p a rtners and public stakeholders (e.g., nongovernmental organizations, indus t ry groups, citizens, academia) have been active participants in planning and scoping meetings, identifying their needs for the IRIS Toxicological Review of Inorganic Arsenic , and makin g scientific recommendations. Of note is tha t 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

This document is a draft for review purposes only and does not constitute Agency policy. DRAFT – November 2015 2-2 Arsenic is coordinated with ongoing assessments of food

- related risks conducted by the U.S. Food 

### 1 2

3 4 5 6

7 8 9 10 11 12 13 14

15 16 17 18 19 20 21 and Drug Administration

. 

## 2.3. **Transparency**
EPA is committed to making certain the Toxicological Review proceeds transparent ly

. Preliminary m at er ials being used to develop the Toxicological Review are available to the public on the I RIS inorganic arsenic webpage 8 and the HERO project page for inorganic arsenic

. 9


## 2.4. **Timeline for Completion** 
The comments received at the June 2014 IRIS Public Science Meeting and the plan described here in form th e development of the draft Toxicological Review . Th e draft Toxicological Review will undergo internal EPA review , r ev iew by other federal agencies , and the Executive Office of the President . I t will be made publicly available for comment b efore it is released for external peer revie w , which NRC will perform

. Following revisions and additional review by EPA, other f ederal Agencies , an d the Executive Office of the President , EPA anticipates posting the final IRIS T

ox icological R eview of Inorganic Arsenic to the IRIS database in 2017.


## 2.5. **Overall C onceptual**  **M odel**  The conceptual model EPA has developed for the Toxicological Review is illustrated in Figure 2 -1

. I n Figure 2-1 , b lack lines and darker blue boxes indicate relationships and elements that EPA w ill consider in the Toxicological Review ; gray lines and lighter blue boxes indicate aspects of inorganic arsenic exp o sure that are outside the scope of th is Toxicological Review

. Additional discussion of the conceptual model is f o und in Draft Development Materials for the Integrated Risk Information System (IRIS) Toxicological Review of Inorganic Arsenic on the IRIS website

. 10

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

. 10 http://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=524796#_ga=1.136360240.1891222957.14444057

14.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 2-3 

### 1 2 3 Source: Ada pted from NRC (2009)

. **Figure 2-1.**  **Overall c**  **onceptual m**  **odel 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 1

2

3 4

5 6 7 8 9 10 11 This section describes the analysis plan. Figure 3-1 illustrat es t he technical activities as a

ser



### 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 analytic al requirements.



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

Aspects of EPA’s IRIS Assessment of Inorganic Arseni c ( 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 ). i es 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 revi ew ed and evaluated the available literature on inorganic arsenic to guide expert judg ment , as NRC recommended in its report, Review of EPA's Integrated Risk Information System (IRIS) Process ( NRC , 2 014 ) . 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.

**Literature Identification** 

### 12 13 14 15 16 The initial literat ure 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 c onducted s earches using the HERO interface , update d through July 2014

. The r e sulting literature search products are publicly available on the HEROAssessment 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 T he outcome of th e literature search process wa s a 

### 1 2 3 comprehensive list of the available scientific literature on inorganic arsenic.

**F ig**  **ur e**  **3-1**

**. Overview of the**  **a nalysis**  **p lan for**  IRIS Toxicological Review of 

### 4 5
6 7 8 9 10 11 12 13 14 15 16 17 Inorganic Arsenic

**.** Figure 3-2 o utlines the literature search strategy for information on health effects and mechanistic data for the IRI S T oxicological Review of Inorganic Arsenic

. PubMed, Web of Science,

an d TO XLINE w ere searched using the chemical name and CAS (Chemical Abstracts Service) number

. The results from the three databases were combined, and d u p licat e records w ere removed. The gray lines in Figure 3- 2 indicate literature set aside during the literature search process ; the dark lines indicate t he progression of literature being considered during development of the Toxicological Review

. Al t h ough not explicitly depicted in this figure, pharmacokinetic information is also c aptured in the “Mechanistic Data Cluster .” N on - peer - r eviewed articles, abstracts , posters, and review articles were separated in the initial screening of t h e comprehensive li st of references. The Agency uses only peer - reviewed articles in IRIS Tox ico logical Review s. Posters are often not publicly available or peer reviewed, and although abstracts and r ev ie w 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

This document is a draft for review purposes only and does not constitute Agency policy. DRAFT – November 2015 3-3 peer - reviewed references, the Toxicological Review rel ies on data from primary source material. As 

### 1 2 3 4 5 shown in Figure 3-2 , t he remaining references in the considered lis t were grouped using natural language processing. A computer algorithm was initially used to group references into “clusters” based on text si mil arit ies in the title s and abstract s. The clustering process is a tool to organize the arsenic literature databa se.



### 6
7 8 9 10 11 12 13 **Figure 3-2** 

**. Process for**  **i dentifying**  **, sorting, and evaluating**  **susceptibility, mechanistic**  **, an**  **d health effect**  **s tudies for the**  IRIS Toxicological Review of Inorganic Arsenic

**. Studi**  **es 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**  **li terature searched.)** 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 3-4 Following the screening by title and abstract, the full text of a ll epidemiologic and toxicolog y 

### 1 2 3 4 5

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 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 i norganic arsenic

. 12

**Risk**

**- of** 

**- Bias Analysis**  Epidemiologic and toxicolog y s t u dies considered relevant for hazard identification were subject to risk

- of

- b ia s evaluations. Risk

- of

- bias evaluations assess some aspects of internal validity of st udy 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 h a zard identification (see Section 3

. 2 ). The risk

- of

- bias evaluation should not be considered a checklist or inclusion/exclusi on criteria but rather a way to characterize p o tential strengths and weaknesses of individual studies mo r e t ransparently . R isk of bias for each study was evaluated using the questions and considerations proposed in the Office of Health Assessment and Translation ( O H AT ) approach ( N TP, 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 h e lps evaluate the approach’s efficacy for application to epidemiologic d a ta

. The OHAT approach will not necess arily be applied for other IRIS Toxicological Review s , n or does this change necessarily signal a departure from current assessment approaches

us ed for other NCEA products. N o t e that each study was evaluated in isolation; if clarification of a risk

- of

- b ias i ssue is reported in another paper, this was not considered.

Individual studies were evaluated using series of questions regarding potential sources of bias ( T able 3 -1 )

. R isk of bias was assessed for each study question using a four

- point scale developed by OHAT that includes r a tings of definitely low bias, probably low bias, probably high bias, and definitely h igh bias ( Table 3-2 )

. T he supporting rationale for each rating applied was documented by t h e reviewer . I n cases where the rationale for one of the bias domains might differ for different health effects presented in one study, those differences were n o ted. R isk

- of

- bias evaluations n e cessarily require subjective conclusions by an expert scientist. E ach study was evaluated i ndependently b y two scientists who refer red to the draft OHAT approach for systematic review ( N TP, 2013 ) and arsenic

- specific clarifications developed for each question

. After independently reviewing a study, the two reviewers discuss ed differences and resolve d any discrepancies between t h eir ratings and rationales

. T he same risk

- of

- bias questions were applied across all epidemiologic studies o r animal toxicology studies using different rating guidelines and arsenic

- sp ecific clarifications for each discipline

. T he OHAT approach does not produce an “overall” risk

- of

- b ias r ating for each study , and no overall risk

- of

- bias ratings or other descriptors were developed f or the arsenic s tudies 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 **Table 3-1.**  **Example risk**

**- of** 

**- bias**  **considerations** 

### 1
Category Risk

- of

- bias q uestions 1
Selection 1. W as administered dose or exposure level adequately randomized?
2. W as allocation to study groups adequately concealed?
3. W ere the comparison groups appropriate?
4. D id the study design or analysis account for important confounding and modifying variables?
5. D id researchers adjust or control for other exposures that are anticipated to bias results? Performance 6. W ere experimental conditions identical across study groups?
7. Did researchers adhere to the study protocol?
8. W ere the research personnel and human subjects blinded to the study group during the study?
Attrition 9. W ere outcome data complete without attrition or exclusion from analysis?
Detection 10. W ere the outcome assessors blinded to study group or exposure level?
11. W ere confounding variables assessed consistently across groups using valid and reliable measures?
12. C an we be confident in the exposure characterization?
13. C an we be confident in the outcome assessment? Selective r eporting b ias 14. W ere all measured outcomes reported?

Other 15. W ere there no potential threats to internal validity (e.g., statistical methods were appropriate)?

1 I n consultation with OHAT, the wording of Q uestions 7, 9 , and 15 included in the 2013 draft ( NTP, 2013 ) was 

### 2 3 4
5 changed so that answering “yes” would consistently indicate lower risk of bias, while answering “no” would indicate higher risk of bias.

**T able**  **3 -2.**  **Ge neral risk** 

**- of** 

**- bias**  **ratings**
Rating Description (++) Definitely l ow risk of bias There is direct evidence of low risk

- of

- bias practices ( d irect evidence is an explicit statement (s) , generally in the study report or through contacting the authors)

. (+) Probably l ow 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 ( i ndirect evidence provides information to address the risk

- of

- bias question but falls short of direct evidence)

. (

- ) Probably h igh risk of b ias There is indirect evidence of high risk

- of

- bias practices OR there is insufficient information provided about relevant risk

- of

- bias practices

. (

- - ) Definitely h igh 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 **Evidence Tables** 

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

18 19 20 21 22 23 24 25 26 27 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 i nc l uded in the evidence table s. The hazard identification sectio ns f o r each health outcome will further discuss strengths and weaknesses of studies included in the evidence tables. Evide n ce tables include information for comparing key features such as study design, exposure metrics, and dose

- res p onse information. In ad dition, EPA has searched fo r and specifically identif ied studies that partially or fully meet the following criteria NRC recommended: individual measures of arsenic exposure, measurements of arsenic that pr ec ede outcome, and low

- to

- mod er ate exposure to ino rganic arsenic (≤100 μg/L drinking water). These latter studies w ill b e 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

- resp o nse 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 R ev iew

. Adopting this approach does not n ecessarily signal a departure from current assessment approaches for other NCEA products.


## 3.2. **Health Hazard Identification** 
For t he hazard identification process for inorganic arsenic , the relevant evidence of health effe cts identified through the literature search will be summarized and then integrated as described in th e C ancer Guidelines ( U .S . EPA, 2005 ) and the Integrated Science Assessment s for lead and

ozone ( U.S. EPA, 2013a , b ) , as supported by NRC (2013)

. These document s describe the Agency’s process for integrating evidence and making judgments about causality for both cancer and noncancer endpoints. The p rocess is depicted in Figure 3-3 and described in more detail in the following sections. App l ication of the Integrated Science Assessment framework for assessing causality to noncancer examinations wit h in the IRIS P rogram 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
**Figur e**  **3-3. Overview of hazard identification for 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 3-7 **Evidence Synthesis**  

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 Epidemiologic studies, animal toxicolog y studies, and mechanistic st u dies ca n all inform the e valuation of health effects a s sociated with inorganic arsenic exposure

. T h e se st udies will be synthesized in hazard identification sections. T hese sections are not intended to provide d etailed summaries of individual studies but rather to highlight the most informative evidence for considering causality . H azard identification for inorganic arsenic w ill focus on studies conducted using relevant pollutant exposures. As N RC (2014) recommended , evidence will be integrated using expert judgment informed by the results of the risk

- of

- b i as evaluations. M echanistic data could provide additional information pertaining to causal determinations , h uman relevance of animal data , and insights into mode l choices for low

exposure extrapolation in the absence of observational data in the range of U

. S

. exposure levels

. (R elevance to dose

- r es ponse characterization is discussed below

. ) Evidence for s usceptibility and population variability in responses also w i l l be ascertained. Finally , the health effect synthesis sections will describe strengths and weaknesses in the available database and data gaps th a t limit the utility of the available data to inform hazard identification

. A dverse health effects under consideration are shown in Box 3-2

. Other effects identified in the hazard identification process will also be considered.

**Evaluate A**  **d verse**  **O utcome**  **P athway or**  **N etwork**  **D ata for**  **H azard**  **I dentification**  As N RC (2013) noted, mode of action analyses “ permit the integration of data to advance understanding of the coherence, biologic al plausibility, and human relevance of findings throughout the exposure

- r e sponse continuum, and provide a transparent means of synthesizing the data.” As part of the evidence synthesis for haza rd identification, EPA will collect and analyze AO P/ N information for e ac h health endpoint of significant concern

. For this Toxicological Review , EPA plans to consider b o th disease - and chemical

- specific information in build ing conceptual models of mechanisms and link initial molecular

- in it iating events to population

- level responses, as feasible. In addition to influencing hazard identification, AOP/ N an alyses might inform the shape of the dose

response curv e b ey ond the range of the observational data. (See the description of dose

- response model selection in S e ction 3.3 for more discussion.) The analyses also could be used to inform

susce p tibility and variability features, i ntegrate mechanistically related outcomes, and help evaluate multiple r isk modifiers (e.g., preexisting disease backgrounds, differences in genetic susceptibilities, smoking, alcohol consumption, diet )

. EPA plans to fol low the NRC -recommended steps for mechanistic analyses a nd t he Organization for Economic Co

- operation and Development guidance on AOP development ( O EC D, 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 diseaseAssessment 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 3-8 suggest that data might not be available to execute the NRC vision fully . Tables and diagrams will be 

### 1 2 3

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

27 28 29 30 31 32 33 34 35 36 created in the AOP/ N analys i s section to summarize the available information considered during evaluatio n of underlying mechanisms for adverse effects

.
**Evaluate Susceptibility Factors**  Several factors c ould modify the association between exposure to inorganic arsenic and health outcomes among potentially susceptible populations. To identify su sceptibility fa ctors , the synthesis sections on health effects will evaluate the available evidence on factors such as life stage and early

- l ife exposures , intrinsic variability (e.g., genetic makeup) , and influence of environmental factors using a n e vidence

- of

- susceptibility framework (see Chapter 5 in U.S. EPA (2013a) for additional discussion). The evaluation process will f ocus on studies identified through a literature search within the overall arsenic literature database. The susceptibility analysis will focus primarily on human su sceptibility , 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., e pidemiologic) that compare populations or life stages exposed to similar inorganic arsenic concentrations within the same study design. Animal toxicol og y studies also might provide evidence of susceptibility factors that i nfluence 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 toxicologi c a nd epidemiologic findings and the biologic al plausibility of t h e health effect. The results will be used to determine whether a particular factor alter s th e occurrence of effects from inorganic arsenic exposure and to inform the exposure

outcome relationship , as feasible

. Tables will be created to summarize the available information considered during evaluation of potential popula tions of concern for the IRIS T oxicological Review of I n organic A rsenic

. **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 provi d es more discussion, and additional information on the process of evidence integration is provided in the draft development ma terials for this Toxicological Review ( U.S. EPA, 2014 ) and EPA’s guidelines for carcinogen ris k 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, r ecommendations from the N RC 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 

## 3.3. **Dose**

**- response Analyses**  1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

27 28 29 30 31 32 33 34 35 36 37 Dose

- response analyses will be developed for cancer and noncancer health endpoints for which inorganic arsenic e xposure is “causal” or “likely causal.” Consistent with NRC (2013) recommendations, one focus of the dose

- response analyses w ill be epidemiologic observations for exposures ranging from background levels i n drinking water to 100 μg/L in drinking water, which would encompass exposures commonly found in the United States

. ( B ackground levels of exposure would result in concentratio ns o f 1– 5 μg/L or less in urine, summing inorganic, monomethyl, and dimethyl arsenic forms. ) O ther, higher exposure levels also will be considered informative. As noted above, AO P/ N information will be evaluated for the potential to inform dose

- response analyses for endpoints that have inadequate epidemiologic data f or characteriz ing dose

- response at lower exposures. Additionally, AOP/ N an alyses could help characteriz e human variability and susceptibility. Variability and uncertainty will be characterized, including variability and uncertainty within and across models ( and associated with model choices) , among s tudies , and between i n dividuals

. 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 a nd estimating changes in incidenc e above clinical or other thresholds (e.g., changes in blood pressure that lead to hypertension). Outputs for cancer and noncancer evaluations w ill be equations describing the dose

response relationships. Accompanying t h ese equations will be tables and pl ots that express risks associated with various e xposure s (e.g., in ppm), dose s (e.g., in mg/kg

- day), or biomarker (e.g., urinary) le v els of inorgan ic arsenic (e.g., exposures, doses , or concentrations associated with estimated lifetime cancer risk of 1 i n one million , 1 in one hundred thousand, 1 in ten thousand)

. These risk s 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 -r**  **es ponse Analyses**  For inorganic arsenic, dose

- r esponse analyses will be performed for health effects for which inorganic arsenic is determined “c ausal” or “likely causal.” These analyses likely will be performed using epidemiologic data. Meta

- an alyses 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 ( o r comparable equivalent) and exposu re metrics that ar e suitable for combined analyses. In addition, other studies that do not meet these criteria but c ontribute to our understanding of potential health effects and exposure

- response relationships will be analyzed, i ncluding data with “suffic ient” or “adequate” evidence of susceptibility. These dose- r esponse analyses will inform the potential dose

- response differences in susceptibleAssessment 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 population s. Other factors influencing selection of studies for dose

- response analyses of individual 

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 studies and meta

- analyses include elements that potential ly bias study results (e.g., methods of endpoint evaluation , controlling for confounders, studies with and without individual data, exposure misclassification ). Although a n exposure assessment is beyond the scope of the Toxicological Review , a spects of ex posure characterization ar e relevant to the use of such data in dose

- response analyses. For estimating total daily exposure, N RC indicated that delineation of exposure sources ( i.e., drinking water, diet, ai r ) should be characterized, preferably u sing probabilistic approaches ( NRC, 2013 ) . In response to this recommendation, EPA will qualitative ly and, where possible, quantitative ly delineate between sources of exposure and consider information provided by biomarkers of exposure. S t u dies conducted on U.S. populations and other populations (e.g., Taiwan ese , Bangladesh i ) w ill be evaluated for hazard identification and a determination made on whether an adjustment in estimated dose

- r e sponse 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, base d 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 a lso w ill consider exposure uncertainty in collecting data for dose

- respon se analyses

. For example, s t ud ies 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 ; o r s t udies might report arsenic exposure concentrations from a particular source (e.g., a community water supply) rather than individual exposure levels. Furthermore, these source concentrations mig h t be estimated from samples taken over a limited period or a single time point and extrapolated t o lifetime exposures. Therefore, studies with exposure data for individuals are assumed t o introduce les s uncertainty to associations between health effect s and inorganic arsenic. To c omplement the conceptual model described in this document and to inform hazard i dentification and dose

- r e sponse analyses, EPA will evaluate arsenic exposures and exposure pathway considerations. Based on NRC ’s r e commendation, urinary arsenic concentratio ns of 1

– 5 μg/ L ( su mming inorganic, monomethyl, and dimethyl arsenic forms) will be assumed a reasonable

es timate of background for the U .S. p op ulation. If necessary, descriptions of background might be generated for non -U .S . p opulations, based on available data. Supplementary materials for exposure pathway considerations will include :

• ev aluation of the applicability of a physiologically based pharmacokinetic m odel(s) to estimate biomarkers of exposures such as inorganic arsenic or its metabolite levels in urine ;

• us e of physiologically based pharmacokinetic m odel(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

- es t imated biomarkers ; andAssessment 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- 11 • consider ation of dosimetry and pharmacokinetic issues concerning analyses of 

### 1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16 17 18 19 20

21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 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 b e selected for dose

- response analyses. Otherwise, human or animal toxicology or in vitro data might p rovide a mechanistic understanding and interpretation of low

- d ose effects observed in epidemiologic studies. Specifically, these data could be used to inform variability and uncertain t y in the dose

- response analysis and selection of dose

response modeling approaches.
**Variability and Uncertainty in Dose** 

**- response Analyses**  V a riability and uncertainty are important components of risk characterization. Variability represents t he diversity o r 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 t he 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 biologic al su sceptibility due to genetic, lifestyle, health , a nd 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 w ill use observational and mechanistic data , as feasible, to info rm the variability and uncertainty characterizations. I n addition, EPA will develop sensitivity analyses for life stage and potentially other f actors that influence dose- response analyses for inorganic arsenic.

**D ose**  **- response Modeling Approaches**  D o se - resp onse 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 incorpo rating 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 avail able scientific information and p romotion of research to characterize these factors. The approaches used i n the IRIS Toxicological Review of Inorganic Arsenic are specific to inorganic arsenic at this time ; adopting such an approach does not necessarily si gnal a change from current assessment approaches for other NCEA p roducts. 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

- r esponse will be restricted to a relatively small set of simple models, and risk estimates will be derived based on the units of expo s ure 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

- d ose points ofAssessment 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- 12 departure (such as benchmark doses and lower limits of benchmark doses) that have been used in 

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 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 com parisons 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 tier s 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 w ill use more advanced

a p proaches, including explicitly probabilistic models, to evaluate uncertainty and variability in dose- r esponse. 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 dis tributions 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 biomarker s, such as urinary arsenic. The range of model forms also is more extensive in the higher tiers, with approaches “fine

- t uned” to specific data sets as appropriate. As feasible, mechanistic data will inform model selection and evaluation in the higher tiers

. **Extrapolation for Dose**

**- r**  **esponse Analyses** NRC recommended using observed data to characterize dose

- r esponse relationships. They also r ecommended limited extrapolation , to within an order of magnitude of observed data, using the modeled shape of the dose -r e sponse relationship to provide data

- informed estimates of the potential dose

- r esponse relationship below the range of observation. Model choices will allow for nonlinear or threshold phenomena, as supported by the data. N RC further recommended characteriz i ng dose

- response relationships down to (but not necessarily at exposures below) background levels, which the y es timated to be 1– 5 μg/L inorganic arsenic in urine for U.S. populations. NRC indicated that the risks below b ackground concentrations should be charac t erized to the extent feasible but also assumed the needs of risk assessors would be met if risk can be characterized d own to background concentrations. Extrapolations in the Toxicological Review w ill be informed by these recommendations. As feasible , EPA will consider statistical methods and measures such as confidence or prediction limits th at might help develop these extrapolations; details will be provided in the supplementary materials for EPA’s dose

- r esponse analyses. B io logic al considerations a lso 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 **Table 3-3.**  **Summary of proposed inorganic arsenic dose** 

**- response analysis**  

### 1 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 r egression, benchmark

- dose type models, etc.)  Complex parametric and non parametric 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 

# 4. REFERENCES 1

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 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://ww w.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.ht ml

. NRC (National Research Council). (2013). Critical aspects of EPA's IRIS assessment of inorganic arsenic: Interim report. Washington, D.C: The National Aca demies Press. NRC (National Research Council). (2014). Review of EPA's Integrated Risk Information System (IRIS) process. Washington, DC: The National Academi es Press. http://www.nap.edu/catalog.php?record_id=18764

. NTP (National Toxicology Program). (2 013). 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 (Org anisation 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

- o p erations 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

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### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 organic and inorganic arsenic: A report of the US EPA Science Advisory Board. (EPA

- SAB

07

- 0 08). 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

- SAB

11

- 0 03). 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/PLAW

112publ74.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. Environment al 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.getfi le?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 repor t) [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. (E PA/630/R

- 14/101). Washington, D.C.: Office of Research and Development, Biomonthly Public Meeting: June 2014. http://www.epa.gov/iris/publicmeet ing/iris_bimonthly

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preliminary_draft_materials.pdf

. Villeneuve, PJ; Weichenthal, SA; Crouse, D; Miller, AB; To, T; Martin, RV; van Donkelaar, A; Wal l, 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.00000000000 00294

.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-1 

# Appendix A. E vidence Integration 1



## The Evidence

- Integration Process 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 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 t hat involves scientific judgment. The evidence

- i ntegration 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. Mechanist i c 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 t o the agent. State

- of

- th e - art approaches to evidence integration apply a standardized approach for grading the strength of the evidence and use clear and consistent summative language ( N RC, 2011 ). As the IRIS P rogram evaluates multiple health outcomes of many chemical agents, the terms used in these conclusions should be co nsistent 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 a ssessments, each major class of health outcome (e.g., cancer, reproductive toxicity, neurotoxicity, respiratory

- t ract toxicity, liver toxicity) can be the subject of a separate exercise in evidence integration. In practice, draw i ng inferences at a finer level of specificity of effect (e.g., learning and memory , p regnancy outcomes) and then us ing these inferences to draw conclusions about the major health outcomes o ften makes sense . Human studies often enable the synthesis of evidence for specific health o u tcomes (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 integ r ation. 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 toxic it y 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 , forAssessment 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 some health outcomes, toxicological understanding might be sufficient to justify the integration of 

### 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

31 32 33 34 35 36 37 human and animal evidence at a site

- specific level. A similar complication can arise if the human and animal studies inv estigate 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, mixture

related human findings would be integra te d 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 inferen ce s from different disciplines. Initial views of one type of evidence can change when other lines of evidence are considered. For example:

• W hen the human evidence has alternative explanations , animal or mechanistic evidence can strengthen or diminish the p lau sibility of some explanations of the human evidence.

• W hen uncertain ty 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.

• W h en the animal response is strong , evidence establishing that the mechanisms underlying the animal response do es n ot 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.

• S imilarly, 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 f or human prostate canc er), 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 h umans).

• W hen 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 pos it ive 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 E vidence

- Integration Narrative The evidence

- i ntegration narrative presents the reasoning behind the evi dence

- integration process. The evidence

- i ntegration narrative assembles the major findings from human studies, animal studies, and mechanistic studies for each major class of health outcome. The evidence

integration narrative:

• p resents the conclusions from each line of evidence ,

• ex plains 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 • cites the studies that were pivotal to these conclusions , 

### 1 2 3 4 5 6 7 8 9 10 11 • identifies the key issues and how they were resolved, and

• i ntegrates all lines of evidence to characterize the agent ’ s association with each health outcome

. The evidence

- i ntegration 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., i ncreased incidence of endpoint) and null (i.e., no increased incidence of endpo int) could result from differences in internal dose of a key metabolite. Conversely, unexplained inconsistency would indicate gaps in knowledge.