Appendix B

Workshop Agenda

Inorganic Arsenic: Scientific Considerations for
Hazard Identification and Dose–Response Analysis

April 4, 2013

National Research Council, Lecture Room
2101 Constitution Avenue, NW, Washington, DC

7:30 am REGISTRATION
7:45 am Welcome and Introduction
Joseph Graziano, Committee Chair
8:00 Update on EPA’s Inorganic Arsenic Activities
Kenneth Olden and Vincent Cogliano, U.S. Environmental Protection Agency
Strengths and Weaknesses of Recent Epidemiologic Studies of Inorganic Arsenic
8:15 am Cancer Evidence and Dose-Response Relationships
Kenneth Cantor, National Cancer Institute
8:45 am Noncancer Evidence and Dose–Response Relationships
Craig Steinmaus, California Environmental Protection Agency, University of California at Berkeley
Integration of Metabolism and Mode of Action Information in Hazard Identification and Dose–Response Analyses
9:15 am Metabolism, Its Consequences, and Implications for Low Dose Assessments
David Thomas, U.S. Environmental Protection Agency
9:40 am Mode of Action and Mechanism Identification and Implications for Low Dose Assessments
Samuel Cohen, University of Nebraska Medical Center
10:05 am Interplay Between One-carbon Metabolism, Arsenic Metabolism and Epigenetics
Mary Gamble, Columbia University
10:30 am BREAK
10:45 am Mode of Action for Lung and Cardiovascular Effects
R. Clark Lantz, University of Arizona
11:10 am Impact of In Utero and Whole Life Exposure and Implications for Dose Response
Michael Waalkes, National Institute for Environmental Health Sciences
11:35 am Panel Discussion:
Moderators: Aaron Barchowsky and Rebecca Fry

1.  Are there data that support low dose mechanisms and modes of action?

2.  Is there a continuum of common thread in cancer and noncancer mechanisms and modes of action?



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Appendix B Workshop Agenda Inorganic Arsenic: Scientific Considerations for Hazard Identification and Dose–Response Analysis April 4, 2013 National Research Council, Lecture Room 2101 Constitution Avenue, NW, Washington, DC 7:30 am REGISTRATION 7:45 am Welcome and Introduction Joseph Graziano, Committee Chair 8:00 Update on EPA’s Inorganic Arsenic Activities Kenneth Olden and Vincent Cogliano, U.S. Environmental Protection Agency Strengths and Weaknesses of Recent Epidemiologic Studies of Inorganic Arsenic 8:15 am Cancer Evidence and Dose-Response Relationships Kenneth Cantor, National Cancer Institute 8:45 am Noncancer Evidence and Dose–Response Relationships Craig Steinmaus, California Environmental Protection Agency, University of California at Berkeley Integration of Metabolism and Mode of Action Information in Hazard Identification and Dose–Response Analyses 9:15 am Metabolism, Its Consequences, and Implications for Low Dose Assessments David Thomas, U.S. Environmental Protection Agency 9:40 am Mode of Action and Mechanism Identification and Implications for Low Dose Assessments Samuel Cohen, University of Nebraska Medical Center 10:05 am Interplay Between One-carbon Metabolism, Arsenic Metabolism and Epigenetics Mary Gamble, Columbia University 10:30 am BREAK 10:45 am Mode of Action for Lung and Cardiovascular Effects R. Clark Lantz, University of Arizona 11:10 am Impact of In Utero and Whole Life Exposure and Implications for Dose Response Michael Waalkes, National Institute for Environmental Health Sciences 11:35 am Panel Discussion: Moderators: Aaron Barchowsky and Rebecca Fry 1. Are there data that support low dose mechanisms and modes of action? 2. Is there a continuum of common thread in cancer and noncancer mechanisms and modes of action? 115

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116 Critical Aspects of EPA’s IRIS Assessment of Inorganic Arsenic 3. Are there gender and species differences in metabolism or modes of action that impact dose response and disease susceptibility? 4. Do the kinetics and dynamics of inorganic arsenic and its metabolites in different organs promote organ-specific disease? 12:30 pm BREAK Probabilistic Dose–Response and Harmonization Approaches for Cancer and Noncancer Effects 1:30 pm  Lessons Learned from Lead and Particulate Matter Joel Schwartz, Harvard School of Public Health 2:00 pm  Extrapolation of Mode of Action Data to Dose–Response Modeling of Human Health End Points Harvey Clewell, The Hamner Institutes of Health Sciences 2:30 pm Panel Discussion: Moderators: Gary Ginsberg and Robert Wright Discussant: Daniel Axelrad, U.S. Environmental Protection Agency 1. Do the available gene expression data define a coherent mechanism for cancer and noncancer effects? 2. Do these data adequately describe the array of effects at low dose? 3. How might the mode of action based dose response be affected by population variability? 4. How would one construct a probabilistic assessment of noncancer dose response from which the probability of an adverse effect can be estimated at any dose? 5. What are the implications of mode of action based and probabilistic-based assessments for risk–benefit analysis? 3:00 pm BREAK Risk Assessment Approaches and Application of IRIS Values 3:15 pm  Systematic Review and Evidence Integration for Literature-Based Environmental Health Assessments Andrew Rooney, U.S. National Toxicology Program 3:45 pm  Perspectives of Risk Assessors and Users of IRIS Values Question: Given your experience in risk assessment activities, what aspects of the Toxicological Review of Inorganic Arsenic would be critical for maximizing the utility and credibility of the review for the risk assessments that you undertake? Barbara Beck, Gradient Corporation Michael Hansen, Consumers Union Kate Sande, Minnesota Department of Health Joyce Tsuji, Exponent, Inc. 4:10 pm Panel Discussion: Moderators: Sandra Baird and Hugh Barton Question 1: Joyce Tsuji and Michael Hansen 1a. “Science and Decisions” (NRC 2009) recommended that EPA adopt a unified dose–response assessment framework for cancer and noncancer end points. It has been suggested that an arsenic IRIS assessment might provide: a. Risk estimates for noncancer end points (rather than or in addition to a concentration assumed to be health protective, such as an RfD) b. Nonlinear cancer assessment c. Multiple risk estimates for a single toxicity end point (e.g., alternative mode of action hypotheses, estimates from different studies, multiple dose–response models fitted to the same data) d. Risk estimates for many toxicity end points. What recommendations do you have for EPA on use of these approaches?

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Appendix B 117 1b. If the toxicological review of inorganic arsenic contains risk estimates derived from the dose-response approaches described in Question 1a, how would that impact the practice of risk assessment in the activities you are involved in? Question 2: Barbara Beck and Kate Sande 2a. EPA has been asked by stakeholders to explicitly include consideration of populations that may have increased susceptibility to the adverse effects from arsenic (e.g., life stages, genetics, pre-existing disease, and environmental stressors such as co-exposures and nutritional deficiencies). What type of quantitative estimates of susceptibility would be useful in your risk assessment activities? If quantitative estimates cannot be derived, how do you recommend EPA provide information on susceptibility so that it can be used to inform your risk assessment activities? 2b. What types of documentation (and level of detail) are necessary to assist you and other users of an IRIS assessment if one of these approaches (which are not currently standard methods) were used? 5:00 pm Additional Questions for Workshop Speakers and Panelists from Committee 5:20 pm OPEN MICROPHONE Each speaker has a maximum time limit of 5 minutes. Accompanying written materials are encouraged. 6:00 pm ADJOURN