1 Examples in Stakeholder Collaboration for Risk Assessment Science Andrew Maier Jacqueline Patterson Michael Dourson

2 Presentation Overview A few words on the importance of collaboration A few words on the importance of collaboration Some examples of collaborative processes Some examples of collaborative processes Take home message: Take home message: We are all committed to protecting public health, although the issues are frequently complex they can often be solved through collaborative approaches (we’ll get farther faster).

3 Toxicology Excellence for Risk Assessment About TERA: A non-profit, 501(c)(3) corporation A non-profit, 501(c)(3) corporation Mission to protect public health Mission to protect public health Founded in 1995 with a current technical staff of 12 and several visiting scientists and associates. Founded in 1995 with a current technical staff of 12 and several visiting scientists and associates. Completes roughly 50 technical projects per year for government and industry sponsors (strives for 50:50 balance) in areas including developing chemical assessments, risk methods development, and peer review and consultation; provides ITER database Completes roughly 50 technical projects per year for government and industry sponsors (strives for 50:50 balance) in areas including developing chemical assessments, risk methods development, and peer review and consultation; provides ITER database Focus on – solving risk science issues through 1) technology leadership, 2) building bridges among stakeholder groups Focus on – solving risk science issues through 1) technology leadership, 2) building bridges among stakeholder groups

4 Key Benefits of Collaboration Promotes science-based decision making to protect human health by ensuring all key data and ideas are fully considered Promotes science-based decision making to protect human health by ensuring all key data and ideas are fully considered Enhances harmonization and consistency in risk assessments thru an open, transparent, multi-stakeholder approach that ultimately foster harmonization and information sharing Enhances harmonization and consistency in risk assessments thru an open, transparent, multi-stakeholder approach that ultimately foster harmonization and information sharing Makes use of groups of experts that are normally not available within a single organization Makes use of groups of experts that are normally not available within a single organization Shares costs and human resources among multiple stakeholders to increase output for the broader risk community Shares costs and human resources among multiple stakeholders to increase output for the broader risk community This can all be achieved while allowing groups to control their own process and can receive broad acceptance with thoughtful management of biases This can all be achieved while allowing groups to control their own process and can receive broad acceptance with thoughtful management of biases

5 Benefits of Collaboration Many international initiatives reflect desire of risk science community for increasing partnerships Many international initiatives reflect desire of risk science community for increasing partnerships SRA Europe – June 2007 : “Building Bridges Issues for Future Risk Research” SRA Europe – June 2007 : “Building Bridges Issues for Future Risk Research” International Programme for Chemical Safety (IPCS) Harmonization Project International Programme for Chemical Safety (IPCS) Harmonization Project

6 Harmonization Harmonization is not standardization Harmonization is not standardization Understanding the methods and practices used by various organizations Understanding the methods and practices used by various organizations Developing confidence in and acceptance of assessments using different approaches Developing confidence in and acceptance of assessments using different approaches Willingness to work toward a convergence of methodologies as long-term goal Willingness to work toward a convergence of methodologies as long-term goal

7 Does similar momentum for collaboration exist in U.S.? Yes - we think so.

8 A Few Examples of Collaboration Peer involvement processes - Voluntary Children’s Chemical Evaluation Program Peer involvement processes - Voluntary Children’s Chemical Evaluation Program Genotoxicity MOA Cooperative Research and Development Agreement (CRADA) Genotoxicity MOA Cooperative Research and Development Agreement (CRADA) Alliance for Risk Assessment (ARA) Alliance for Risk Assessment (ARA)

9 Peers: Experts of equal standing as the authors Peer Involvement: Gathering advice and review on risk assessment products from peers Peer Consultation: a formal or informal process to gather expert peer opinion and advice on a work product Peer Review: a formal, external, and independent review of an intended final work product Peer Input: soliciting information, data, or opinion, generally at an early stage of a work product’s development Peer Involvement

10 Development StageType of Peer Involvement Problem Formulation, Issue Identification, and Data Gathering Peer Input Data requests Workshops, Meetings, informal or formal Informal discussions Expert Elicitation to fill data gaps or address uncertainties Draft Work ProductPeer Consultation Requests for written comments or review Panel meetings or conference calls On single issues or entire work product Final Draft Work Product Peer Review Written or letter review Panel meetings or conference calls On near final work product

11 VCCEP A joint effort of multiple stakeholders: A joint effort of multiple stakeholders: Companies that manufacture, import, or use chemicals covered by TSCA Companies that manufacture, import, or use chemicals covered by TSCA EPA OPPT EPA OPPT Children ’ s health groups Children ’ s health groups Chemical testing interest groups Chemical testing interest groups Animal welfare groups Animal welfare groups Purpose - to enable the public to better understand the potential health risks to children associated with certain chemical exposure Purpose - to enable the public to better understand the potential health risks to children associated with certain chemical exposure Industry prepares assessments of hazard, exposure and risk to children and recommends data gaps and data needs. Industry prepares assessments of hazard, exposure and risk to children and recommends data gaps and data needs. Assessments reviewed by diverse and balanced panels under TERA peer consultation program. Core and ad hoc panel members used. Assessments reviewed by diverse and balanced panels under TERA peer consultation program. Core and ad hoc panel members used. EPA uses PC report as input as it decides whether further testing is needed. EPA uses PC report as input as it decides whether further testing is needed.

12 TERA’s Role in VCCEP Under a Cooperative Agreement from EPA, TERA is designing, developing and managing a Peer Consultation process to serve as a public scientific forum. One of the major activities undertaken by TERA under this agreement is the VCCEP. Under a Cooperative Agreement from EPA, TERA is designing, developing and managing a Peer Consultation process to serve as a public scientific forum. One of the major activities undertaken by TERA under this agreement is the VCCEP. TERA ’ s primary role in managing the VCCEP Peer Consultation is to ensure that it is a rigorous, science-based process for reviewing chemical assessments that stakeholders recognize as impartial and of significant technical merit and value. TERA ’ s primary role in managing the VCCEP Peer Consultation is to ensure that it is a rigorous, science-based process for reviewing chemical assessments that stakeholders recognize as impartial and of significant technical merit and value. TERA selects panelists, conducts all aspects of the meetings, and prepares the reports. TERA selects panelists, conducts all aspects of the meetings, and prepares the reports.

13 Using Peer Involvement to Advance Resolution of Pesticide Issues Industry develops document or work product Industry develops document or work product Vetted by Independent Peer Consultation Panel in an open and transparent fashion Vetted by Independent Peer Consultation Panel in an open and transparent fashion Shared with EPA and others for their potential use as input to support decision-making Shared with EPA and others for their potential use as input to support decision-making A supplement to EPA SAP for appropriate issues A supplement to EPA SAP for appropriate issues Captan cancer reclassification is an example of such an application of the process Captan cancer reclassification is an example of such an application of the process

14 Captan Tumor Mode of Action A Success Story in Stakeholder Involvement A Success Story in Stakeholder Involvement EPA’s cancer assessment for Captan was based on EPA’s 1986 Cancer Guidelines. EPA’s cancer assessment for Captan was based on EPA’s 1986 Cancer Guidelines. EPA OPP indicated they were not planning a re-evaluation, but would consider an independently reviewed reassessment. EPA OPP indicated they were not planning a re-evaluation, but would consider an independently reviewed reassessment. The Captan Task Force sponsored an updated analysis, which supported a non-linear mode of action. The Captan Task Force sponsored an updated analysis, which supported a non-linear mode of action. TERA convened an independent peer review panel. The panel provided several recommendations, but agreed with the nonlinear mode of action. TERA convened an independent peer review panel. The panel provided several recommendations, but agreed with the nonlinear mode of action. EPA OPP accepted the conclusions of the independent peer review. EPA OPP accepted the conclusions of the independent peer review. See: See:

15 A NEW STRATEGY TO IDENTIFY CHEMICALS THAT ARE MUTAGENS AND CARCINOGENS BUT NOT NECESSARILY MUTAGENIC CARCINOGENS NCTR Martha Moore, Robert Heflich TERA Lynne Haber, Mike Dourson ENVIRON Annette Shipp, Robinan Gentry Bruce Allen Consulting Bruce Allen Bruce Allen University of Arkansas for Medical Sciences Ralph Kodell Disclaimer: Not Official FDA Policy

16 MOA CRADA Stakeholder identifies chemical for which reassessment of Cancer MOA is needed Stakeholder identifies chemical for which reassessment of Cancer MOA is needed NCTR conducts in vivo mutagenicity/ tumorigenicity assay NCTR conducts in vivo mutagenicity/ tumorigenicity assay NCTR, TERA, Environ evaluate mutation frequency and tumor data to test concordance with Hill criteria (dose-response and temporal response) NCTR, TERA, Environ evaluate mutation frequency and tumor data to test concordance with Hill criteria (dose-response and temporal response) Analysis provided to EPA to consider in weight of evidence for cancer reassessments Analysis provided to EPA to consider in weight of evidence for cancer reassessments

17 Design for in vivo Mutation Studies Addressing Cancer MOA  Use transgenic model that will detect point mutations (base pair subs, frameshifts, very small deletions/insertions)  Big Blue transgenic model  Chronic treatment (up to 12 months) modeled on the tumor bioassay  Same species/strain as cancer study  Same exposure route as cancer study  Detection of mutation in the target tissue(s)  Multiple doses (6 or 7) based on tumor data--Enough doses to adequately characterize the dose response  Evaluate mutation, toxicity, cell proliferation at 28 days, 3, 6, 9, 12 months (Time-to-mutation)

18 Riddelliine: Dose Response Concordance Fitted dose-response curves for MF and cancer incidence on a probability scale. Cancer dose-response ( ) is based on fitting a multistage model. Two probability dose-responses for MF are shown, resulting from different assumptions regarding the background rate of response (0.058 or 0.01).

19 DCA: Dose Response Concordance Fitted dose-response curves for MF and cancer incidence on a probability scale. Cancer dose-response ( ) is based on fitting a multistage model. Two probability dose-responses for MF are shown, resulting from different assumptions regarding the background rate of response (0.26, ; or 0.01, ).

20 Alliance for Risk Assessment (ARA) A process to A process to facilitate communication and collaboration toward development of useful and timely risk science products.

21 Alliance for Risk Assessment (ARA) States, Fed. Agencies, Public Interests, Industry Initiation of Risk Issue Document Draft Peer Reviews Release to Public Hazard Assessment Notification System (HANS) Risk Document Development Peer Consult Risk Research And Tools ITER Training and Certification Peer Review Non-profit Collaborators Alliance “Menu” OptionsStakeholder Process Risk Communication Steering Committee

22 ARA Work Flow Federal Agencies, Industry Hazard Assessment Notification System (HANS) ITER Steering Committee States, Tribes, Env. NGOs TERA and Non-Profit Collaborators Unfunded Project Requests Funded Projects

23 ARA Funds Flow Federal Agencies ARA Process Industry Funded Projects Unfunded Projects Federal Funds Contracts 100 Risk Issues per Year by Year 5

24 The ARA Sand Box The ARA seeks collaboration building and there is a role for all players… The ARA seeks collaboration building and there is a role for all players… Players: federal government, local government, tribes, industry, for-profit consultants, NGOs. Players: federal government, local government, tribes, industry, for-profit consultants, NGOs. Roles: Roles: users - use of work products, use of information exchange, work product vetting, users - use of work products, use of information exchange, work product vetting, experts assisting other (e.g., peer review panel member) experts assisting other (e.g., peer review panel member) developing work products developing work products Steering Committee membership Steering Committee membership

25 ARA Steering Committee Provides advice to ARA Partners on mission- relatedness, project prioritization, Conflict of Interest, Provides advice to ARA Partners on mission- relatedness, project prioritization, Conflict of Interest, Scientists: Scientists: 2 States 2 States 1 Tribe 1 Tribe 1 Env. Group 1 Env. Group 2 Federal 2 Federal 1 Industry 1 Industry 1 Academic 1 Academic 2 ARA Partners 2 ARA Partners

26 Why Would Diverse Groups Provide Funding? The Alliance for Risk Assessment (ARA) mission… The Alliance for Risk Assessment (ARA) mission… Aligns with many public health goals. Aligns with many public health goals. Provides value as a timely resource for technical products with enhanced credibility. Provides value as a timely resource for technical products with enhanced credibility. Allows Stakeholder input – e.g., via involvement in Science Steering Committee, as participants in technical panels. Allows Stakeholder input – e.g., via involvement in Science Steering Committee, as participants in technical panels. Gives an opportunity for harmonizing risk values and methods – which eases burden for stakeholders that must meet requirements in multiple constituencies. Gives an opportunity for harmonizing risk values and methods – which eases burden for stakeholders that must meet requirements in multiple constituencies. Over the years nonprofit corporations have demonstrated the concept can work [e.g., peer consultation with Voluntary Children’s Chemical Evaluation Program (VCCEP) of EPA]. Over the years nonprofit corporations have demonstrated the concept can work [e.g., peer consultation with Voluntary Children’s Chemical Evaluation Program (VCCEP) of EPA]. NLM & TERA have success in building ITER; ~200,000 hits per year demonstrates likely value of ARA NLM & TERA have success in building ITER; ~200,000 hits per year demonstrates likely value of ARA Aligns with stated needs of stakeholders – e.g., Environmental Council of States (ECOS) call for harmonized process. Aligns with stated needs of stakeholders – e.g., Environmental Council of States (ECOS) call for harmonized process.

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28 NLM’s Toxnet

29 Does Stakeholder Interest Exist? In exploring the needs for this ARA, TERA has provided briefing and/or received input from many potential stakeholders (over 100 individuals) Including: In exploring the needs for this ARA, TERA has provided briefing and/or received input from many potential stakeholders (over 100 individuals) Including: 30 States 30 States 2 Tribes 2 Tribes 4 Environmental NGO’s 4 Environmental NGO’s 30 Industry groups 30 Industry groups 6 U.S. Federal Agencies 6 U.S. Federal Agencies 4 Countries 4 Countries Feed back has been positive. Suggestions have led to refinements in the proposed ARA. Nearly all responding contacts have encouraged moving forward. Feed back has been positive. Suggestions have led to refinements in the proposed ARA. Nearly all responding contacts have encouraged moving forward. Diverse groups are beginning to provide funding or suggest projects Diverse groups are beginning to provide funding or suggest projects

30 Does This Effort Duplicate Current Federal Efforts? This effort does not duplicate ATSDR MRLs, EPA IRIS, FDA ADIs, Health Canada TDIs or RIVM TOCs. This effort does not duplicate ATSDR MRLs, EPA IRIS, FDA ADIs, Health Canada TDIs or RIVM TOCs. To the contrary, ARA shares resources to avoid duplication because: To the contrary, ARA shares resources to avoid duplication because: It does not replace individual regulatory processes; ARA users tap in as appropriate. It does not replace individual regulatory processes; ARA users tap in as appropriate. Many risk values/issues will never be worked by federal groups. Many risk values/issues will never be worked by federal groups. Current federal approaches have resource limitations; thus, new chemicals addressed without duplicate effort. Current federal approaches have resource limitations; thus, new chemicals addressed without duplicate effort. Update of older values can benefit federal groups as one technical input to internal deliberations. Update of older values can benefit federal groups as one technical input to internal deliberations. ARA goes beyond risk values/issues – it is also a shared resource for training and data communication. ARA goes beyond risk values/issues – it is also a shared resource for training and data communication.

31 ARA Supports Existing Risk Values Provides guidance for sources of toxicity information that may be used in performing human health risk assessments ITER can supplement existing toxicity data ARA can provide Tier III values EPA OSWER Directive

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33 Summary We are all committed to protecting public health, although the issues are frequently complex they can often be solved through collaborative approaches (we’ll get farther faster).

34 Collaboration is Powerful

35 Questions?