Dr. Bernard Gadagbui and Dr. Andrew Maier February 6, 2007 The Evolving Practice of Risk Assessment – Opportunities for Collaboration and Communication Dr. Bernard Gadagbui and Dr. Andrew Maier February 6, 2007

Objectives of Presentation Briefly describe: Chemical risk assessment How EPA quantifies risk posed by chemicals Trends in risk assessment The growing need for information sharing Introduction of Alliance for Risk Assessment as a resource for information exchange

Risk Assessment Risk is defined as… “the possibility of loss or injury; someone or something that creates or suggests a hazard; and the degree of probability of such loss” “the probability of an adverse outcome” Casarett & Doull, 2001

Risk Assessment Human Health Risk Assessment is… The scientific process of evaluating the toxic properties of a chemical and the conditions of human exposure to it, in order to both ascertain the likelihood that exposed humans will be adversely affected, and to characterize the nature of the effects they may experience. Human health risk assessors evaluate issues such as: the quality of community air and water due to emissions, the safety of food and consumer products, and the need to clean-up contaminated sites

NAS Risk Assessment Paradigm (1983) Risk Management HAZARD IDENTIFICATION DOSE RESPONSE ASSESSMENT EXPOSURE RISK CHARACTERIZATION BEST AVAILABLE TECHNOLOGY ENGINEERING OPTIONS PUBLIC RESPONSE POLITICAL CONSIDERATIONS COST

Trends in Risk Assessment Past: Analysis efforts focused on selected high profile chemicals. Heavy reliance on default assumptions Humans are equally or more sensitive than test animals Humans are highly variable in their sensitivity Effects observed in high dose animal studies are relevant to effects that might occur in humans exposed to low doses Ambient exposure related empirically to disease without regard to the assessment of biological modes of action. Overall, the use of default assumptions resulted in environmental risk assessments with significant uncertainty.

Trends in Risk Assessment Present: Increasing emphasis on hazard characterization and screening assessments for large numbers of chemicals Exploration of mechanisms/modes of action at cellular and molecular levels Increasing use of data to replace or inform default assumptions Use of weight of evidence (WOE) approach WOE characterized by use of “totality of the evidence” in making risk assessment decisions The risk assessment process encompasses all available toxicological data and scientific evidence on the plausible toxicities of a chemical or chemicals

Trends in Risk Assessment Future: WOE has opened door for innovative solutions in risk assessment and toxicology Ability to employ innovative solutions has been driven by Improved biology understanding (understanding of the mode of action or MOA) Increased sophistication and validation of alternative study designs and consideration of study design (e.g., gene knock-outs) Improved quantitative tools (including biomathematical modeling, data mining and collection platforms (toxicogenomics) and predictive toxicology and Quantitative Structure Activity Relationships, QSARs)

Evolving Risk Assessment Triggered by… Control technology better able to reduce gross contamination, focusing effort on smaller releases New technologies for detecting lower amounts of pollutants is increasing knowledge of chemicals in the environment Significant advancement in scientific knowledge Advances in basic biology (molecular and cellular biology), chemistry (computational chemistry), and mathematics (better statistical and dose-response tools) More subtle effects as opposed to gross effects

Evolving Risk Assessment Triggered by…. Need to estimate long-term effects from exposure to environmentally relevant concentrations – i.e. effects of exposure not immediately known. Recognition of need to conduct risk assessment on broader range of chemical inventory as opposed to individual chemicals European Union REACH Health Canada Domestic Substances List (DSL) U.S. EPA HPV All these factors have increased public awareness regarding the environmental decision making, including risk assessment.

Current Risk Assessment Challenges Extrapolation of toxicology data extrapolating results not only from animal toxicity studies, extrapolating from the very high doses usually used in animal experiments to the very low doses that are characteristic of human exposure. Lack of adequate information Of the hundreds of thousands of chemicals in commerce – publicly available information is limited to only a few thousand – and in many cases the information is not complete. These issues generate uncertainty in conducting risk assessments.

Toxicity Information Sources Some On-line Databases of Chemical Human Hazard Data Sources Toxicology Data Network (TOXNET) (http://toxnet.nlm.nih.gov/) TSCATS (http://www.syrres.com/esc/tscats.htm) EPA IRIS (http://epa.gov/iris/) IPCS INCHEM (http://www.inchem.org/) NTP (http://ntp-server.niehs.nih.gov/) ATSDR (http://www.atsdr.cdc.gov/toxpro2.html) EPA HPV Challenge Program (http://www.epa.gov/chemrtk/volchall.htm) RTECS (Registry of Toxic Effects of Chemical Substances) CDC/NIOSH EINECS (European INventory of Existing Commercial Chemical Substances Information System) IUCLID (International Uniform Chemical Information Database) - OECD RAIS (Risk Assessment Information System) (DOE) Regional and CA EPA List serves e.g., Risk Anal and mailing lists Societies and organizations – MSWG, ECOS, SOT, local chapters, etc.

Toxicity Information Sources Some On-line Structure Activity Resources Public Domain Tools for conducting similarity of substructure searches: CHEMIDPlus. http://chem.sis.nlm.nih.gov/chemidplus/cmplxqry.html TSCATS (The Toxic Substance Control Act Test Submission database): http://esc.syrres.com/efdb/tscats.htm AIM (Analog Identification Methodology) (in development)

The Need for Information Sharing Nearly all risk assessment folks now adopt the NAS risk assessment/risk management paradigm for their daily risk activity. ATSDR, EPA, FDA, Health Canada, RIVM, and other federal groups can likely address their workloads, but cannot be expected to address all of the needed work for states or for private entities. A venue for governmental, industrial, environmental, and non-profit organizations to collaborate to produce the high quality risk assessment science.

Alliance for Risk Assessment (ARA) A proposal to provide federal, state, local, tribal, and private stakeholders with additional… scientifically-based, independently-derived, peer-reviewed, & verifiable risk values & methods for… environmental decision making

ARA A collaboration of organizations that fosters the development of technical chemical risk assessment products and services, through a collaborative effort of specialists and organizations dedicated to protecting public health The ARA will coordinate with Federal and Sate Agencies whenever possible, to ensure the best use of available resources

ARA Tools Hazard Notification System (HNS) Will be a National Library of Medicine (NLM), web-based system for coordinating work on chemical risk value and methodology documents that are under development or revision Will provide a platform for notification of human health risk assessment projects in progress or completed projects that have either not been peer reviewed and/or are ineligible for inclusion on the International Toxicity Estimates for Risk (ITER) database of chronic human health risk data HNS will also identify risk assessment data gaps and will contain non-chemical information related to human health risk assessment, such as training modules, white papers and risk documents. Groups working on a chemical or issue of interest will be identified and this will allow stakeholders an opportunity to provide input on ongoing assessments or develop collaborations with document authors. Will be linked with the ITER database and will be fully searchable against other databases in the TOXNET system.

ARA Tools International Toxicity Estimates for Risk Database (ITER) Free internet database of human health risk values and cancer classifications from a variety of national and international organizations, as well as independent groups Currently contains risk values for more than 600 chemicals, and is part of the National Library of Medicine’s TOXNET compilation of databases Only database that presents risk data in a tabular format for easy comparison Risk values or documents developed under this alliance will be published on ITER after appropriate peer review and approval of the risk values/documents. This will ensure that new credible risk values developed by both State regulatory agencies and independent groups are widely available to interested parties.  In addition, peer reviewed risk values already developed by State agencies and independent groups can be uploaded to ITER to foster data sharing.  The inclusion of individual state’s risk assessment values on ITER would facilitate sharing of information between state and/or local agencies.  

ARA Project Areas Risk Issues Document Development for Contaminants Need for new risk assessment issues documents will be identified by reviewing existing assessments (including coordination through HNS), sharing internal priorities among funding partners and State groups, and evaluating requests made by interested parties.   For assessments not currently under development, non-profit risk assessment consultancies and academic centers could author such documents for use by the broader risk assessment community.  Assessments will be conducted according to generally-accepted state-of-the science methods Newly developed risk assessment values will be posted on ITER after appropriate peer review and acceptance of proposed values. 

ARA Project Areas Peer Consultation conducted by an expert panel comprised of a core group of highly experienced risk assessment scientists from various organizations Specific experts will address data interpretation issues and provide scientific judgments during document development.  Individuals from State, academia, public interest groups, and industry.  The core group will develop and apply a consistent approach to addressing issues encountered in the development of risk values.  The purpose of this group is to ensure that the documentation meets basic requirements, to apply a consistent approach to addressing generic issues, and to identify key chemical-specific issues that would be useful to highlight during the next step of peer review.  After the peer consultation, the document authors will revise the document, which can then be submitted for peer review.

ARA Project Areas Peer Review A peer review process will be established to address the higher-level, chemical-specific issues that are part of the assessment, and to reach a consensus position on the appropriate risk values or interpretations.  The peer review panel consists of ad hoc members convened to address issues specific to the chemical or issue at hand, and would include chemical-specific experts, and experts on issues key to the specific assessment.  

ARA Project Areas Training Develop a mechanism for risk assessment training Formal training courses and “hands-on” experiences.  Formal training courses would be conducted for state, provincial, tribal, funding partners, and other interested risk assessors on a variety of topics

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

Key Benefits of the Alliance Promotes science-based decision making to protect human health Enhances harmonization and consistent use of innovative solutions in risk assessments thru an open, transparent, multi-stakeholder approach Provides user control of own process, while providing parallel process for shared help. Maintains essential core group of experts that are normally not available within a single agency or state Shares costs and human resources among multiple stakeholders to increase output

ARA Work Flow Steering Committee Federal Agencies, Industry Hazard Role: Provides Advise to Non-Profits on: Mission-related COI Task Priority Membership: (2) Federal Agency (2) State Ag. (1) Tribe (1) NLM (1) TERA (1) Env. NGO (1) Industry (1) Academic Funded Projects Hazard Notification System (HNS) Non-Profit Collaborators States, Tribes, Env. NGOs Unfunded Project Requests ITER

ARA Funds Flow ARA Process Federal Agencies Federal Funds TERA StateHELP ARA Funded Project Surcharge Industry and Federal Grants Federal Agencies Federal Funds Unfunded State Projects 100 Risk Issues per Year by Year 5 Contracts Funded Projects Industry Contracts

Why Would Diverse Groups Provide Funding? The Alliance for Risk Assessment (ARA) mission… Aligns with many public health goals. 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. 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]. NLM & TERA have success in building ITER; ~200,000 hits per month demonstrates likely value of ARA Aligns with stated needs of stakeholders – e.g., Environmental Council of States (ECOS) call for harmonized process.

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: 30 States 4 Tribes 4 Environmental NGO’s 30 Industry groups 6 U.S. Federal Agencies 4 Countries 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

Does This Effort Duplicate Current Federal Efforts? This effort does not duplicate ATSDR MRLs, EPA IRIS RfDs/RfCs, FDA ADIs, Health Canada TDIs or RIVM TOCs. To the contrary, ARA shares resources to avoid duplication because: It does not replace individual regulatory processes; ARA users tap in as appropriate. Many risk values/issues will never be worked by federal groups. 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. ARA goes beyond risk values/issues – it is also a shared resource for training and data communication.

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 9285.7-53

Tiers of Toxicity Data The guidance (2003) sets forth three tiers of toxicity data for human health risk assessments: Tier I – IRIS values Tier II – other EPA provisional values Tier III – Other scientifically valid and peer review values Tier II values are only developed for sites on the Superfund National Priorities List (NPL). Therefore, sites not on the NPL with specific chemical issues must use Tier III if chemical toxicity data is not in IRIS.

www.allianceforrisk.org

Thank You

Discussion Topics What information sharing resources does your group use for sharing information of innovation in risk assessment? Are the current information exchange resources adequate? What ideas/suggestions do you have for increased information sharing ?