Results of the Society of Toxicology’s Expert Panel Workshop “Risk Assessment of Mixtures: Development of Testable Hypotheses As Science Input Into Policy Decisions” Jay I. Goodman Michigan State University International Conference on Chemical Mixtures, Atlanta, GA,

Risk Assessment of Mixtures: Development of Testable Hypotheses A Workshop Organized by the Society of Toxicology September 8-9, 2002

The Society of Toxicology’s Core Purpose is to Enhance Human, Animal and Environmental Health Through the Science of Toxicology “Toxicology is part of the solution!”

SOT Expert Panel Workshop Chris Borgert James Bruckner Edward Carney Janice Chambers Rory Conolly Chris DeRosa Pat Durkin Hisham El-Masri Elaine Faustman Chris Gennings John Groton Richard Hertzberg Kannan Krishnan Lynn McCarty Joel Pounds Paul Price Glenn Rice Thomas Sinks Nigel Walker John Wysner Raymond Yang Tim Zacharewski

Sponsors Society of Toxicology Agency for Toxic Substances Disease Registry Chlorine Chemistry Council National Institute of Environmental Health Sciences Society for Environmental Toxicology and Chemistry U.S. Environmental Protection Agency

Steering Committee John Bucher - NIEHS Jim Bus - Dow Chemical Co. Bill Farland - U.S. EPA Jay Goodman (Chair) - Michigan State University Shawn Lamb - Society of Toxicology Ann Mason - Chlorine Chemistry Council Moiz Mumatz - Agency for Toxic Substances and Disease Registry Rod Parrish - SETAC Claudia Thompson - NIEHS

The Initial Stages Formation of a Working Group to identify broad technical issues. Hold a Workshop to build upon the issues identified by the Working Group: Identify Testable Hypotheses. Chlorine Chemistry Council, National Institute of Environmental Health Sciences, Environmental Protection Agency to make a good faith effort to incorporate the “testable hypotheses” into their existing mechanisms to fund research.

Working Group Meeting, September 2000 Members: Linda Teuschler (Chair) - U.S. EPA Jim Klaunig (Co-Chair) - Indiana University Ed Carney - Dow Chemical Co. Janice Chambers - Mississippi State University Rory Conolly - CIIT, Ctrs. Hlth. Research Chris Gennings - Virginia Commonwealth University John Giesy - Michigan State University Richard Hertzberg - U.S. EPA Curt Klaassen - University of Kansas Ralph Kodell - National Center for Toxicological Research. Dennis Paustenbach - Exponent Environmental Group Raymond Yang - Colorado State University

Working Group “… a substantially enhanced toxicology research program is required in order to provide a strong, science-based approach to the assessment of the potential toxicity of mixtures.” Teuschler et al. (2002). Support of science- based decisions concerning the evaluation of the toxicology of mixtures: A new beginning. Regulatory Toxicology and Pharmacology, in press.

White Paper “… a consensus paper suggesting that … toxicology must advance into largely uncharted territory that places a strong emphasis specifically upon three key ideas….” 1. Focus on real world exposures 2. Use a collaborative, multi-disciplinary team approach 3. Novel approaches and new technologies need to be employed to obtain the mechanistic information necessary to develop biologically-based models that can enhance our ability to predict potential health risks from real world exposure to complex mixtures.

Workshop, September 8-9, 2002 Risk assessment of Mixtures: Development of Testable Hypotheses Charge: Propose biologically-based hypotheses and experimental approaches to enhance the scientific quality of risk assessments. Goal: To facilitate the generation of productive research strategies, leading to information that will improve the scientific foundation of mixture regulatory practices and policies.

The starting points: Enhancement of the scientific basis for risk assessment of mixtures is necessary. The three “basic themes” presented in the White Paper provide the basis upon which the Workshop shall move forward. All discussion of models will be centered upon those that are biologically-based.

Breakout Sessions to Identify Key Questions, Data Gaps and Critical Needs for Decision Making Session 1: Exposure Session 2: Dose Session 3: Biologically-Based Models

Breakout Sessions to Identify Key Hypotheses to be Tested to Answer the Critical Needs Session 4: Individual Components vs. Whole Session 5: Real World Exposure Session 6: High to Low Dose

The Focus: Real world exposure Toxicity testing at environmental doses Biologically-based models Note: It is possible to perform hypothesis- driven research aimed at explaining why a threshold may exist.

Breakout Session 1: Exposure Key Scientific Questions/Data Gaps How does mixture change [e.g., dose, route, physical state] from source to exposure media to populations of concern? People have complex environmental exposure histories that are not usually reflected by experimental [laboratory] studies. Biomonitoring results may not be reflective of short lived, poorly detectable, and unknown compounds from biologic media.

Breakout Session 2: Dose Key Scientific Questions/Data Gaps Interaction thresholds: Are environmental levels of exposure of any physiological significance for understanding “adverse” response? Is there a general relationship between thresholds of toxicity and interaction thresholds? What dose metrics represent “common currency” for complex mixtures within and across levels of biological organization?

Breakout Session 3: Biologically- Based Models Key Scientific Questions/Data Gaps Do binary interactions predict mixture toxicity? What are the modeling-specific data needs? How to bridge the gap between empirical and mechanistically-based models ?

Research Hypotheses Additivity prevails at low exposure levels. Apparent dose thresholds for interactions are higher than individual chemical thresholds. Mixture toxicity and interaction thresholds can be predicted from known interaction processes.

Research Hypotheses The mechanism/mode of action is the same at all doses. Unique responses at molecular levels in mixtures compared to individual chemicals suggest novel effects of mixtures. Populations susceptible to individual chemicals are more susceptible to complex mixtures than the general population.

Research Hypotheses Toxicokinetics/toxicodynamics of a mixture can be predicted from the toxicokinetics/ toxicodynamics of the individual chemicals. The “unidentifiable fraction” of a mixture contributes nothing to the complex mixture. Mixtures toxicity estimation can be simplified by grouping components with similar properties.

Overall Conclusions Enhancing science-based safety assessment: A win-win situation. The ability to make progress can be enhanced by academia, government and industry working together. The Society of Toxicology can play a key role as a facilitator of these activities.