Session III: Assessing Cumulative Effects of Endocrine Active Substances 9:15 - 9:30 Introduction” Rick Becker (Session Chair and Panel Moderator) 9:30 – 10:30 Point – Counterpoint: “Techniques For Assessing Endocrine Cumulative Risk” Bob Golden “Limitations of EDSP Data For Assessing Cumulative Risk” Chris Borgert 10:30 11:45 Panel Presentations and Discussion “Perspectives” Tim Pastoor “Perspectives” Jane Ellen Simons Panel Discussion: Chris Borgert, Bob Golden,Tim Pastoor, Jane Ellen Simons, 11:45- 12:30 Lunch (Included with Registration)

Session III: Assessing Cumulative Effects of Endocrine Active Substances What is cumulative risk and why is it of interest? What do we know about physiology and pharmacology of the endocrine system that can inform approaches to cumulative risk evaluations? What’s known about responses to mixtures that can be applied to endocrine active substances?

In the broadest sense “Cumulative risk” means “the combined risks from aggregate exposures to multiple agents or stressors.” Not single chemicals or stressors May be biological or physical agents or activities, direct or indirect effects Requires combining effects; not necessarily ‘adding’ A ‘cumulative risk assessment’ need not be quantitativeA ‘cumulative risk assessment’ need not be quantitative U.S. EPA, Framework for Cumulative Risk Assessment. Risk Assessment Forum, Washington. EPA/630/P-02/001F. Cumulative Risk: What Is It?

December 2008, National Research Council report “Science Policy and Decisions: Advancing Risk Assessment” Panel proposed cumulative risk assessment be defined as “evaluating an array of stressors (chemical and non-chemical) to characterize – quantitatively to the extent possible – human health or ecological effects taking account of such factors as vulnerability and background exposures.” Cumulative Risk: What Is It?

December 2008, National Research Council report “Science Policy and Decisions: Advancing Risk Assessment” With respect to cumulative risk overall – not phthalate specific -- the Panel recommended that the focus for cumulative risk assessments in general should be on health outcomes, not only on mechanism. They point out that many mechanisms can lead to the same outcome. They use the term “common adverse outcomes” to describe the method they recommend. Cumulative Risk: What Is It?

Cut & Pasted from: Jerry Heindel Ph/D. NIEHS EED Gordon Conference June 2008 Allegations of Effects Concerns for Health Effects from Mixtures

Silva E, Rajapakse N, Kortenkamp A, Something from "nothing" - Eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects Environ. Sci. Technol. 36 (8): APR Charlees G et al. Analysis of the interaction of phytoestrogens and synthetic chemicals: An in vitro/in vivo comparison Toxicology and Applied Pharmacology Volume 218, February 2007, Pages

Operational Definitions Aggregate Risk: FQPA amendments of FFDCA directed OPP to consider “aggregate exposure” in its decision-making. “Aggregate exposure” refers to the combined exposures to a single chemical across multiple routes (oral, dermal, inhalation) and across multiple pathways (food, drinking water, residential). Cumulative Risk: For pesticide tolerances, FQPA amendments of FFDCA directed OPP to “…assess the risk of the pesticide chemical residue based on… available information concerning the cumulative effects on infants and children of such residues and other substances that have a common mechanism of toxicity”

Cumulative Risk: What Is It? OPP’s Guidance for Pesticide Actives 1.Begins with the identification of a group of chemicals – the common mechanism group - induce a common toxic effect by a common mechanism of toxicity 2.Dose-response analysis on each member to determine its toxic potency for the common toxic effect 3.For estimating toxic potency – needs to be be conducted on a uniform basis (i.e., same measure of potency, for the same effect, from the same test species/sex using studies of comparable methodology) 4. Use of dose addition for determining the combined risk

At doses near the NOAEL, Cumulative Effects reported in animals for: Anti-androgenic endpoints Estrogenic endpoints Immune endpoints At up to 100X environmentally relevant concentrations, No Cumulative Reproductive Effects found for complex mixtures of ground water contaminants Can we accurately/confidently predict cumulative Adverse Effects based on presumed modes of action within EDSP (EAT) at doses that greatly exceed human exposures? Cumulative Risk: Is It Relevant for Endocrine Active Substances?

Session III: Assessing Cumulative Effects of Endocrine Active Substances 9:15 - 9:30 Introduction” Rick Becker (Session Chair and Panel Moderator) 9:30 – 10:30 Point – Counterpoint: “Techniques For Assessing Endocrine Cumulative Risk” Bob Golden “Limitations of EDSP Data For Assessing Cumulative Risk” Chris Borgert 10:30 11:45 Panel Presentations and Discussion “Perspectives” Tim Pastoor “Perspectives” Jane Ellen Simons Panel Discussion: Chris Borgert, Bob Golden,Tim Pastoor, Jane Ellen Simons, 11:45- 12:30 Lunch