Session III: Assessing Cumulative Effects of Endocrine Active Substances
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Session III: Assessing Cumulative Effects of Endocrine Active Substances. Session III: Assessing Cumulative Effects of Endocrine Active Substances. What is cumulative risk and why is it of interest?

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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?


Cumulative risk what is it
Cumulative Risk: What Is It? 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 quantitative

U.S. EPA, 2003. Framework for Cumulative Risk Assessment. Risk Assessment Forum, Washington. EPA/630/P-02/001F.


Cumulative risk what is it1
Cumulative Risk: What Is It? Active Substances

  • 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 it2
Cumulative Risk: What Is It? Active Substances

  • 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.


Cut & Pasted from: Active Substances

Jerry Heindel Ph/D. NIEHS

EED Gordon Conference June 2008

Allegations of Effects

Concerns for Health Effects from Mixtures

http://e.hormone.tulane.edu/pdfs_ehormone’heindelGRCslides.pdf


Charlees Active Substances 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 280-288

Silva E, Rajapakse N, Kortenkamp A, Something from "nothing" - Eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effectsEnviron. Sci. Technol. 36 (8): 1751-1756 APR 15 2002


Operational Definitions Active Substances

  • 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
Cumulative Risk: What Is It? Active SubstancesOPP’s Guidance for Pesticide Actives

Begins with the identification of a group of chemicals – the common mechanism group - induce a common toxic effect by a common mechanism of toxicity

Dose-response analysis on each member to determine its toxic potency for the common toxic effect

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)

Use of dose addition for determining the combined risk


Cumulative Risk: Active SubstancesIs It Relevant for Endocrine Active Substances?

  • 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?



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