Review of the Environmental Protection Agency's State-of-the-Science Evaluation of Nonmonotonic Dose-Response Relationships as they Apply to Endocrine Disruptors (2014) / Chapter Skim
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3 The Environmental Protection Agency's Evaluation of Implications of Nonmonotonic DoseResponse Relationships for Current Toxicity-Testing Strategies and Risk-Assessment Practices
3 The Environmental Protection Agency's Evaluation of Implications of Nonmonotonic DoseResponse Relationships for Current Toxicity-Testing Strategies and Risk-Assessment Practices
Pages 38-46
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From page 38... ...
Thus, the same issues and problems discussed in Chapter 2 carry over to the review of the evidence in this chapter. THE ENVIRONMENTAL PROTECTION AGENCY'S EVALUATION OF THE ADEQUACY OF TOXICITY TESTING In trying to answer Question 2, EPA posed three more specific questions: 38
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From page 39... ...
2c. Do EPA chemical testing strategies detect relevant adverse effects for chemicals which produce NMDR curves for specific endpoints?
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From page 40... ...
The MOAs associated with those effects should then be evaluated in the context of additional supportive data, if available, to help in understanding the sequences of key events that ultimately lead to the adverse effects. As the SOTS evaluation noted, not all measured end points are themselves adverse or necessarily key events associated with an adverse response, so careful consideration is needed.
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From page 41... ...
In response to this question, the SOTS evaluation states that "for estrogen, androgen or thyroid MoA[s] that provide adequate information to make an assessment, our evaluation shows that there is not sufficient evidence of NMDRs for adverse effects below the NOAELs or BMD derived from the current testing strategies." However, the evaluation provides no analysis of EPA's testing protocols for their adequacy to detect NMDR curves for adverse responses at doses below NOAELs or BMDs derived from traditional toxicology-testing protocols.
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From page 42... ...
The SOTS evaluation does not include an analysis that considered both the extent of end-point coverage and the quality of the response. THE ENVIRONMENTAL PROTECTION AGENCY'S EVALUATION OF THE IMPLICATIONS OF NONMONOTONIC DOSE–RESPONSE RELATIONSHIPS FOR RISK-ASSESSMENT PRACTICES Question 3 of the SOTS evaluation was: Do NMDRs provide key information that would alter EPA's current weight of evidence conclusions and risk assessment determinations, either qualitatively or quantitatively?
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From page 43... ...
Those types of analyses are needed to determine whether NMDR curves provide key information that would alter EPA's current WOE conclusions and risk-assessment determinations. Noticeable omissions in the draft SOTS evaluation are consideration of human studies -- including the physiologic, clinical, and epidemiologic evidence -- and discussion of how evidence of NMDR curves in ranges relevant to humans would be incorporated into risk assessments.
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From page 44... ...
Because the SOTS evaluation is to be a foundational synthesis of the literature on NMDR curves for the estrogen, androgen, and thyroid pathways, a higher standard of evaluation is required. Developing at least a simple framework that identifies the testing methods and evaluates their ability to detect endocrine-mediated adverse effects and NMDR relationships is necessary to answer, fully and transparently, questions about the ability of current testing strategies to characterize hazards related to endocrine disruptors appropriately.
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From page 45... ...
If such data are included, they could be used to highlight species differences in chemical interactions with respect to the three hormone pathways, including pharmacokinetic and pharmacodynamics processes that are important considerations in conducting risk assessments. REFERENCES EFSA (European Food Safety Authority)
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From page 46... ...
EPA (U.S. Environmental Protection Agency)
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