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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2 Review of the Environmental Protection Agency's Methods for Evaluating Evidence on Nonmonotonic DoseResponse Relationships
2 Review of the Environmental Protection Agency's Methods for Evaluating Evidence on Nonmonotonic DoseResponse Relationships
Pages 16-37
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From page 16... ...
. To address its first task, to determine whether EPA "fairly and soundly evaluated the weight of evidence" on NMDR curves, the committee first identified the key design elements of a thorough, systematic, and transparent evaluation and synthesis of environmental health data (see Box 2-1)
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From page 17... ...
. EVALUATION OF THE ENVIRONMENTAL PROTECTION AGENCY'S APPROACH EPA's strategy for developing the SOTS evaluation was to pose three central scientific questions about NMDR curves with respect to the estrogen, androgen, and thyroid hormone pathways.
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From page 18... ...
Thus, it was unclear how the authors concluded that NMDR curves were found more often in in vitro studies, at high doses, and for exposures of short duration. Inconsistency.
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From page 19... ...
to be clear and reasonable. Question 1 is framed broadly and is open-ended with respect to determining the "conditions" under which NMDR curves might occur.
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From page 20... ...
. That definition is vague and confuses two concepts -- "low dose" and "low effect" -- both of which are important in understanding endocrine disruptors and for identification of NMDR curves.
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EPA is aware of this problem and has indicated that it is monitoring systematic approaches being developed by the National Toxicology Program and EPA's Integrated Risk In 1 "A biochemical change, functional impairment, or pathologic lesion that affects the performance of the whole organism, or reduces an organism's ability to respond to an additional environmental challenge" (EPA 2014)
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From page 22... ...
In the sections below, the committee considers whether the selection criteria in the SOTS evaluation were clearly presented and whether they would ensure that an appropriate set of studies is considered in the analysis. General Issues with Study-Selection Criteria in the State-of-the-Science Evaluation EPA's SOTS evaluation states that it did not "attempt to design exclusion/inclusion criteria for studies uncovered in all literature searches; for reasons of resource limitations, this was done primarily for the description of the data on the thyroid hormone pathway" (EPA 2013a, p.
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From page 23... ...
; no explanation of chemicals" "adequately described" 4.1.1 Aquatic 58 Unable to determine whether Chemicals with effects on either: Restrictions: Unable to determine models (Thyroid) criteria used for aquatic models (HPG axis)
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From page 24... ...
paper. Abbreviations: HPG, hypothalamic-pituitary-gonadal; LOAEL, lowest observed-adverse-effect level ; LOEL, lowest observed-effect level; MOA, mode of action; NIS, sodium-iodide symporter; NMDR, nonmonotonic dose response; NOEL, no-observed-effect-level; PHAHs, polyhalogenated aromatic hydrocarbons; PTU, propylthiouracil; TPO, thyroperoxidase.
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From page 25... ...
, a minimum of six doses is specified, but in vivo studies that tested fewer doses were allowed for inclusion provided that the studies tested a "broad doserange" so that studies cited by others as displaying NMDR curves could be included. However, no definition of a broad dose range was provided.
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From page 26... ...
. Using statistical significance as an absolute criterion for selecting studies with respect to NMDR curves is not recommended, because it can be influenced by several factors that should be explored before a determination of how informative a study would be in addressing the question (see Chapter 3 for further discussion of this issue)
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From page 27... ...
Evaluation of study quality for the SOTS evaluation should include whether a study has the design elements needed to determine the presence or absence of an NMDR curve. Most standard toxicity-testing protocols have low sensitivity and little statistical power for detecting NMDR curves, particularly at the lower end of the dose–response curve, because they typically test only three or four doses.
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From page 28... ...
For example, ANOVA is not designed to detect NMDR curves, so criteria for using such other approaches as biologically based dose–response models, polynomial functions, or splines should be considered. A Response Minimum significant difference 1 10 100 1000 log Dose B Response Minimum significant difference 1 10 100 1000 log Dose FIGURE 2-1 Relationship between the statistical power of a toxicologic experiment and the ability to reveal a nonmonotonic dose–response (NMDR)
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From page 29... ...
. Consistency of Study Descriptions Using a consistent format to present data from the individual studies that evaluated NMDR curves would allow multiple authors to contribute while permitting consistency in style and substance; this would make it easier for readers to understand the data and follow the conclusions.
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From page 30... ...
do the best job of summarizing the overall findings of the studies that demonstrated NMDR curves. This type of data synthesis and interpretation is lacking in the androgen and estrogen sections.
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From page 31... ...
For example, a table could specify by publication the end points evaluated and the dose–response evidence, which would illustrate studies that did and did not show NMDR curves. Alternatively, separate tables could be created for each end point.
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From page 32... ...
Although such an approach might be appropriate as an internal scoping exercise for the agency, the SOTS evaluation is to be its foundational synthesis of the literature on NMDR curves for the estrogen, androgen, and thyroid pathways and addresses biologic responses that are often counterintuitive. The document will probably be a milestone event in the history of EPA's engagement with endocrine disruptors because it draws conclusions about the existence of NMDR curves and the conditions under which they occur that will to be used to inform decisions about the agency's toxicity-testing strategies and risk-assessment practices.
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From page 33... ...
Alt hough statistical significance is an important consideration, it should not be an absolute criterion for including or excluding studies, inas much as standard toxicity-testing strategies generally do not have suffi cient sensitivity and statistical power to detect NMDR curves. o Study quality criteria should be established.
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From page 34... ...
Materials Submitted to the National Research Council, by Integrated Risk Information System Program, U.S. Environmental Protection Agency, January 30, 2013[online]
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From page 35... ...
2006. Selecting studies for systematic review: Inclusion and exclusion criteria.
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From page 36... ...
2001. National Toxicology Program's Report of the Endocrine Disruptors Low Dose Peer Review.
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From page 37... ...
In press. The navigation guide: An improved method for translating environmental health science into better health outcomes.
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