May 1998, Questions for The SAP Meeting
Questions for SAB/SAP Peer Review or "Consultation"
on the EDSTAC Report
Questions for the Review Panel
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The draft report describes a conceptual framework used to guide development of the screening and testing program (Chapter 3, 74 KB), a scheme to set priorities among chemicals for screening (Chapter 4, 277 KB), the screens and tests being recommended (Chapter 5, 297 KB) and a section on communication of program elements and results to the public (Chapter 6, 35 KB). The following questions were developed by EDSTAC members and EPA staff to assist in focusing the discussion at the May meeting. The questions are presented in the general order of the draft report and follow the meeting agenda topics.
- The Food Quality Protection Act requires EPA to screen pesticides for estrogenic effects that may affect human health. At its first meeting, EDSTAC decided that it was more scientifically appropriate to focus on estrogen, androgen and thyroid effects and to include effects on wildlife as well as human health effects in designing a screening and testing program for endocrine disrupting compounds. Is the broader scope defined by EDSTAC in it's conceptual framework the appropriate one for the screening and testing program? Are there alternatives that would be more appropriate?
- The EDSTAC's Conceptual Framework lists criteria and principles that guided the EDSTAC's work in developing a strategy for priority setting and screening and testing. Are these criteria and principles appropriate, clear and consistent with the strategy that emerged in chapters 4 (277 KB) and 5 (297 KB).
- The criteria and principles in Chapter 3 (74 KB) were intended to assist in the selection of screening assays in the recommended screening battery (Chapter 5, 297 KB). The Committee also intended them to be used in the future as the science of endocrine disruptors advances and new methods become available. Are the criteria and principles sufficiently well developed for this purpose?
- The EDSTAC struggled with describing the term "endocrine disruptor." Does the description, as presented, adequately reflect the state of the science? Is it appropriate for use in the recommended screening and testing program?
Endocrine Disruptor Priority Setting Process
- The EDSTAC is recommending that all pesticides, non-polymeric chemicals produced at over 10,000 pounds annually, and selected mixtures be examined through high throughput pre-screening (HTPS) assays. The HTPS is comprised of several reporter gene assays for the estrogen-alpha, estrogen-beta, androgen, and thyroid receptors. This technology has been developed primarily to screen compounds for pharmaceutical activity, but may have wider application in examining xenobiotic compounds for endocrine activity. Can the Panel comment on the feasibility and usefulness of this approach considering the wide array of chemical structures represented by TSCA and FIFRA chemicals/pesticides?
- The EDSTAC is recommending principles for setting priorities. It recommended a compartment-based approach to priority setting as a way to accommodate the priority setting principles and given the real world situation of uneven data. Are these principles and the approach to priority setting reasonable?
- The EDSTAC is recommending a priority setting strategy that included initial sorting based on an examination of existing information. The initial sorting strategy leads to four possible outcomes: I) polymers; ii) chemicals with sufficient data to proceed to tier 2 testing; iii)chemicals with sufficient data to proceed to hazard assessment; and iv) chemicals with insufficient data. The EDSTAC recommends the early initiation of the HTPS to provide a minimum of biological data to better inform initial priority setting efforts, especially as they relate to chemicals falling into the last outcome category. Given the large number and wide range of chemical substances under consideration, and the limited relevant test data which are available for many industrial chemicals, is this a reasonable approach and sorting strategy to support priority setting?
- Given the nature of polymers, the EDSTAC recommended treating them separately. Further, EDSTAC recommended that polymers with an average molecular weight greater than 1,000 daltons be excluded from priority setting and screening unless their monomers, oligomers, or leachable components are shown to have endocrine disrupting potential in Tier 1 Screening. What is your opinion of EDSTAC's proposed recommendation for handling polymers?
- The EDSTAC developed a preliminary inventory of existing databases
related to chemical exposure and effects, and used this preliminary
inventory to develop sets of exposure, effects, and statutory
criteria to be used to assist in developing priorities for screening.
- a. Are the sets of criteria adequate?
- b. Have the types of data that should be gathered and analyzed for priority setting been identified?
- c. Are their strengths and weaknesses described correctly, and are the guiding principles for their use appropriate?
- d. Will the relational database be helpful in determining the number of chemicals which would fit into each of the prioritization categories?
- The EDSTAC is recommending the development of a relational database to assist in developing priorities for screening. The relational database is intended to allow synthesis of existing data and information, as well as the estimation of certain parameters through modeling. The relational database was considered to have great value in helping to identify the specific compartments under the EDSTAC's compartment-based priority setting approach. The database will also be helpful in selecting chemicals for the first and subsequent rounds of screening. Can the panel comment on the approach or provide additional insights to improve the content of the relational database or its implementation?
- The EDSTAC believes EPA should screen and, if appropriate, test
representative mixtures to which large or identifiable segments
of the population are exposed. The high priority mixture categories
identified by EDSTAC include: chemicals in breast milk; phytoestrogens
in soy-based infant formulas; mixtures commonly found at Superfund
sites; common pesticide/fertilizer mixtures found in ground and
surface water; disinfection byproducts; and gasoline. The EDSTAC
proposes screening and testing one representative mixture from
- a. Can standardized presumptive mixtures be developed? If so, how should the chemical combinations, ratios, and doses be selected for mixtures?
- b. Is the proposal a reasonably pragmatic approach to address the practicality of screening and testing mixtures?
- c. Are the six categories of mixtures the most appropriate to address first?
- d. Are there other mixtures categories that should be included in addition to, or instead of those identified (e.g., Should fish tissue contaminants be one of the first mixtures)?
Proposed Endocrine Disruptor Screening Battery and Testing Scheme
- The EDSTAC is recommending a screening battery consisting of in vitro and in vivo assays to address estrogen, androgen, and thyroid effects. Will the battery, once validated, be capable of detecting such effects in a consistent and reliable manner?
- The EDSTAC is recommending that the Tier 1 screening in vivo assays be conducted at one dose, with appropriate use of range finding studies and other information (i.e., HTPS results) to inform dose selection. Does the Panel agree with the approach of running the Tier 1 screening in vivo assays with only one dose?
- The EDSTAC attempted, but could not identify existing vertebrate screening assays that incorporated exposure in utero or in ovo. Is the Panel aware of any such screening assays?
- Is adequate coverage of the thyroid provided in the recommended tier 1 screening battery? Does the Tier 1 screening battery provide adequate coverage of non-receptor mediated pathways?
- The EDSTAC believes that "weight of evidence" (WOE) must reflect
professional judgment because not all possible combinations of
outcomes or conclusions can be determined a priori.
Nevertheless, the EDSTAC has provided principles which it believes can govern how WOE may be applied to screening battery results.
- a. Is the approach articulated by the EDSTAC in Chapter 5 (297 KB) appropriate?
- b. Can additional principles or guidance be given regarding WOE and when chemicals should proceed to testing?
- Given the description of endocrine disruptor, can the term endocrine disruptor ever be applied to substances based on the results of tier 1 screening? If so, under what circumstances?
- The EDSTAC recommended a testing battery to delineate dose-response relationships of chemicals that yield positive results in the screening battery. Do the tests provide sufficient rigor to address endocrine disruption dose response for the estrogen, androgen, and thyroid endpoints?
- Will the tier 2 tests be adequate to detect all of the estrogen, androgen and thyroid endpoints in chemicals that bypass tier 1 screening?
- Given the apical nature of tier 2 tests, it may not be possible to determine that a substance is an endocrine disruptor if it bypasses tier 1 screening. Is it important to be able to identify substances as endocrine disruptors from the standpoint of conducting a hazard assessment?
- The EDSTAC has categorized the recommended screens and tests with respect to their current state of validation. Does the Panel agree with the categorization of each screen and test with respect to the test itself and any additional endpoints that are recommended.
- Does the Panel have any other suggestions or recommendations that would help EPA meet its charge?