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March / April 1999 Charge for the EDSPC Review

Charge for the Science Advisory Board (SAB) and Scientific Advisory Panel (SAP) EDSPC Review

Session 1: Scope of the Program
Session 2: Priority-Setting
Session 3: High Throughput Pre-Screening Approach
Session 4: The Proposed Endocrine Disruptor Screening Program

Session 1: Scope of the Program

1) The amendments to the Food Quality Protection Act (FQPA) and the Safe Drinking Water Act (SDWA) mandate or support the development of a screening program that will determine whether pesticides and certain drinking water source contaminants "may have an effect in humans that is similar to an effect produced by a naturally-occurring estrogen, or other such endocrine effect as the Administrator may designate." Very early in its deliberations, EPA’s Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) determined that there was both a strong scientific basis and feasibility, considering time and resource constraints, to expand the scope of the screening program to include the androgen- and thyroid-hormone systems, and to include evaluation of the potential impact on wildlife as well as on human health. EPA agree and is developing a screening program which incorporates these modifications. Does the Joint Subcommittee agree that this expanded scope is appropriate to serve as the starting point for the Endocrine Disruptor Screening Program (EDSP), given the understanding that the framework for the Program can support for further expansion at a later date?

2) The FQPA and SDWA identify a universe of substances that should be evaluated in a an EDSP. EDSTAC noted that there exist many other substances in addition to pesticides and certain drinking water source contaminants that may exhibit endocrine-disrupting potential. They recommended that the "candidate pool" for the EDSP include substances on the Toxic Substances Control Act (TSCA) Inventory, certain complex environmental mixtures as well as non-pesticide food additives, cosmetics and nutritional supplements. EPA agrees that there are substances in addition to pesticides and certain drinking water source contaminants that warrant consideration for inclusion in the EDSP.. Does the Joint Committee agree that this expanded universe of substances should be included in the EDSP process, at a minimum in the priority-setting phase, and continuing on if a potential for concern is identified?

3) FQPA contains a provision which would exempt from the EDSP "any biological substance or other substance if the Administrator determines that the substance is anticipated not to produce any effect in humans similar to an effect produced by a naturally-occurring estrogen" or, presumably, "such other endocrine effect as the Administrator may designate." EPA has identified some chemical categories that may be candidates for exemption. Examples include certain polymers with a number average molecular weight (NAMW) greater than 1000 daltons, certain List 4 pesticide inerts such as cookie crumbs, strong mineral acids and bases, which are most likely to interact with tissue at the portal of entry giving rise to localized lesions rather than systemic effects, certain biopesticides such as plant pesticides or microbials or non-chemical pesticides such as parasitic wasps. Does the Joint Committee agree that there are categories of pesticides and other substances that should be exempt from the EDSP? In addition to the examples noted here, are there additional categories that should be considered for exemption?

4) EDSTAC concluded, and EPA agrees, that there are important complex environmental mixtures that deserve inclusion in the EDSP. EDSTAC recommended that EPA include in the EDSP representative mixtures to which large or identifiable key segments of the population (e.g. children) are exposed. They suggested that high-priority mixture categories 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. EPA proposes to screen and test (if appropriate) one representative mixture from each category, after it confirms that the screening and testing components of the EDSP are satisfactory for the handling of single substances.

A. Is the proposal a reasonable way to address the practicality of screening and testing mixtures

B. Are the six categories of mixtures the most appropriate to address first?

C. Are there other mixture categories that should be included in addition to, or instead of those identified (Note: During the May Consultation, it was suggested that mixtures found in fish tissue, benthic sites and eggs of Great Lakes birds should replace gasoline as a priority mixture)

D. Can/should standardized representative mixtures be developed? If so, how should the chemical combinations, ratios, and doses be selected for mixtures?

E. If a mixture is positive in the screening tier, should the whole mixture be tested in the testing tier or should only the active component(s) in the screen(s) be tested in the second tier?

Session 2: Priority Setting

5) EDSTAC recommended a compartment-based approach to priority-setting. EPA agrees that this is the appropriate framework. Under this approach, EPA will groups chemicals into sets, based on the existence of factual information in a given area. Thus, priority ranking can be made fairly among substances, i.e., chemicals will compete for priority with others on the basis of comparable data and will not be assigned lower priority for lack of information. Are these principles and the component-based approach to priority setting reasonable? Are there approaches that would be more useful?

6) EPA is developing a relational database to assist in developing priorities for screening. The relational database is intended to import existing data and allow its synthesis, 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. Would the Joint Subcommitee comment on the approach and provide additional insights to improve the content of the relational database or its implementation?

Session 3: High Throughput Pre-screening Approach

7) EDSTAC recommended, and EPA proposes to implement a priority setting strategy that includes initial sorting based on an examination of existing information. This initial sorting strategy leads to four possible outcomes: i) polymers; ii) chemicals with sufficient data to proceed to testing; iii)chemicals with sufficient data to proceed to hazard assessment; and iv) chemicals with insufficient data, which presumably, would go into the screening phase. EPA anticipates that a large number of substances will end up in category iv-chemicals with insufficient data. To provide at least a minimum number of biological data to assist in the sorting process, EPA proposes to conduct High Throughput Prescreening on a significant number of substances (perhaps, as many as 15,000), using in vitro assay systems incorporating transcriptional activation or reporter gene systems for the estrogen-, androgen- and thyroid-hormone systems.

A. On the assumption that the technology can be shown to be applicable to 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?

B. EPA has been funding a pilot study, using about 80 chemicals, to determine the applicability of the high throughput technology in a prescreening component of the EDSP. Based upon your review of the data developed to date, does the Joint Subcommittee believe that this technique can be used as a prescreening device? If not, what modifications/improvements must be made in order to assure its usefulness?

Session 4: The Proposed Endocrine Disruptor Screening Program

8) EPA is proposing to develop and implement an Endocrine Disruption Screening Program that consists of two phases. The first phase is screening, currently consisting of eight components. The second phase is testing, currently envisioned to have one to five components, depending upon the need for identifying effects in various sectors of the animal kingdom. Is it reasonable and appropriate to develop and implement a two-phase program, the first phase focused on identifying a substance’s potential to interact with one or more of the three hormone systems, the second phase to characterize the effects of concern that interaction with these hormone systems might elicit?

9) EDSTAC recommended, and EPA proposes to implement, a screening battery consisting of eight assays, three in vitro and five in vivo, to address estrogen-, androgen- and thyroid-hormone system effects. At the time (a year ago or so) and continuing to today, based upon our knowledge of the state-of-the-science, the Agency believed that these eight assays, once validated and standardized, would detect all substances currently-known to interact with the three hormone systems to be covered in the Program. Does the Joint Subcommittee agree with this assessment? If not, what changes should be made in the battery to assure the identification of substances of potential concern?

10) Interaction with a receptor is the principal or key mechanism by which substances exert their effects on the estrogen- and androgen-hormone systems. This appears NOT to be the case for the thyroid-hormone system. In light of this, does the Joint Subcommittee believe that there is adequate coverage of the thyroid provided in the proposed screening battery? If not, what modifications should/could be made?

11) EPA would prefer to have a screening battery which included assays containing an in utero or in ovo exposure component, given its great and continuing concern about the potential for effects on the developing vertebrate organism. At the time the proposed screening battery was being assembled, EPA was not aware of the existence of any such screens. Is the Joint Subcommittee aware of any such assays that may exist or are under development that could supplant or complement one or more components of the proposed screening battery?

12) EDSTAC recommended, and EPA would prefer, for efficiency and cost reasons given the numbers of substances that may be involved in the EDSP, to conduct each in vivo screening assay using only one dose, with the appropriate use of range finding studies and other information to inform dose selection. Does the Joint Subcommittee agree with this approach, and if not, what suggestions would it have to modify the approach, keeping pace, volume, cost and efficiency in mind? What would be the public health consequences of these false negatives? (Note: At the May consultation, some members raised concern about relying on a single dose and suggested that a minimum of two doses, and perhaps even three, be used to ensure that the screens do not yield false negative results.  It has also been suggested, elsewhere, that this issue could/should be solved during validation/standardization.)

13) EDSTAC recommended, and EPA is proposing, a testing phase in the EDSP which could have as many as five components (i.e. covering mammals, birds, fish, invertebrates and amphibians). Each test would be designed to delineate the dose-response relationships of effects of concern for chemicals which yielded positive results during the screening phase. The testing protocols to be used are either upgrades or modifications of exisiting guidelines, except for the amphibian. In this case, a protocol is being developed de novo. Does the Joint Subcommittee believe that these test protocol designs will provide sufficient rigor to identify effects of concern and establish their dose responses for disruption in the estrogen-, androgen- and/or thyroid-hormone systems?

14) There could be circumstances in which substances bypass the screening phase, and go directly into the testing phase. EPA is proposing for those cases that the chemical under evaluation be tested in all five tests. Dose the Join Subcommittee believe that the tests in the testing phase will be adequate to detect all known critical endpoints in the estrogen-, androgen- and thyroid hormone systems? If not, what modifications should be made?

15) If the results of any of the testing phase tests are negative, what, if any, additional screening or testing should be conducted to assure that the chemical is not an endocrine disruptor in the estrogen-, androgen- or thyroid hormone systems of that sector of the animal kingdom?

16) Testing phase tests will identify effects of concern that are the consequence of endocrine disruption. They may also identify effects of concern that are not the consequence of endocrine disruption. Thus, it may not be possible to determine if a substance is an endocrine disruptor if it has not been subjected to some or all components of the screening battery. Is it important to be able to identify substances as endocrine disruptors from the standpoint of conducting a hazard assessment. If so, why? If not, why not?

17) EPA is proposing a validation program in which the maximum validation effort will consist of conducting each assay in three laboratories. EPA believes that there currently is a wide variation in the state of validation of each of the proposed screens and tests, and that the validation efforts should be tailored for each assay/test accordingly. EPA plans to focus first on the validation of the mammalian assays as they are both better developed than the non-mammalian assays and are more directly relevant to meeting the FQPA and SDWA mandates for a screening program for potential human health impacts.

EPA’s preliminary assessment of the work needed is as follows:

The uterotrophic assay requires the development of a standardized protocol but may need little or no additional laboratory/protocol development effort since the assay has been in extensive use for many years.

The Hershberger assay may require some, but not much, additional laboratory/protocol development in addition to standardization.

The pubertal male and pubertal female assays need some additional developmental work and will require the full regime of interlaboratory validation.

The mammalian two-generation reproduction test will require limited testing in one laboratory to validate the new endpoints since the basic protocol is already considered to be valid.

Both of the non-mammalian screens and some of the non-mammalian tests will require the full validation regime; some will require further pre-validation development (e.g. amphibian test).

Does the Joint Committee agree with the Agency’s assessment of the current status of the screens and tests? If not, what is the Joint Committee’s own assessment of any screen or test which differs from EPA’s, and what is the basis for your opinion?

18) Does the Joint Subcommittee have any other suggestions or recommendations that would help EPA meet its charge?

Scientific Advisory Panel (SAP): March/April 1999 Meeting

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