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Page 410 Addendum Endocrine Disruptor Screening and Testing Advisory Committee The 1996 Food Quality and Protection Act (FQPA) and the Safe Drinking Water Act (SDWA) mandated that the U.S. Environmental Protection Agency (EPA) develop a screening and testing strategy for endocrine disruptors by August 1998 and to implement the plan by August 1999. In response to this mandate, EPA formed the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to advise EPA on the screening and testing of pesticides and chemicals for their potential to disrupt the endocrine system. EDSTAC is composed of representatives from several federal agencies, industry, academia, and environmental groups. EDSTAC has held 10 public meetings to develop a screening and testing strategy for endocrine disruptors. A draft of EDSTAC's final report to EPA was released in August 1998. Below is a summary of the major recommendations in that report and discussion of how those recommendations compare with the recommendations of the committee. Summary of Edstac's Recommendations The charge to EDSTAC was to develop recommendations for a screening and testing program for endocrine-disrupting chemicals. EDSTAC interpreted this charge to include the provisions of the Federal Insecticide, Fungicide, and Rodenticide Act, the Toxic Substances Control Act, and the Federal Food, Drug, and Cosmetic Act, in addition to the 1996 FQPA and SDWA provisions. Because these acts require testing on a variety of chemicals for human health and ecological effects, EDSTAC recommends that the scope of EPA's screening and testing program for endocrine disruptors shouldbreak
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Page 411 · address human and ecological (wildlife) effects; · examine effects on estrogen, androgen, and thyroid hormone-related processes and on other hormones and their processes as more data and assays become available; and · evaluate endocrine-disrupting properties of chemical substances and common mixtures. EDSTAC estimates that approximately 86,000 chemicals and mixtures will need to be considered for endocrine-disruptor screening and testing. To handle the immense number of chemicals in the program, EDSTAC recommends an initial sorting and prioritizing of the chemicals, followed by a tiered testing approach to detect endocrine-disrupting chemicals and quantify their effects. Those core elements of the approach are described below. Initial Sorting Initial sorting involves an evaluation of existing data on a chemical. On the basis of that information, a chemical is classified into one of four categories: ( ) chemicals (primarily polymers) that have sufficient data indicating that they are not likely to interact with the estrogen, androgen, and thyroid (EAT) hormone systems and therefore require no further analysis (they will be placed in a "hold box"); (2) chemicals that have insufficient data and therefore require tier 1 screening for hormonal activity; (3) chemicals that have sufficient evidence of hormonal interaction and therefore require tier 2 testing; and (4) chemicals that have sufficient evidence of hormonal interaction and hormone-related effects and therefore require hazard assessment. Priority Setting Chemicals that are placed in the second category of having insufficient data will be prioritized for screening on the basis of exposure-related information. effects-related information, and statutory criteria, and then phased into the screening program. Tier 1 Screening Chemicals and mixtures will be tested in a battery of in vitro and in vivo screening assays for their potential to interact with the EAT hormonal systems. If the weight of evidence from the screening assays indicates hormonal interaction, tier 2 testing will be required. If the weight of evidence indicates no hormonal interaction, the chemical will be placed in the hold box. EDSTAC recommends the following battery of assays for tier 1 screening:break
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Page 412 · In Vitro Assays -estrogen-receptor binding and reporter-gene assay -androgen-receptor binding and reporter-gene assay -steroidogenesis assay with minced testis · In Vivo Assays -rodent 3-day uterotrophic assay -rodent 20-day pubertal female with thyroid -rodent 5-7-day Hershberger assay -frog metamorphosis assay -fish gonadal recrudescence assay Because those assays are designed to work as a whole, EDSTAC believes that all of them are necessary for EPA to make accurate decisions about chemicals that are screened. EDSTAC recommends that the assays be standardized and validated before final adoption. Tier 2 Testing Chemicals and mixtures will be tested to determine whether they exhibit endocrine-mediated adverse effects and to identify, characterize, and quantify those effects for EAT hormones. If endocrine-mediated effects are found, the data will be used in a hazard assessment: further testing might also be required to determine whether the identified effects are endocrine mediated. If endocrine-mediated effects are not identified, the chemical is placed in the hold box. EDSTAC recommends the following battery of assays for tier 2 testing: · two-generation mammalian reproductive toxicity study or a less comprehensive test (e.g., alternative mammalian reproductive test) · avian reproduction test · fish life-cycle test · mysid life-cycle test · amphibian development and reproduction test EDSTAC recommends that those assays be standardized and validated before final incorporation into the screening and testing program. As with the tier 1 tests, tier 2 tests are designed to work as a whole. However, the performance of the entire battery with multiple generations might not always be necessary and EDSTAC has provided some guidance in the selection of tier 2 tests. EDSTAC recognizes that questions have been raised about the adequacy of conventional toxicology study designs for assessment of endocrine-active substances, particularly with regard to low-dose selection and identification of no observed-adverse-effect levels (NOAELs). To address the questions, EDSTACcontinue
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Page 413 recommends that a research program be conducted to resolve the underlying uncertainties and controversy about these issues. In addition to the major recommendations described above, EDSTAC has provided EPA with more detailed guidance on all aspects of the screening and testing program. The reader is referred to EDSTAC's June 17, 1998 report for details on those recommendations. Comparison of NRC and EDSTAC Screening Recommendations Chapter 11 details the NRC committee's evaluation of the available data and methods for screening HAAs. The major conclusion of the committee is that no generally accepted, validated methods are available to screen for HAAs, and therefore a battery of different assays evaluating different end points will be necessary for reliable determinations of hormonal activity. The committee made the following general recommendations for screening HAAs: A battery of short-term assays should be developed for rapid and inexpensive screening for putative HAAs. The assays should detect diverse responses that depend on hormone receptors, should detect other indirect responses, and should be readily adapted for use in multiple laboratories. Short-term assays should be validated, replicated, and deployed in a rational fashion. Investigations should also be conducted to determine whether short-term assays predict in vivo toxicity. Some potential biomarkers of exposure to HAAs in wildlife and humans are available and should be applied. Additional biomarkers should be developed and validated before application. In particular, assays should be developed that screen for embryonic and fetal events (markers) that predict long-term, delayed effects. Species- and tissue-specific effects resulting from exposure to environmental HAAs need to be investigated further. Differences in response to HAAs between adults and developing fetuses need to be investigated with regard to the possibility of unique effects due to exposure during critical periods in development when genetic imprinting is occurring. Wildlife can serve as environmental sentinels. Populations known to be exposed to HAAs should be monitored for both obvious and subtle responses to exposures. Studies of caged, pinioned, or telemetered animals could provide information about the location, duration, and magnitude of exposure, which could be used to interpret the results of field studies. Dose-response characteristics of recognized actions of various HAAs should be further investigated in in vitro and in vivo studies using concentrations found in the environment.break
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Page 414 These recommendations are consistent with EDSTAC's more specific recommendations that recognize the need for multiple assays evaluating diverse hormonal responses. Similar to EDSTAC, the committee recommends that validated and standardized assays be used to assess the effects of HAAs on various species and tissues and include a consideration of developmentally critical or sensitive life stages. The committee also recognizes the need to investigate further the action of HAAs in vivo and in vitro using concentrations of HAAs found in the environment.break
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