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Endocrine Disruptor Screening Program: Tier I Screening Battery
Citation:
LAWS, S. C., B. W. Riffle, T. E. STOKER, J. M. GOLDMAN, V. S. WILSON, L. E. GRAY, AND R. L. COOPER. Endocrine Disruptor Screening Program: Tier I Screening Battery. 3rd, Chapter 12, Ronald D. Hood (ed.), Developmental and Reproductive Toxicology: A Practical Approach. Informa Healthcare, London, Uk, , 388-408, (2011).
Impact/Purpose:
The U.S. EPA implemented an Endocrine Disruptor Screening Program (EDSP) that is designed to detect chemicals that alter the estrogen, androgen, and thyroid systems in humans, fishes, and wildlife.4 This program, based largely upon recommendations made in 1998 by the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC),5 provides an approach for: (1) the initial sorting and prioritization of chemicals under the purview of the U.S. EPA, (2) the identification of chemicals for further testing, using a Tier I Screening (TIS) Battery that includes both in vitro and in vivo mammalian and ecotoxicological assays, and (3) the characterization of adverse effects and establishment of dose response relationships for hazard assessment, using a Tier II Testing Battery. The two-tiered approach allows a systematic evaluation of environmental chemicals for endocrine activity mediated through the estrogen, androgen or thyroid (EAT) hormone pathways, as well as effects on the hypothalamic-pituitarygonadal (HPG) axis.
Description:
In response to emerging concerns that environmental chemicals may have adverse effects on human health by altering the function of the endocrine system,' the Food Quality Protection Act and subsequent amendments to the Safe Drinking Water Act and Federal Food, Drug and Cosmetic Act (FFDCA) mandated that the U.S. EPA "develop a screening program using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances 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 "[21 U.S.C. 346a(p).2,3Working toward this goal, the U.S. EPA implemented an Endocrine Disruptor Screening Program (EDSP) that is designed to detect chemicals that alter the estrogen, androgen, and thyroid systems in humans, fishes, and wildlife.4 This program, based largely upon recommendations made in 1998 by the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC),5 provides an approach for: (1) the initial sorting and prioritization of chemicals under the purview of the U.S. EPA, (2) the identification of chemicals for further testing, using a Tier I Screening (TIS) Battery that includes both in vitro and in vivo mammalian and ecotoxicological assays, and (3) the characterization of adverse effects and establishment of dose response relationships for hazard assessment, using a Tier II Testing Battery. The two-tiered approach allows a systematic evaluation of environmental chemicals for endocrine activity mediated through the estrogen, androgen or thyroid (EAT) hormone pathways, as well as effects on the hypothalamic-pituitarygonadal (HPG) axis. Assays included in the TIS Battery have complementary endpoints to support a 'weight-of-evidence' evaluation based on a number of results for each hormone pathway and to provide information that can be used to more carefully examine a potential mode of action (MOA) in the Tier II assays. The later tier is composed of in vivo tests that encompass multiple taxa (including invertebrates and vertebrates) with various exposure routes and life stages. Tier II tests are designed to ascertain the overall effect of the chemical, establish quantitative relationships between dose and adverse effects, and serve as a guide for the Agency's regulatory decision process. In 2008, the U.S. EPA submitted a proposed TIS Battery consisting of eleven assays to a Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Science Advisory Panel for review.13 The SAP received documents supporting the validation of the assays, and heard statements provided by U.S. EPA officials, stakeholder representatives, and public comment. After discussion and evaluation of the materials provided, the Panel recommended that the U.S. EPA adopt the entire TIS Battery as proposed." Thus, test guidelines for the eleven assays (Series 890: EDSP Test Guidelines) were published by the Office of Chemical Safety and Pollution Prevention (OCSPP) for use in the testing of pesticides and toxic substances and for the development of test data for submission to the Agency.l" The U.S.EPA subsequently announced the initial list of chemicals to be screened for endocrine activity using the TIS Battery, and issued the first test orders for those chemicals in 2009. 15, 16 A second list of chemicals was announced in 2010 17 and test orders are expected to be issued during 2011. Here we review the in vitro and in vivo assays that are included in the TIS Battery and provide an overview of the mode of action that each reflects. Each assay is discussed with respect to its purpose, technical considerations, and individual strengths as well as the contribution that each brings to the screening battery as a whole. Examples are presented to demonstrate the complementary nature of the assays, and how the together the assays provide a robust and effective approach for identifying chemicals that can alter estrogen-or androgen-receptor mediated responses, steroidogenesis, thyroid homeostasis (hypothalamic-pituitary-thyroid (HPT) axis), or disruption of the hypothalamic-pituitary gonadal (HPG) axis. Finally, considerations for evaluation of data and future directions for the TIS Battery are presented.