On June 19, 2015, the U.S. Environmental Protection Agency (EPA) announced a plan for incorporating validated high throughput assays and a computational model into the Endocrine Disruptor Screening Program (EDSP) to screen chemicals for their ability to interact with the endocrine system. These proposed new methods would serve as an alternative for three of the eleven current assays in the EDSP Tier 1 screening battery, specifically the estrogen receptor binding (ER), estrogen receptor transactivation (ERTA), and uterotrophic assays.
These computational high-throughput (HTP) tools will have the potential to impact significantly the prioritization for testing and will have a significant impact on List 2 test orders. EPA states that use of these alternative methods will accelerate the pace of screening, decrease costs, and reduce animal testing. In addition, this approach advances the goal of providing sensitive, specific, quantitative, and efficient screening using alternative test methods to some assays in the Tier 1 battery to protect human health and the environment. EPA has stated its commitment to the development of HTP and computational tools to improve regulatory science, as recommended in the 2007 National Research Council report, “Toxicity Testing in the 21st Century: A Vision and a Strategy,” and to meet its statutory obligations in the face of challenging budget constraints.
Comments are due by August 18, 2015. EPA specifically seeks comment on the following issues, which are related to its stated intention to use the scientific tools discussed as alternatives to some of the current EDSP Tier 1 screening assays:
- The use of the ToxCastTM “ER Model” for bioactivity as an alternative method for the current ER binding and ERTA Tier 1 screening assays.
- The use of the ToxCastTM “ER Model” for bioactivity as an alternative method for the current uterotrophic Tier 1 screening assay.
- The use of results from the ToxCastTM “ER Model” for bioactivity on over 1800 chemicals as partial screening for the estrogen receptor pathway.
EPA concludes that the ToxCastTM “ER Model” meets the criteria for use as “other scientifically relevant information” to satisfy Tier 1 for the ER, ERTA, and uterotrophic assays. EPA’s conclusion is based upon the findings of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) peer review held in December, 2014 that endorsed the ToxCastTM “ER Model” as a replacement for the ER and ERTA assays, and additional data developed by EPA to address the SAP’s concerns regarding the uterotrophic assay. Recipients of EDSP Tier 1 test orders would have three options for addressing the Tier 1 requirements with respect to the three EDSP Tier 1 endpoints that EPA considers validated:
- Cite existing ToxCastTM “ER Model” data, if it is applicable.
- Generate new data using the 18 ER HTP assays and the ToxCastTM “ER Model.”
- Generate Tier 1 data using the validated methods for the ER, ERTA, and uterotrophic endpoints in the traditional EDSP Tier 1.
EPA is careful to note that activity in the ToxCastTM “ER Model” is not a determination that a chemical causes endocrine disruption, only that is has the potential to do so, and that further testing (Tier 2) would be needed to make a determination regarding the ability to cause “adverse effects in an intact organism or its progeny, or subpopulations,” as stated in the World Health Organization International Programme on Chemical Safety definition.