Bergeson & Campbell, P.C. serves small, medium, and large pesticide product registrants and other stakeholders in the agricultural and biocidal sectors, in virtually every aspect of pesticide law, policy, science, and regulation.

By Lara A. Hall, Lisa M. Campbell, and Jane S. Vergnes, Ph.D.

 

The release of the first Tier 1 assessments in the Endocrine Disruptor Screening Program (EDSP) by the U.S. Environmental Protection Agency (EPA) on June 30, 2015, is a significant bench-mark in the program since the original List 1 test orders were initially issued in October 2009.  Fifteen of the original 67 List 1 chemicals were subsequently cancelled or discontinued by the respective pesticide registrants.  The intended purpose of the Tier 1 screening was to identify potential interactions of the remaining 52 chemicals with three hormonal pathways (estrogen, androgen and thyroid) in the endocrine system.  EPA evaluated the data from 11 screening assays (five in vitro and six in vivo), along with other scientifically relevant information (OSRI) comprised of existing toxicology studies and peer reviewed published literature, and drew preliminary conclusions about the potential of these 52 chemicals to disrupt endocrine functions. Importantly, EPA noted on the EDSP webpage that “a result indicating potential should not be construed as meaning that EPA has concluded that the chemical is an endocrine disruptor.” 

 

The individually published weight-of-evidence (WoE) assessments and anticipated data evaluation records (DER) can be accessed online for the 52 chemicals involved in the Tier 1 screening assessment.  EPA summarized its conclusions from EPA’s Tier 1 WoE assessments as follows:

 

  1. No evidence of potential interaction with any of the endocrine pathways was identified for 20 chemicals.
  2. Fourteen chemicals showed potential interaction with one or more pathways, but based on the available information, do not pose a risk for endocrine disruption. 
  3. Eighteen chemicals showed potential interaction with the thyroid pathway, 17 of which also showed potential interaction with the androgen pathway, and 14 of which showed potential interaction with the estrogen pathway.

 

To explore further any potential adverse effects on the endocrine system that may be caused by the 18 chemicals that EPA categorized in the third group noted above, EPA has recommended the following Tier 2, multigenerational studies across various species for them:

 

  • A comparative thyroid assay for four chemicals that EPA found to have potential interaction with the thyroid pathway in mammals;
  • The Medaka Extended One Generation Reproduction Test, MEOGRT (Draft Test Guideline OCSPP 890.2200), for 13 chemicals that EPA found to have potential interaction with the estrogen or androgen pathways in wildlife; and
  • The Larval Amphibian Growth and Development Assay, LAGDA (Draft Test Guideline OCSPP 890.2300), for five chemicals that EPA found to have potential interaction with the thyroid pathway in wildlife.

 

EPA has not yet issued its final Tier 2 non-mammalian Office of Chemical Safety and Pollution Prevention (OCSPP) test guidelines (890 Series).  Public comment on the proposed guidelines closed on March 31, 2015.  It is expected that the release of these remaining guidelines will signal the approach of the Tier 2 test orders, which EPA is likely to issue in 2016.  Although a formal public comment period is not expected to be opened for the Tier 1 assessments, affected registrants should have the opportunity to respond directly to EPA regarding WoE assessments and forthcoming DERs. 

 

This release of the Tier 1 WoE assessments, the anticipated release of Tier 2 test guidelines, along with EPA’s commitment to further the development of high-throughput (HTP) assays and computational tools will significantly influence the prioritization of List 2 chemicals in the EDSP and the timing of the List 2 test orders.  The revised List 2 includes 109 chemicals for Tier 1 screening.  As with List 1, List 2 candidates reportedly were selected based on EPA’s review concerning their possible presence in public drinking water and/or registration review status within EPA, and not because of their potential to interfere with the endocrine systems of humans or other species.


 

By Lisa M. Campbell and Jane S. Vergnes, Ph.D.

 

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:

 

  1. The use of the ToxCastTM “ER Model” for bioactivity as an alternative method for the current ER binding and ERTA Tier 1 screening assays.
  2. The use of the ToxCastTM “ER Model” for bioactivity as an alternative method for the current uterotrophic Tier 1 screening assay.
  3. 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:

 

  1.  Cite existing ToxCastTM “ER Model” data, if it is applicable.
  2. Generate new data using the 18 ER HTP assays and the ToxCastTM “ER Model.”
  3. 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. 

 

More detailed information on the Endocrine Disruptor Screening Program and its use of computational tools is available at:  http://www.epa.gov/endo/ or http://www.epa.gov/endo/pubs/pivot.htm.