In the Spotlight
The US EPA’s Endocrine Disruptor Screening Program: Part 1
Published: April 10, 2012
Results of First EPA Test Orders Issued under EDSP
The impact of the first round of test orders issued by the EPA under the EDSP in early 2010 on nine of 67 substances was published in the Federal Register on March 14, 2012 (77 FR 15101). Companies that manufacture or import these chemicals, which are used as inert ingredients in pesticide formulations, were required under these test orders to submit Tier 1 screening data using 11 tests intended to identify effects on the endocrine system. The EPA reports the following: “In response to the test orders, companies have agreed to develop data and have asserted data compensation rights for two inert ingredients, acetone and isophorone. No companies are developing data for the remaining seven inert ingredients. For di-sec-octyl phthalate and toluene, EPA plans to issue new test orders as both chemicals meet the selection criteria for endocrine testing under the Safe Drinking Water Act (SDWA). EPA has no plans to issue further test orders for methyl ethyl ketone, butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, and dimethyl phthalate, but plans to no longer approve their use as inert ingredients in pesticide products.” Products that include any of these five chemicals must be reformulated or removed from the market. Companies could still commit to submitting the required data by the end of the comment period of May 14, 2012.
Background on the EDSP
The EPA established the Endocrine Disruptor Screening Program in 1998 as a two-tiered testing program based on a series of Tier 1 and Tier 2 screening assays. Tier 1 screening consists of a battery of 11 in vitro and short-term in vivo assays; proposed Tier 2 testing will involve 5 multi-generation in vivo assays. Tier 1 screening is intended to identify chemicals with the potential to interact with the endocrine system; Tier 2 screening is intended to identify chemical and dose-related health effects.
Studies in the 1990s indicated that certain chemicals had the potential to cause developmental and reproductive abnormalities in fish and wildlife. Disruption of the endocrine systems of humans by the hormone-like effects of the same types of chemicals was proposed. To provide the EPA with the mandate to address these concerns, Congress enacted legislation in 1996 that requires the EPA to test pesticides and other chemicals for their potential to act as endocrine disruptors.
…Congress passed the Food Quality Protection Act and the Safe Drinking Water Act Amendments in 1996 requiring that EPA screen pesticide chemicals for their potential to produce effects similar to those produced by the female hormones (estrogen) in humans and giving EPA the authority to screen certain other chemicals and to include other endocrine effects.
Following this legislation, the EPA established the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to provide recommendations on how to implement the EDSP. This committee recommended the two-tiered testing approach and expanding the EDSP to include male hormones (androgens), the thyroid system, and effects on fish and wildlife. The Endocrine Disruptor Methods Validation Subcommittee (EDMVS) replaced the EDSTAC in 2001 as a subcommittee of the EPA’s National Advisory Council for Environmental Policy and Technology (NACEPT) with the mission “to provide technical input to EPA for the assays recommended by EDSTAC.”
The role of the NACEPT and EDMVS is “to ensure that scientifically-sound assays are developed for animal- and non-animal-based endocrine disruptor screens and tests during the validation process.” Since the EPA is a charter member of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the EPA committees followed the ICCVAM “validation framework in the development and refinement of assays to reduce animal use, refine procedures involving animals to make them less stressful, and replace animals where scientifically appropriate.” The EPA also worked to validate and harmonize endocrine disruptor screening assays with the Organization for Economic Cooperation and Development’s (OECD) Endocrine Testing and Assessment Task Force.
The three major elements of the EDSP are described by the EPA as follows:
1) Tier 1 and Tier 2 assay development and validation
When the EDSP was established, there were no tests or screening assays considered as sufficiently validated for the purpose of evaluating the endocrine activity of chemicals. The 11 assays in the Tier 1 Screening Battery were subjected to validation studies by the EPA and/or OECD. While the state of validation of these assays has not been evaluated by the ICCVAM, and some have questioned the actual state of validation of these assays [see comments in docket EPA-HQ-OPP-2008-0012], the EPA has accepted them for use for Tier 1 testing. They were published in 2009 as test guidelines by the EPA Office of Chemical Safety and Pollution Prevention (OCSPP) (890 Guideline Series). Current efforts are focused on validation of the Tier 2 in vivo assays and potential replacement Tier 1 assays.
2) Priority setting activities and selecting chemicals for testing
The EDSP defines priority setting as “identifying which chemicals will undergo Tier 1 Screening first.”
Initial EDSP screening was announced in 2009 with a list of 67 chemicals. Test orders were issued from October 2009 to February 2010 for these chemicals to be tested using the eleven Tier 1 assays to assess their potential to interact with the estrogen, androgen, and/or thyroid hormone systems. The 67 chemicals include pesticide active ingredients and pesticide inert ingredients, which were prioritized and selected based on expected exposures using pathway analysis. The status of responses to the test orders as of March 19, 2012 is available on the EPA website. Additional testing of these chemicals with the Tier 2 assays will be determined based on Tier 1 test results [see paragraph below on Weight-of-Evidence guidance].
A second list of 134 chemicals for Tier 1 screening was published on November 17, 2010. This list includes pesticides, two perfluorocarbon compounds (PFCs), three pharmaceuticals (erythromycin, nitroglycerin, and quinoline), and others. These chemicals were selected for “EDSP testing based only on their pesticide registration status and/or because such substances may occur in sources of drinking water to which a substantial population may be exposed.” The final version of the Second List of Chemicals is still under review.
3) Development of EDSP policies and procedures
On December 17, 2007, a public workshop was held to discuss draft policies and procedures for the initial screening of chemicals under the EDSP.
On April 15, 2009, the EPA published the Endocrine Disruptor Screening Program: Policies and Procedures for Initial Screening, which describes the policies and procedures for the initial screening of chemicals that “the EPA generally intends to adopt.” This document describes the statutory requirements, format of test orders, EPA cost sharing, data confidentiality, and revisions made after consideration of public comments from the 2007 workshop. The EPA also published the Draft Policies and Procedures for Screening Safe Drinking Water Act Chemicals (November 17, 2010), which is intended to supplement the policies and procedures published on April 15, 2009.
The Draft Addendum for the Second List of Chemicals; Tier 1 Screening of Certain Chemicals Under the Endocrine Disruptor Screening Program (November 17, 2010) describes information collection activities for the Tier 1 screening of the proposed 134 additional chemicals under the existing approved Information Collection Request, and provides an estimate for the burden (time, effort, and costs) associated with providing this information.
An EDSP Comprehensive Management Plan (CMP) is currently under development for release in 2012. The CMP is being developed in response to a report from the Office of Inspector General (OIG) of the EPA that was initiated at least in part by concerns from Congress on program progress, and possibly by other stakeholder concerns/comments [for example, public comments submitted on EPA dockets such as EPA-HQ-OPPT-2007-1081]. The OIG report found that 14 years after legislation was enacted requiring the EPA to screen certain substances for potential endocrine disrupting effects that the EDSP had made insufficient progress in addressing this mandate. The OIG report, EPA’s Endocrine Disruptor Screening Program Should Establish Management Controls to Ensure More Timely Results (Report No. 11-P-0215, May 3, 2011), made the following recommendations to the EPA: (1) define and identify the universe of chemicals for screening and testing, (2) develop and publish a standardized methodology for prioritizing the universe of chemicals for screening and testing, (3) finalize specific Tier 1 and Tier 2 criteria to evaluate testing data, (4) develop performance measures, (5) develop a comprehensive management plan, and (6) hold annual program reviews. The EPA’s OCSPP responded to the OIG report (Appendix A), but the OIG responded to that initial EPA response that “We consider recommendations 1, 2, 3, and 6 unresolved.” The OCSPP submitted a Revised Corrective Action Plan on November 17, 2011 that provided additional responses for addressing the OIG recommendations.
In September 2011, the EPA published two additional documents that provide guidance for the EDSP: (1) Weight-of-Evidence: Evaluating Results of EDSP Tier 1 Screening to Identify the Need for Tier 2 Testing (September 14, 2011), and (2) Endocrine Disruptor Screening Program for the 21st Century: EDSP21 Work Plan (September 30, 2011).
The Weight-of-Evidence (WoE) document provides guidance to EPA staff on how the results from Tier 1 screening are to be evaluated. Standard Evaluation Procedures (SEPs) to provide guidance for the review and scientific evaluation of Tier 1 assay data have also been developed for each 890 Guideline. A WoE approach will be used to evaluate the results of the Tier 1 assays for the identification of chemicals with the potential to interact with one or more of the endocrine pathways (estrogen, androgen, or thyroid). “Other sources of scientific and technical information may also be considered in the evaluation,” and this is described in the WoE guidance (pages 15-21). The results of the WoE analysis will determine which chemicals should undergo further evaluation with Tier 2 testing. The decision “to move to Tier 2 testing will be based on the totality of the scientific evidence,” and in some cases a modified or tailored approach could be recommended.
The EPA published a 6-page summary overview of the EDSP Comprehensive Management Plan, the Endocrine Disruptor Screening Program for the 21st Century: EDSP21 Work Plan (September 30, 2011), which identifies advanced scientific methods such as in silico modeling and high-throughput screening (HTS) assays for the screening and prioritization of potential endocrine effects of chemicals. The EDSP21 Work Plan will be discussed in greater detail in Part 2 of this series on the EDSP.
Part 2 of this article describes recent EDSP activities, such as the EDSP21 Work Plan and Tier 1 and Tier 2 assay development/validation, as well as some of the current stakeholder actions.