On September 28, 2011, the U.S. Environmental Protection Agency (EPA) published its final guidance on the weight-of-evidence (WoE) analysis it will use to evaluate the results of data submitted in response to test orders issued for Tier 1 screening under the Endocrine Disruptor Screening Program (EDSP). What follows is a brief overview of the Final WoE Guidance, which is available at http://www.regulations.gov.
First some background: On November 4, 2010, EPA issued a draft document entitled "Weight-of-Evidence Guidance Document: Evaluating Results of EDSP Tier 1 Screening to Identify Candidate Chemicals for Tier 2 Testing." According to EPA, the purpose of this draft was "to set forth some general principles, criteria, and considerations EPA generally believes to be relevant using a WoE approach to evaluate data submitted as part of EPA's EDSP… Tier 1 screening assays." Unfortunately, the Draft WoE Guidance provided little actual scientific guidance that could be used to evaluate results of Tier 1 screening assays or to identify candidate chemicals for Tier 2 testing — and so provoked much criticism.
Final WoE Guidance
In the new document, EPA provides much more information on WoE considerations. It lists the four Tier 1 assays capable of detecting a chemical's androgenic or anti-androgenic effect, what the in vitro androgen-receptor binding assay examines, and how the three in vivo assays can be used to evaluate the androgen pathway.
In the Draft WoE Guidance, EPA acknowledged it would use a WoE approach for other scientifically relevant information (OSRI) and described in very general terms appropriate OSRI-type studies. However, it did not discuss specific studies or other information EPA might consider OSRI, nor did it provide additional guidance as to how the agency would conduct the WoE analysis for OSRI or how that would compare to WoE analysis for Tier 1 screening data. In the Final WoE Guidance, EPA describes two sources of OSRI: "results from EPA or OECD equivalent test guideline studies and information from published or publicly available peer-reviewed studies."
EPA also states that published or publicly available peer-reviewed studies may be used in a WoE evaluation. However, the agency notes: "For non-guideline, as well as guideline studies, to be considered as primary or secondary sources of information in a WoE evaluation with Tier 1 screening results, EPA would generally evaluate the quality and relevance of the information indicated in EPA Information Quality Guidelines…." Despite this enhanced discussion of what OSRI EPA may consider relevant, it also is clear that EPA's determinations about whether a chemical is a candidate for Tier 2 testing will be "primarily based" on the Tier 1 assays.
A new section in the Final WoE Guidance pertains to how EPA will evaluate the quality of the scientific and technical information provided. It references the Information Quality Guidelines. EPA also discusses its Science Policy Council recommendations for the use of five general assessment factors: 1) soundness; 2) applicability and utility; 3) clarity and completeness; 4) uncertainty and variability; and 5) evaluation and review. However, EPA does not describe which considerations may receive more weight than others or how it will factor these considerations into any WoE determinations.
EPA will begin determinations by assembling and evaluating the pertinent individual studies. The agency intends to tabulate the results of individual studies by study type and by endpoint to "provide a structured and transparent approach to facilitate the WoE determination."
It will determine whether Tier 2 testing is warranted for a substance based on the "totality of the evidence." Once EPA identifies and assesses all the assays and scientifically relevant information, and develops a data evaluation report or other review, it will conduct an integrated analysis to evaluate "whether or not the toxicity database is internally consistent with the purported or hypothesized endocrine interaction." EPA discusses how it will review data to determine whether effects are consistent or isolated, and states that a "consistent pattern of responses" could "support a recommendation that a chemical be considered as a candidate for Tier 2 testing."
EPA has developed, to a much greater extent than in the draft guidance, a document for conducting WoE evaluations of the EDSP Tier 1 assays. The Final WoE Guidance includes a description of EPA's guiding principles, the criteria by which it will evaluate studies, and the methods for how it will weigh the evidence and reach conclusions. Readers with interests in EDSP matters are urged to review the document because any determination to conduct Tier 2 testing will be a costly one with many commercial implications.
LYNN BERGESON is Chemical Processing's Regulatory Editor. You can e-mail her at Lbergeson@putman.net.
Lynn is managing director of Bergeson & Campbell, P.C., a Washington, D.C.-based law firm that concentrates on chemical industry issues. The views expressed herein are solely those of the author.