October 11, Dear Dr. Smith:

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1 PEOPLE FOR THE ETHICAL TREATMENT OF ANIMALS HEADQUARTERS 501 FRONT ST. NORFOLK, VA PETA (FAX) PETA.org StopAnimalTests.com October 11, 2011 Jane Smith Pesticide Re-Evaluation Division Office of Pesticide Programs Environmental Protection Agency 1200 Pennsylvania Ave., N.W. Washington, DC Re: Petition to Maximize Practical Utility of List 1 Chemicals Screened Through EPA s Endocrine Disruptor Screening Program; Notice of Availability (76 FR 49743); Docket ID number EPA HQ OPP ; Dear Dr. Smith: These comments are submitted on behalf of People for the Ethical Treatment of Animals and the Physicians Committee for Responsible Medicine. The parties to this submission are national animal protection, and health and science advocacy organizations with a combined constituency of more than two million Americans who share the common goal of promoting reliable and relevant regulatory testing methods and strategies that protect human health and the environment while reducing, and ultimately eliminating, the use of animals. In the Federal Register on August 10, 2011, the Environmental Protection Agency (EPA, hereafter referred to as the Agency), announced the availability of a Petition to Maximize Practical Utility of List 1 Chemicals Screened Through EPA s Endocrine Disruptor Screening Program (hereafter referred to as the Petition) submitted jointly by Crop Life America (CLA), Consumer Specialty Products Association (CSPA), and the Responsible Industry for a Sound Environment (RISE) (hereafter referred to as the Petitioners), requesting the Agency develop and publish guidance explaining the criteria by which EPA will make its decisions on data received in response to the test orders issued under the Endocrine Disruptor Screening Program (EDSP). The petition is asking EPA to provide detailed guidance for conduct of the Endocrine Disruptor Screening Program (EDSP), building on earlier recommendations from the Office of Management and Budget (OMB), appropriations language from Congress, and EPA s Office of the Inspector General (OIG). Specifically, the petition requests that the Agency:

2 1. Provide scientifically valid, peer-reviewed critical process and procedure guidance documents for Tier I screening; 2. Provide sufficient time for the List 1 chemical test order recipients to prepare and submit their Tier 1 screening results in compliance with the guidance once developed; and; 3. Fully analyze the List 1 Chemical EDSP screening data and revise the Program guidance based on lessons learned prior to the issuance of List 2 Chemical test orders. The EDSP is thus far the most animal-intensive mandatory chemicals testing program initiated by the EPA. In the interest of ensuring that the practical utility of the EDSP is maximized, thus minimizing the numbers of animals consumed in the generation of the requested information, we fully support the actions called for in this Petition. Our organizations have submitted comments to EPA and met with EPA and members of OMB on a number of occasions to discuss the very issues highlighted in the Petition. We have repeatedly stated the need for a transparent, scientifically-based, standardized methodology for evaluating data and making decisions under the EDSP. Without such technical and programmatic guidance, the likelihood of duplicative testing and the generation of equivocal results remains high, ultimately diverting resources from development of meaningful, scientifically relevant data on endocrine disrupting substances. We understand that EPA is in the process of providing some of the requested guidance documents, including the recently released final Guidance Document on Weight-of-Evidence (WoE) evaluation, 1 but we are concerned that these documents are not satisfactory to address the concerns expressed by ourselves, the above mentioned entities, or this Petition. We agree with the Petitioners assertion that [i]n order to provide meaningful EDSP results that will meet the goals of Congress and the Program, EPA is obligated to develop a thorough scientific guidance document for conducting WoE evaluations of the Tier I screening battery, including a clear delineation of guiding principles, clear criteria for evaluating studies, and methods by which the Agency will weigh the evidence and reach conclusions. As mentioned in the Petition, this request emphasizes instructions given to EPA by the Office of Information and Regulatory Affairs (OIRA) within OMB as well as OIG, whose report requested detailed guidance from EPA. In response to the OIG report, EPA agreed to address OIG s concerns by the issuance of three documents: 2 1 Endocrine Disruptor Screening Program Weight-of-Evidence: Evaluating Results of EDSP Tier 1 Screening to Identify the Need for Tier 2 Testing, EPA Off. Chem. Safety Poll. Prevent. September 14, Available at docket/document number: EPA-HQ-OPPT EPA Memorandum to Arthur Elkins, Inspector General, regarding EPA s Corrective Action Plan, issued July 28, Available at: _IG_Comment_on_Response.pdf. 2

3 1. Weight of Evidence Guidance Document (issued Sept 14, 2011) 1 2. EDSP21 Work Plan (promised completion September 30, 2011; not yet issued as of this writing) 3. EDSP Management Plan to be issued June 30, 2012 While EPA s final Guidance Document on WoE is certainly an improvement over the draft WoE guidance issued for public comment in November, 2010, it is still a selfdescribed general guidance document that lacks the rigor and specificity required to provide a transparent, consistent review of data. The final WoE Guidance describes the assays and endpoints applicable to each endocrine pathway. While these descriptions, together with the Standard Evaluation Procedures EPA is currently in process of providing for each of the Tier 1 assays (although these SEPs were not subject to Peer Review as stipulated by OIRA, and would have been more helpful had they had been published before List 1 chemical testing began), will better promote consistency of data supplied to EPA in response to test orders, they do not lend clarity to WoE evaluations. The Guidance also includes general considerations in evaluating the quality of scientific information and lists general factors to consider when evaluating data (e.g., soundness, applicability and utility, clarity and completeness, uncertainty and variability, and evaluation and review), but does not then go on to describe how data from the Tier 1 assays will be evaluated according to these criteria. The Guidance points out that specificity, sensitivity, and rigor of validation are important considerations, but does not include evaluation of the Tier 1 assays in this light. Instead, the Guidance gives one general illustration of a hypothesis-driven evaluation. In Table 2, the Guidance provides an example of how data might be tabulated, but misses a critical opportunity to explain how such data would be evaluated according to a WoE approach. The Guidance also provides only a general overview of how data might be used to decide whether any Tier 2 testing is indicated. Over all, the final WoE document falls well short of the type of guidance being called for by OIG, OIRA, or the Petition under review (see specific elements listed in the third paragraph on page 14 of the Petition). Several other groups, including ours, have provided examples of WoE approaches to evaluating endocrine testing data. 3,4 Guidance for evaluating EDSP data that is more appropriate in terms of rigor and completeness has been described by Borgert et al. 5,6 These publications, especially the latter of the two, 3 Willett CE, Bishop PL, Sullivan KM Application of an integrated testing strategy to the U.S. EPA Endocrine Disruptor Screening Program. Toxicol. Sci. 123(1): Bars R, Broeckaert F, Fegert I, Gross M, Hallmark N, Kedwards T, Lewis D, O'Hagan S, Panter GH, Weltje L, Weyers A, Wheeler JR, Galay-Burgos M Science based guidance for the assessment of endocrine disrupting properties of chemicals. Regul. Toxicol. Pharmacol. 59(1): Borgert CJ, Mihaich EM, Quill TF, Marty MS, Levine SL, Becker RA Evaluation of EPA s Tier 1 Endocrine Screening Battery and recommendations for improving the interpretation of screening results. Regul. Toxicol. Pharmacol. 59:

4 outline the detailed information and logical structure required to perform a consistent and transparent WoE evaluation of EDSP Tier 1 data. We agree with the authors who argue that data from the List 1 chemicals should be used to inform the WoE guidance. This is especially important for several of the assays for which validation studies indicated insufficient specificity or reproducibility (i.e., the pubertal assays, the amphibian metamorphosis and fish short-term assays). The complicating effects of an undefined methodology have already been evident in EPA s evaluation of Other Scientifically Relevant Information (OSRI) submitted by test recipients in lieu of ED testing for List 1 chemicals. Of the more than 400 claims made thus far that OSRI could satisfy one or more required Tier 1 tests, EPA rejected 323 (78%), although the basis of these rejections is far from clear. In many cases, it appeared that OSRI was rejected simply because it was not the exact same test as the Tier 1 test. In other cases, if a single measurement, out of many, had not been made, the results of the study as a whole were withdrawn from consideration. It was obvious from EPA s treatment of OSRI for List 1 chemicals that the body of knowledge for a particular chemical had not been fully considered in a WoE approach, nor had a consistent weighting scheme been applied with regard to the quality of studies and results submitted. It was also evident from the OSRI submitted, that in the absence of clear guidance from EPA on the selection and evaluation of these data, submissions from test order recipients varied widely both in what data were presented and how those data were interpreted. Some OSRI reports were lengthy and extremely well-researched and attempted to present results according a rational WoE approach, whereas other reports were quite brief and somewhat dismissive of EPA s request for more test data in light of the extensive amount of toxicity information that already existed for many of the chemicals in List 1. Without clearly articulated, standardized methods on how EPA will evaluate OSRI and what it considers acceptable, future test order recipients will waste resources on preparing detailed, well-reasoned reports in support of cited OSRI only to have data inexplicably rejected, while others may invest little or no time in preparing reports and end up conducting unnecessary tests that are costly in terms of both dollars and animal lives. Adding to this confusion, the definition of OSRI described in the final WoE guidance document seems to differ from that in EPA s White Paper describing OSRI. 7 In its White Paper, EPA describes OSRI as any information that may either be functionally equivalent to information obtained from the Tier 1 assays or may include data that provide information on a potential consequence or effect that could be due to effects on the estrogen, androgen or thyroid systems. The description of Scientifically Relevant Information in the final WoE Guidance seems to indicate that this other information will 6 Borgert CJ, Mihaich EM, Ortego LS, Bentley KS, Holmes CM, Levine SL, Becker RA Hypothesis-driven weight of evidence framework for evaluating data within the US EPA s Endocrine Disruptor Screening Program. Regul. Toxicol. Pharmacol. In press: doi: /j.yrtph EPA EPA s Approach for Considering Other Scientifically Relevant Information (OSRI) under the Endocrine Disruptor Screening Program. Docket No. EPA-HQ-OPPT

5 be considered in addition to Tier 1 data, rather than as possibly satisfying Tier 1 information requirements, when the clear intention of the OIRA terms of clearance was to ensure existing data was used to satisfy the Tier 1 testing requirement to the greatest extent possible. We agree with the Petitioners that providing scientific and programmatic guidance offers a tremendous opportunity to avoid redundant testing, and will therefore reduce the use of animals in the program. Moreover, clear guidance is necessary to provide consistent review and decision-making by EPA, and avoid individual staff bias in decision making, particularly with regard to the need for additional testing. Clear, transparent, logic-driven guidance will also facilitate the acceptance of data review by international regulators further reducing the potential for redundant testing. However, clear guidance is only one element of ensuring practical utility of the data generated in the EDSP; practical utility is also dependent on the reliability and relevance of the assays used. Therefore, it is critical that EPA fully analyze the List 1 chemical data and not only revise Program guidance accordingly, but also review the performance of Tier 1 assays. As the Petition mentions, and as we, the Petitioners, and others have demonstrated in submissions of OSRI to EPA, there is an enormous wealth of existing animal data for the List 1 chemicals that can provide additional support for WoE guidance and assay evaluation. We further agree with the Petitioners assertion that issuance of test orders for List 2 chemicals is premature and will likely result in unnecessary screening and unusable data. Following the recommendations of its own SAP and SAB, 8 among many others, to review and refine test methods using data for substances, EPA should first complete the process with the List 1 chemicals, evaluate its approach and methodology, and consider lessons learned before moving on to a new set of chemicals. With the rapid advances in computational toxicology, high through-put assays, development of biomarkers for evaluation of toxicity pathways, and EPA s stated dedication to increasing the efficiency of, reducing, and ultimately eliminating, whole-animal toxicity testing, a better-implemented EDSP program would seem to offer many opportunities towards meeting these important goals. In summary, we fully support the principles of the Petition and agree that to enhance the practical utility of the Program: 1. Rigorous and detailed Program guidance is necessary for transparent, reproducible and reliable assessment of data. 2. EPA should carefully analyze List 1 chemical data and revise both the Guidance and the Tier 1 battery accordingly. 3. Revisions should be completed before any further test orders are issued. 8 USEPA Review of EPA s Proposed Environmental Endocrine Disruptor Screening Program, EPA- SAB-EC , available at 5

6 Thank you for considering our comments. Sincerely, Patricia L. Bishop, M.S. Research Associate Regulatory Testing Division People for the Ethical Treatment of Animals Catherine Willett, PhD Science Policy Advisor Regulatory Testing Division People for the Ethical Treatment of Animals Kristie Sullivan, MPH Science & Policy Advisor Physicians Committee for Responsible Medicine 6