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Endocrine Disruptor Methods Validation Subcommittee (EDMVS) Public Meeting
April 24, 2001

On April 24, 2001, the U.S. Environmental Protection Agency (EPA) convened a public meeting to discuss the proposed Endocrine Disruptor Methods Validation Subcommittee (EDMVS). The meeting provided an opportunity for known stakeholders and the public to voice individual ideas regarding method validation for EPA's Endocrine Disruptor Screening Program (EDSP). It provided EPA an opportunity to outline the processes and organizational interactions for EDSP validation and peer review and to report on the status of ongoing EDSP validation studies. The meeting deliberations focused on four major topics: 1) the proposed Subcommittee's mission statement; 2) the proposed Subcommittee's organizational processes; 3) the division of validation responsibilities; and 4) coordination with other related activities.

For this meeting, EPA invited 14 individuals representing diverse stakeholder interests to participate in a dialogue focused on issues relating to the proposed EDMVS. Invited participants were asked to express their individual points of view. No attempt was made to develop group recommendations or consensus. The meeting was an open public meeting that provided an opportunity for members of the public to provide comments regarding the development of the proposed Subcommittee and the discussion of the invited participants. In addition, all attendees were encouraged to submit written comments to EPA. A list of invited participants is attached (see Appendix A). The list of people who provided comments during the public comment session is contained within this summary.

Tuesday, April 24, 2001

I. Welcome and Preliminaries

Susan Hazen, Deputy Assistant Administrator, EPA Office of Prevention, Pesticides and Toxic Substances, welcomed participants to the meeting. Meeting participants introduced themselves and stated their agency and organization affiliations.

Ms. Hazen then summarized the goals of the meeting for EPA: to hear stakeholders concerns and ideas, to outline the processes of the EDSP, and to provide information on the ongoing studies. She indicated that this meeting and the proposed EDMVS build on recommendations of the Endocrine Disruptor Screening and Testing Advisory Committee and begin to focus on the scientific and technical aspects of the issues. Ms. Hazen expressed EPA's desire to have ongoing dialogue as an element of the EDSP. She acknowledged that there will be differences of opinions but stressed a common goal of protecting the environment and human health.

Paul De Morgan, Senior Mediator with RESOLVE, reviewed the agenda and groundrules for the meeting and explained his role as facilitator of the process. Mr. De Morgan reminded participants that the goal of the meeting was not consensus but to hear the opinions of various stakeholders. He also noted that background materials had been distributed to the participants and would be referred to during the meeting (see Appendix B for a list of the distributed documents and information on obtaining copies).

II. Overview Presentations by EPA

A. Establishment of Endocrine Disruptor Methods Validation Group under the Federal Advisory Committee Act (FACA) - Anthony Maciorowski, Office of Science Coordination and Policy

Mr. Maciorowski began by telling participants that efforts to publish the Federal Register notice regarding nominations for the Subcommittee were moving forward. He added that the notice will stipulate a 30-day period for nominations. (Later in the meeting, Ms. Hazen indicated that she had heard from her office that publication of the FR notice would go forward in the near future.)

Mr. Maciorowski then summarized the purpose, objectives, scope of activity, composition, and organization of the proposed EDMVS as presented in the Proposal to Establish an Endocrine Disruptor Methods Validation Subcommittee under the National Advisory Committee for Policy and Technology.

Highlights of the presentation included:

. EDMVS will be a Subcommittee of the National Advisory Council for Environmental Policy and Technology (NACEPT).

. The purpose of EDMVS is to provide advice and counsel to the EPA, through NACEPT, on scientific issues associated with the conduct of studies necessary for validation of Tier 1 and Tier 2 methods for the EPA's Endocrine Disruptor Screening Program.

. Specific areas for advice and counsel include: initial protocol development, pre-validation studies, validation studies, and preparation of validation documents for external review.

. EDMVS will be composed of approximately 25 members selected on the basis of their relevant scientific expertise and diversity of perspectives on endocrine disruptor screening and testing methods and procedures, toxicity test methods standardization and validation, and chemical and pesticide regulatory processes.

. Subcommittee members shall be appointed with balanced representation from the following sectors: the agrichemical and commodity chemical industries; environmental/public interest organizations; public health organizations; animal welfare organizations; federal agencies; state, local and tribal governments; academia; consumers, and the public.

. Workgroups and ad hoc teams may be established on an as-needed basis consisting of EDMVS members, or supplemented with specialists qualified in the technical area of the workgroup or team appointed by the agency.

B. EDSP screen and test method validation process and organizational interactions (EPA/ICCVAM/OECD) - Gary Timm, Office of Science Coordination and Policy

Mr. Timm outlined the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) validation process and then discussed the EDSP process.

Highlights of the presentation included:

. EDSP will have stakeholder involvement throughout and will follow the ICCVAM process for validation. For domestic test guidelines, EPA will administer the process. Some stakeholders want ICCVAM to administer the process. Guidelines will be harmonized internationally through OECD.

. For domestic guidelines, the process will involve:

. A federal advisory committee (FAC) of stakeholders;

. A contractor to conduct laboratory work;

. Expert workgroups drawn from the contractor, government staff and outside experts;

. SAP/SAB for peer review; and

. ICCVAM, through representation on the FAC, for consultation between Prevalidation and validation and through comments at peer review.

. The process for international guidelines will also follow ICCVAM requirements and include an independent external scientific peer review. The FAC will be kept informed of international validation activities and will provide input for the U.S. position through the National Coordinator comment process. The OECD Endocrine Disrupter Testing and Assessment Task Force will be the primary body for validation of international test guidelines.

Following Mr. Timm's presentation, the invited participants asked some clarification questions and offered some initial observations.

Mary Beth Sweetland, People for the Ethical Treatment of Animals, observed that Mr. Maciorowski had said that test relevance would be examined in the validation stage, while Mr. Timm said validation would look at reliability. She asked Mr. Timm to clarify when relevance would be considered. Mr. Timm responded that relevance would be established primarily in the Prevalidation stage, and validation would focus more on test reliability. Bill Stokes, National Institute of Environmental Health Sciences, recommended that relevance be listed explicitly as part of validation because it should continue past the Prevalidation stage.

In response to questions from Richard Liroff, World Wildlife Fund, and Mr. Stokes, Mr. Timm stated that ICCVAM could recommend peer reviewers to the SAP/SAB and that the public could make recommendations as well. He commented that he was unsure whether public recommendations had been solicited for past SAP/SABs, but that it could be done through the FR notice.

Rick Becker, American Chemistry Council, noted that the SAP/SAB Standing Committee was convened to examine the EDSP, while now there is discussion of assay-specific review. He wondered what implications this would have for SAP/SAB composition. Mr. Timm said that there would likely be some continuity from the Standing Committee, but additional expertise would be included as necessary on a case-by-case basis.

Mr. Stokes asked whether EDMVS will be able to comment on OECD studies. Mr. Timm responded that the Subcommittee would certainly be able to comment on the U. S. portions of the process. The Subcommittee will have opportunities for input on the rest of the process, but EPA is not yet sure how that will happen.

Sara Amundson, Doris Day Animal League, in response to one of the "Process Realities" laid out by Mr. Timm, clarified that "some stakeholders" do not necessarily want ICCVAM to administer the EDSP process, but want ICCVAM to manage the assessment and review portion of the process.

C. Overview of EPA's ongoing activities and schedule for EDSP validation - Jim Kariya, Office of Science and Coordination and Policy.

Mr. Kariya presented the status of the Tier 1 and Tier 2 assays, indicating whether or not the literature review, protocol demonstration, Prevalidation and validation had been completed for each assay. He also presented the timeline for the EDSP, noting that Phase I implementation will begin when Tier 1 validation is complete. He commented that EDSP has made considerable progress thus far, despite the lack of a contract in 2000, and observed that with a contract now in place, the pace of the program has accelerated.

Following Mr. Kariya's presentation, the invited participants asked some clarification questions and offered some initial observations.

David Hattan, Food and Drug Administration, asked whether the chemical classes for the 200 chemicals to be screened had been selected. Mr. Kariya replied that the selection is not being done by classes, but they are considering excluding chemicals of low production volumes (less than 10,000 pounds), mixtures, and polymers.

Tim Kubiak, U. S. Fish and Wildlife Service, asked whether the fish assay includes in ovo exposure. Mr. Maciorowski responded that OECD is considering two methods, one that includes in ovo exposure and one that does not. He stated that if OECD does not go ahead with the test including in ovo exposure, EDSP will.

Ms. Sweetland asked how many labs will be used to conduct the assays, particularly the pubertal assay. Mr. Kariya said the number of labs will depend on the assay; for the pubertal assay, two labs will be used in Prevalidation; three labs in validation. Ms. Sweetland also asked whether the tests had shown by what mechanism the chemical acted. Mr. Kariya stated that they were not intended to do so. Ms. Sweetland suggested that they should be designed to show mechanisms.

Mr. Becker inquired about the status of androgen receptor/estrogen receptor (AR/ER) validation. Mr. Kariya responded that EPA has not determined whether "validation" is necessary. He explained that they are considering establishing performance standards rather than validating specific assays, because establishing performance standards would allow the flexibility to use other methods as technology advances. However, he did note that AR/ER assays may be necessary to assist in validating the QSAR results.

Ms. Sweetland observed that Mr. Kariya had not mentioned HTPS (high throughput screening) in his presentation. Mr. Kariya explained that EPA's own HTPS efforts had not gone as well as hoped, but Japan's tests were more promising. He said that EPA is reconsidering using the Japanese data and is examining their results. Gina Solomon, Natural Resources Defense Council, asked whether commenting on HTPS is within the scope of the EDMVS. Mr. Kariya said he believed that EDMVS comments would be helpful, since it is a technical issue, but whether EDMVS will be able to comment will depend on timing.

Invited Stakeholder Discussion Regarding Mission Statement

Mr. De Morgan began the discussion by referring participants to the Proposal to Establish an Endocrine Disruptor Methods Validation Subcommittee under the National Advisory Committee for Policy and Technology and to the first question of Questions and Issues for Stakeholders. The Questions and Issues document states that the mission statement focuses EDMVS efforts on technical issues associated with the standardization and validation of the Tier 1 and Tier 2 screening and test methods; however, the mission statement does not preclude the Subcommittee from deliberating on additional methods within time and resource constraints. The first question asks whether this clarification of the mission statement adequately addresses the stakeholder concerns raised in section III.A. of the Planning Report.

Several participants expressed views that the mission of EDMVS should be broader than addressing only Tier 1 and 2 screening and testing methods and should be flexible enough to incorporate new responsibilities as the process moves ahead. Ms. Solomon stated that the Subcommittee should have the opportunity to look at the prescreening assays, such as QSAR and HTPS. Angelina Duggan, American Crop Protection Association, offered that literature review should be added to the list of specific duties. Nancy Kim, New York State Department of Health, wondered whether it would be useful to have EDMVS comment on the complete test battery, observing that having reviewed the assays, EDMVS may be in a good position to offer advice on the battery. Martin Stephens, Humane Society of the United States, said that beyond not precluding deliberation on additional methods, the mission statement should explicitly include the idea of allowing deliberation on additional methods.

Ms. Amundson noted that the clarification of the mission statement in Questions and Answers for Stakeholders includes a "nod toward" reducing animal use. She stated that it should, as the ICCVAM process does, include the "three Rs": reducing animal use, refining procedures involving animals to make them less stressful and replacing animals where scientifically appropriate. Mr. Maciorowski clarified that this language is included under "The Validation Process" on page 5 of Proposal to Establish an Endocrine Disruptor Methods Validation Subcommittee under the National Advisory Committee for Policy and Technology. Ms. Amundson stressed that if the role of EDMVS is expanded beyond validation, as is being discussed, reduction, refinement and replacement should be explicit in the mission statement.

Several participants expressed confusion as to the meaning of "synthesis" in the mission statement sentence: "The EDMVS will provide advice and recommendations regarding: . . . synthesis of Prevalidation and validation study results for the EDSP Tier 1 and Tier 2 methods into documents suitable for external peer review." Mr. Maciorowski clarified that he intended to mean integrating information from the peer reviews into a final document. He stated that he will reword the sentence to be clearer. Mr. Stephens observed that the clarification would be a critical piece of the mission as it would serve to keep EDMVS in the loop through the step of conveying information.

Ms. Sweetland commented that an early meeting of the new Subcommittee should include a discussion of the rationale for the EDSP, as many of the people on EDMVS will not have been involved in EDSTAC. Mr. Cooper stated that EDMVS should focus on technical aspects; policy discussions should happen, but outside EDMVS. Mr. Liroff echoed this view but added that EDMVS should, of course, pay attention to emerging science in case the EDSP becomes irrelevant. Ms. Solomon also agreed with Cooper, but stressed that relevance and reliability should be examined for each assay. Mr. Kubiak suggested that key points from EDSTAC could be presented at the first EDMVS meeting for the benefit of new members. Ms. Duggan pointed out that the information and rationale of EDSTAC is already available to everyone.

In response to a question by Ms. Amundson, Mr. Maciorowski assured participants that when the EDMVS is formed its members will have the opportunity to discuss its mission. Ms. Hazen commented that EPA, with input from individual stakeholders, will shape the "big box" of the mission, and the subcommittee itself will refine it.

At the close of the discussion, Ms. Hazen reflected that she had heard a lot of similar comments regarding the core responsibilities of EDMVS, but she had also heard the need to be flexible, to allow the group to take on a broader mission and to not exclude new scientific and technical information from the groups purview. She said that she will go back to the mission statement and consider how best to incorporate these ideas. Mr. Hattan cautioned that while it is fine to entertain the idea of looking at new science, EDMVS should recognize the time and effort it has taken to get the previous studies to a usable point. He stressed that EDMVS must consider not only the promise of new science, but also its validation and integration with other methods.

Invited Stakeholder Discussion

Mr. De Morgan began the discussion by drawing participants' attention to the second question of Questions and Issues for Stakeholders: Does EPA's proposal to establish ad hoc work groups for each specific screening and test method adequately address the need to make proper use of the expertise of the Subcommittee within the time and resource constraints faced by EPA?

Mr. Becker voiced his support of the proposal, stating that different assays will require different expertise, and it would be hard to assemble individuals with that expertise without forming technical subgroups. He questioned, though, the ad hoc nature of the subgroups and surmised that a subgroup structure similar to that of the EDSV Task Force might be effective for EDMVS as well. He suggested three possible groups: one for in vitro assays, one for mammalian and one for avian. He suggested alternatively that two groups might also be effective: one for all in vitro assays and one for all in vivo. He observed that a structure of two groups would facilitate development of an integrated battery.

Mr. Liroff expressed a concern that with multiple subgroups, some stakeholders would not be able to participate in all of the meetings. Ms. Sweetland later echoed this concern.

Mr. Timm explained that EPA had considered having each subgroup work on a set of assays, but had proposed a separate subgroup for each assay because of the different expertise required. He estimated that one subgroup could probably review all of the in vitro assays, but that the expertise required for the in vivo assays would be too specific. He noted that it will be the work of the EDMVS to help integrate the assays into an overall battery. He also pointed out the international aspect of some of the guidelines. He stressed that EPA did not want to involve OECD only at the last minute, but would prefer to have international representation on appropriate subgroups.

In response to a question from Mr. De Morgan, Mr. Becker stated his opinion that EDMVS members should be members of the subgroups. Ms. Kim agreed with Mr. Becker, saying that having one to three EDMVS members on a subgroup would provide a valuable communication link back to the full EDMVS. Mr. Stokes later observed that with six EDMVS meetings per year, members will have little time for subgroups.

Several participants expressed concern and confusion about the interaction and potential redundancy of the multiple entities involved in EDSP. Mr. Liroff questioned the role of the EDMVS given that a contractor is now in place, with its own advisory committee and the ability to draw in outside experts as needed, and the work of the contractor will be reviewed by SAP/SAB. Ms. Duggan echoed Mr. Liroff's concern that EDMVS would be made redundant with the contractor in place. She recommended that decision making be as transparent as possible and balanced so that people feel they have had input. Other participants echoed the recommendation of transparency. Ms. Solomon observed that much of the transparency, scrutiny and review will happen through EDMVS; therefore, the layer of subgroups may not be important and may prove cumbersome.

Ms. Sweetland expressed concern about the lack of oversight of the contractor's work in regard to animal welfare. She requested that an animal welfare representative be present at key meetings with the contractor.

Mr. Timm responded that EPA is working to strike a balance between utilizing the resources of the contractor and not cutting out stakeholders. He clarified that EDMVS will advise EPA, and only EPA will instruct the contractor, as stipulated by federal law. He added that EPA would want the contractor to attend EDMVS meetings and potentially the subgroup meetings to hear the groups' discussions. In response to a request for clarification by Ms. Hazen, Mr. Timm stated that to the best of his knowledge, public citizens can attend EPA's meetings with the contractor.

Marilyn Wind, Consumer Product Safety Commission, requested a clarification of the interaction between ICCVAM and the contractor. Mr. Timm responded that EPA did not want the contractor to duplicate ICCVAM. Mr. Stokes clarified that ICCVAM's role is to review data, not to conduct studies.

Mr. Becker commented that he would like to see an efficient process, but it is important to realize that EDSP will require a high level of expertise and adequate technical input at the outset. Mr. Timm stated that the protocols and methods will be reviewed by EDMVS before laboratory work begins, as it is difficult to change a protocol once it has gone to the lab. Mr. Cooper agreed with Mr. Becker, stressing that involving key people in the planning phase can be more efficient in the long run.

Ms. Solomon commented that if EDMVS reviews the protocols, she sees less of a need for the subgroups. She suggested that streamlined ad hoc groups may be a better option than creating another layer of permanent subgroups, as the ad hoc groups would be more focused and could report back quickly to the full group. In response to a question from Mr. Timm, she added that the ad hoc groups could be either assay specific or issue specific as needed. Mr. Kubiak supported Ms. Solomon's suggestion, adding that he would like EDMVS members to have the opportunity to participate in or comment on the work of the ad hoc groups and the contractor so that significant issues can surface before final reports are given to EDMVS.

Mr. Becker again stressed his belief that some sort of small groups would be necessary to allow the focus and to gather the expertise needed to review specific issues and assays. He stated that the EDMVS charter must be flexible enough to allow EDMVS to create such small groups.

Invited Stakeholder Discussion Regarding Division of Validation Responsibilities

Before the discussion of validation responsibilities began, Mr. Stokes, in response to a request for clarification from Ms. Kim, pointed out that he currently is the co-chair of ICCVAM, and Mr. Hattan and Ms. Wind also serve on the committee.

Ms. Amundson asked which section of the Food Quality Protection Act (FQPA) states that SAP/SAB must review the assays comprising the EDSP. Mr. Timm explained that FQPA does not require a review of each assay, but rather a review of the program. Ms. Amundson noted that there is a significant difference between putting the test guidelines through review and putting the validations of the assays through review; the latter is overly cumbersome, unnecessary and time-consuming. Mr. Timm called on Robert Wing, Office of General Counsel, to cite the specific section of the FQPA. Mr. Wing cited section 408(p), and added that the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) section 25 also encourages review.

Mr. Becker commended EPA for staying with a program of scientific rigor while trying to balance this rigor with efficiency.

Ms. Solomon expressed concern about EPA's proposed budget, which includes an 11% cut for EDSP. She asked whether EPA will have the resources to review all the assays and inquired as to what stakeholders could do to help the program. Mr. Timm and Ms. Hazen responded that they did not expect the budget cut to affect the program for at least the coming year as funds leftover from last year and from other programs being phased down can supplement this year's EDSP.

Ms. Sweetland noted that the Proposal to Establish an Endocrine Disruptor Method Validation Subcommittee under the National Advisory Committee for Policy and Technology lists the reasons why SAP/SAB should be the review body for EDSP, but the proposal does not list the reasons why SAP/SAB should not do the review. Specifically, she noted that because this process is not ICCVAM approved, other agencies, such as FDA, will not have to accept the results. She requested that EPA be straightforward in acknowledging SAP/SAB shortcomings and stated a concern that SAP/SAB is not an independent body. Mr. Timm responded that EPA feels that SAP/SABs are independent and not entities of EPA. He expressed his view that the challenge lies in giving SAP/SAB time and opportunity to do adequate reviews. He also noted that review by ICCVAM does not guarantee FDA acceptance and that ICCVAM will have the opportunity to comment on EDSP. Ms. Sweetland asked how stakeholders could be sure that EPA's reluctance to overburden SAP/SAB with documents does not result in inadequate knowledge. Mr. Timm pointed out that ICCVAM is not necessarily a better option than SAP/SAB, as ICCVAM itself is composed of government employees, and waiting for their review can cause delays.

Ms. Amundson raised a concern that ICCVAM involvement in the proposed approach only includes government representatives, not independent reviewers. She indicated that having an independent review body would be a better option and would help to move the program along.

Ms. Duggan noted that EDSTAC had consulted with SAP/SAB during their effort and had also had an opportunity to recommend SAP/SAB members.

Mr. Stokes explained that the ICCVAM review process includes soliciting nominations by Federal Register notice and soliciting comments from national and international industry professionals. He recounted that ICCVAM has done five evaluations in three years, with costs varying by project. He stated that each review is conducted by 12 to 15 scientists, and the results are published and available on the Internet. He noted that ICCVAM ensures that reviewers have no financial or professional conflicts of interest. Mr. Timm stated that EPA also will explicitly address financial and professional conflict of interest for SAP/SAB members and will consider conflict of interest grounds for disqualification from SAP/SAB. Ms. Hazen added that financial and professional ties are usually announced at the start of SAP/SAB meetings.

Mr. Becker, commenting that various options for peer review exist, asked EPA to explain why and how the proposed option was chosen. Mr. Timm responded that they had had several discussions on the roles of ICCVAM and EPA. Ms. Wind and Mr. Hattan explained that the primary considerations were resource constraints and the issue of cross agency relevance. Mr. Hattan stated that ICCVAM is currently saturated with reviews given its resource constraints. Ms. Wind stated that tests must involve a good deal of common interest from multiple agencies to warrant ICCVAM review, adding that they did not believe these tests rose to that level. Mr. Timm added that EPA felt handling EDSP review through an EPA-administered body would better ensure that deadlines would be met. He also reiterated that the review will be done through the ICCVAM process, though it will not be done by ICCVAM institutions.

Ms. Amundson commented that a lack of resources is not an acceptable reason for not using ICCVAM. She also indicated that the assays were likely to be of interest to multiple agencies and should be put through the ICCVAM process. However, she added that stakeholders never intended for every method to be reviewed by ICCVAM, but some assays do warrant ICCVAM review.

Mr. Martin stressed that animal welfare stakeholders look to ICCVAM as an independent review. Ms. Sweetland later added that the international community also accepts ICCVAM review, not EPA SAP/SAB review following the ICCVAM process. Mr. Timm stated that although ICCVAM is known to the international community, it is regarded as a U.S. institution, not an international arbiter of validation.

In response to a request for clarification, Mr. Stokes explained that ICCVAM review is a consultation with inter-agency staff and that public consultation is not solicited.

Mr. Timm pointed out that ICCVAM has an endocrine disruptor subcommittee, which will review documents and reports of the EDSP. He added that SAP/SAB composition will be adjusted to review these assays, and it may include international representation. Mr. Becker commented that for each review, EPA presents SAP/SAB with questions. He noted that by giving advice regarding the questions, EDMVS could have input into what SAP/SAB addresses.

Invited Stakeholder Discussion Regarding Coordination with Other Related Activities

Mr. De Morgan invited meeting participants to share their comments, questions or concerns regarding the coordination of EDSP validation activities with other related activities such as OECD efforts.

Ms. Wind raised the question of how EDSP will deal with OECD-validated assays, given that OECD validation is generally not at the level of U. S. standards. Mr. Maciorowski responded that EPA has given this question a lot of consideration. He stated that EPA is striving to meet ICCVAM standards. He pointed out that EPA, as the OECD national coordinator for the U. S., provides a representative to the OECD process. This process, he observed, is largely a regulatory review process, while ICCVAM's is more of a scientific review process and is, therefore, more scientifically stringent. He explained that for the endocrine disruptor effort, the regulatory review process and the scientific review process, which have not converged before, will converge. He stated that EPA's aim is to ensure that they converge at the front side of the program rather than the back side. He also noted that this is OECD's first effort at doing validation rather than standardization. He stressed that there is a need for better communication among national and international organizations and with the public. Mr. Stokes later expressed his hope that EDMVS would have an opportunity to comment on OECD protocols and methods.

Other issues raised by participants included:

. Ms. Wind commented that OECD does more guidelines than protocols, which can lead to different methods being used by different labs. Mr. Maciorowski clarified that EPA also develops test guidelines and not protocols. Mr. Hattan commented that protocols are important in screening for testing a variety of compounds. Mr. Stokes later raised the question of whether an internationally harmonized guideline should be in place without at least one validated protocol in place.

. Mr. Hattan questioned the timeliness of OECD review, observing that EPA can help with timeliness to some extent but cannot control the speed of the process.

. Mr. Stephens underscored the importance of harmonization among organizations from the animal welfare perspective. He suggested that one step toward harmonization is to have international representation on committees to avoid "eleventh hour" objections. Mr. Becker later echoed the importance of harmonization, stating that it would be disastrous to have to repeat studies because of a slight modification in protocols.

. Ms. Sweetland asked how stakeholders can be sure EPA will not pursue a less rigorous SAP/SAB process when EPA is willing to accept OECD validations of the uterotrophic and Hershberger tests after acknowledging that the OECD process is less scientifically stringent. Mr. Becker clarified that just because OECD asked only certain questions in their process does not mean that their science was less rigorous.

Mr. Maciorowski responded that the data, and not the process, will be peer reviewed to see whether they stand up to scientific rigor. He commented that what ICCVAM has to say is not necessarily germane to the European community, and the U. S. is not the only driver of the OECD process. He summarized that though OECD may use a different process with a different intent, the process may provide data useful to EDSP.

Ms. Amundson observed that the contractor has already begun working though EDMVS is not yet in place and asked what activities the contractor has undertaken so far. Mr. Maciorowski explained that they have been conducting "ongoing and already begun" work resulting from the EDSTAC process. He said that the work is primarily literature research and Prevalidation studies needed to provide background information prior to beginning validation studies.

Ms. Amundson expressed a concern over NACEPT's role in EDSP. She asked what will happen during the step of NACEPT's passing EDMVS recommendations to EPA, observing that NACEPT does not have an animal welfare representative. Mr. Maciorowski stated that there is generally a 30-day period between when NACEPT receives subcommittee recommendations and when NACEPT reports to EPA. Ms. Hazen responded that she could not envision that NACEPT would dramatically or substantively change the subcommittee's recommendations. She offered to follow up on Ms. Amundson's question directly with NACEPT and report back if NACEPT's response differed from her own.

Mr. Cooper echoed support for harmonization of international efforts but added that domestic harmonization, both intra- and interagency, is equally important. He asked what communication will happen among and within agencies. Mr. Maciorowski replied that the Office of Pesticide Programs (OPP) and the Office of Prevention, Pesticides and Toxic Substances (OPPT) already have harmonized guidelines. He commented that other agencies may require different information. He added that while EPA is sensitive to other agencies, EPA is currently the only agency mandated to address the issue of endocrine disruptors. Mr. Becker commented that EDSP tests will have cross-agency applicability and efforts should be coordinated. Mr. Hattan agreed that some EDSP tests have cross-agency applicability. He further cautioned EPA to be aware that while other tests may not have broad applicability now, interest from other agencies may grow as the endocrine disruptor issue develops.

Ms. Sweetland commented that Japan seems to be the "stumbling block" to harmonization. She expressed a concern that EPA was not taking the Japanese effort seriously. She requested that EPA pay serious attention to Japanese efforts and that EDMVS have access to the Japanese HTPS data.

Invited Stakeholder Discussion Regarding Other Issues

Invited participants were given an opportunity to express concerns or comments that had not been raised in the previous discussions.

Mr. Stokes recommended that EDMVS expertise include:

. at least one person familiar with biostatistics as applied to validating test methods,

. toxicologists experienced with GLP (Good Laboratory Practice) methods, and

. a person with experience designing test methods.

Public Comment

Invited members of the public were given an opportunity to share their comments with EPA.

Nicole Cardello, Physicians Committee for Responsible Medicine (PCRM), offered comments on three issues concerning EDSP: relevance, the bifurcated approach to validation, and the dismissal of the high throughput screen (HTPS). Highlights of her comments include:

. She expressed concern that relevance is a key component of the validation process but had not been adequately addressed in EDSP thus far. She urged EPA and the proposed EDMVS to develop a formal way of evaluating and demonstrating relevance.

. She expressed support for having test methods validated through ICCVAM, echoing the animal protection organizations and the National Toxicology Program.

. She expressed concern that the HTPS had been dismissed. She stated that she had heard vague statements that EPA's HTPS efforts did not pan out but had not heard compelling reasons for throwing out this powerful screening tool. She commented that the complexities of endpoints and dramatic interspecies difference in the endocrine system lead to uncertainties and need for extrapolation, making EPA's heavy reliance on in vivo screening methods alarming.

William Owens, an employee of Proctor and Gamble and a member of the former EPA Standardization and Validation Task Force and the current OECD Mammalian Validation Management Committee, offered comments in four areas. Highlights of his comments include:

. He noted that current concern focuses on substances that may interfere with estrogen, androgen and thyroid (EAT) endocrine mechanisms and that these mechanisms appear to be restricted to a few phyla, particularly vertebrates. He recommended that we need a clear target list of which invertebrate phyla have EAT mechanisms so that we may identify invertebrate organisms for testing.

. He stated that regulatory purpose is a key step in the validation journey. He stresses the importance of differentiating between screens (Tier 1) and tests (Tier 2), with screens having a mechanistic orientation and tests having an apical endpoint orientation. He observed that there has been a tendency to mix mechanistic and apical endpoints in some of the assays proposed to date.

. He expressed strong support for establishing technical teams for each assay, stating that it has been his experience that such technical teams are essential to successful validation for an assay.

. He observed that a coherent framework is need. He suggested an operating principle: use the in vitro screens to achieve necessary sensitivity to identify potential candidates, then employ animals in the in vivo screens for a realistic assessment of route of administration, metabolism, elimination, etc., with reasonable limit dose.

. Mr. Owens concluded by asking for careful and thoughtful design of the both individual programs for each assay and for the overall structure or framework into which the assays as a whole will fit.

Tina Nelson, American Anti-Vivisection Society, expressed her support of the comments offered by Ms. Amundson, Mr. Stephens and Ms. Sweetwater.

Closing Remarks by Invited Participants

At the end of the meeting each of the participants highlighted his or her primary concerns or offered closing remarks.

Ms. Kim commented that the use of subgroups needs to be judicious. She stressed that EDMVS should have the flexibility to do what it wants to do. She requested that EPA further clarify how ICCVAM, SAP/SAB, and all the entities involved will interact and work together.

Ms. Amundson remarked that she, too, is still unclear about the structure of the program and requested more clarity on the interaction of EDSP bodies and process. She expressed frustration that ICCVAM is unable to do validation of the in vivo test methods due to both resource constraints and political reasons. Noting Mr. Hattan's statement that FDA and other agencies may have interest in EDSP tests in the future and noting EPA's statutory requirement to consult with other secretaries about the program, she asserted that EDSP is a perfect example of a program that should be reviewed by ICCVAM.

Mr. Becker stressed that it is critical that an adequate validation process be followed and remarked that following the ICCVAM principles is a good start. He cautioned not to let the perfect be the enemy of the good and urged EPA to move ahead with the program while continuing to involve stakeholders.

Mr. Liroff said that the meeting had been very instructive to him, especially regarding ICCVAM and OECD. He echoed Ms. Kim and Ms. Amundson's request for further clarification of the interaction of the involved parties.

Mr. Kubiak urged EPA and stakeholders not to forget the ecological side of this effort. He remarked that in the end, the questions are: do we have enough information being generated to make decisions about human health and the environment, and will the results of EDSP pass muster with existing statutes.

Mr. Stokes commented that stakeholder input will be very useful to EDSP in ensuring that public health and the environment are protected and harm to animals during testing is minimized.

Ms. Solomon remarked that it is important to have lots of communication in the EDSP process, but she urged EPA not to let the process get bogged down by excessive layers and subgroups. She also recommended that the prescreening stage of the process be brought under the purview of EDMVS.

Mr. Stephens requested that the role of ICCVAM in EDSP be maximized, noting that stakeholders hold a significant degree of trust in ICCVAM and that ICCVAM is knowledgeable in the state of the art technology. He also requested that EPA not only make the EDSP process transparent but also involve stakeholders directly.

Ms. Duggan requested that EPA's next steps be made clear. She recommended that EDMVS move forward with increased participation, particularly with representation from the contractor and the international community. She observed that though a variety of concerns had been expressed throughout the day, the concerns were not that different from those expressed in the EDSTAC process. She suggested that EDSTAC structures and methods might be instructive in forming EDMVS.

Mr. Cooper commented that he appreciated the updates and thought-provoking points he had heard from EPA and other meeting participants. He urged that EDMVS stay focused while also being flexible. He also noted that though stakeholders are often involved in program development, they are rarely included in implementation as they are in the proposed EDMVS approach.

Ms. Wind acknowledged the concerns of the animal welfare groups and commented that she is glad to hear of their respect for ICCVAM. She remarked that the ICCVAM process is not static and that EPA will not be working in a vacuum on EDSP; ICCVAM and EPA will interact, and the process will not be as bifurcated as some feel it will be based on the proposal. She cautioned that EDMVS will have to address the relevance of all the assays, noting that human relevance is a major principle of ICCVAM.

Ms. Sweetland reflected that her concerns relate to four areas: relevance, harmonization, validation, and HTPS. She remarked that she is left wondering where stakeholders can make changes given that validation does not seem open for debate. She stressed that she is in favor of keeping the programs momentum going, but the information generated must be useful and the science must be sound. Building on Mr. Kubiak's remark, she urged that the appropriateness of the generated information be examined as well as the amount.

Mr. Hattan noted that EDMVS will have some empowerment and will have the ability to ask EPA to keep it apprised of the progress and implementation of validation.

Next Steps and Closing Comments by EPA

Sherry Sterling, Acting Director of EPA's Office of Science Coordination and Policy, thanked everyone for attending and sharing their comments. She remarked that she herself had not spoken much during the day because she and the other EPA staff had wanted to focus on listening to the concerns and recommendations of the participants and the public so that they might seriously examine the EDMVS proposal in light of those comments.

She reflected that she had heard a range of opinions throughout the day--which she appreciated--but that she had also heard some common themes. She observed that though there may be disagreement on the appropriate balance among the factors, stakeholders agree that these factors are important: transparency, harmonization, flexibility, and respect for scientific integrity. She summarized some of the primary points that had emerged from the discussions:

. In regard to the mission statement, flexibility is key, and the battery of tests should be brought under the purview of EDMVS.

. In regard to organizational processes, the aim should be efficiency, effectiveness and transparency. Also, further effort is needed to clarify how all the bodies involved in EDSP will interact.

. In regard to related activities, harmonization is critical.

She stated that EPA will move ahead with the program and that Ms. Hazen had received approval to proceed with developing the Federal Register notice. She closed by recounting the action items for follow-up to the meeting:

. A list of meeting participants and their affiliations will be prepared and sent to participants and to members of the public who registered when they arrived.

. A summary of the meeting will be prepared and sent to participants and to members of the public who registered when they arrived.

. A copy of the Federal Register notice soliciting nominations for members of EDMVS will be sent to participants and to members of the public who registered when they arrived.

. EPA will verify the relationship between NACEPT and EDMVS in regard to reporting recommendations to EPA and will notify meeting participants if the relationship differs from Ms. Hazen's characterization.

Appendix A

Invited Participants*

Proposed Endocrine Disruptor Methods Validation Subcommittee (EDMVS)

Organizational Meeting

Sara Amundson, Doris Day Animal League

Rick Becker, American Chemistry Council

James Cooper, Synthetic Organic Chemical Manufacturers Association

Peter De Fur, Virginia Commonwealth University

Angelina Duggan, American Crop Protection Association

David Hattan, Food and Drug Administration

Nancy Kim, New York State Department of Health

Timothy Kubiak, U.S. Fish and Wildlife Service

Rich Liroff, World Wildlife Fund

Martin L. Stephens, The Humane Society of the United States

Gina Solomon, Natural Resources Defense Council

Bill Stokes, National Institute of Environmental

MaryBeth Sweetland, People for the Ethical Treatment of Animals

Marilyn Wind, U.S. Consumer Product Safety Commission

*In some instances, other individuals were invited, however these were the individuals who attended as 'invited participants' during the meeting on April 24, 2001.

Appendix B

Documents Distributed at Proposed EDMVS Organizational Meeting

April 24, 2001

1. Meeting Agenda

2. Proposal to Establish an Endocrine Disruptor Methods Validation Subcommittee Under the National Advisory Committee for Policy and Technology

3. Planning Report: An Assessment of Issues Surrounding the Convening of an Endocrine Disruptor Methods Validation Committee

4. Memo and attachments from Angie Sanders, Program Specialist, NTP Liaison Office, NIEHS

5. Copy of slides from Gary Timm's presentation: EDSP screen and test method validation process and organizational interactions (EPA/ICCVAM/OECD)

6. Copy of slides from Jim Kariya's presentation: Overview of EPA=s ongoing activities and schedule for EDSP validation

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