In Vitro 1. Estrogen Receptor ( ER) Binding/ Transcriptional Activation Assay; 2. Androgen Receptor ( AR) Binding/ Transcriptional Activation Assay; and 3. Steroidogenesis Assay With Minced Testis. In Vivo 1. Rodent 3 day Uterotrophic Assay ( subcutaneous); 2. Rodent 20 day Pubertal Female Assay With Thyroid; 3. Rodent 5 7 day Hershberger Assay; 4. Frog Metamorphosis Assay; and 5. Fish Gonadal Recrudescence Assay.

3. The EDSTAC identified the following four assays as possible alternatives to some components of the proposed battery and recommends that they also be standardized and validated:

In Vitro 1. Placental Aromatase Assay In Vivo 1. Modified Rodent 3 day Uterotrophic Assay ( intraperitoneal); 2. Rodent 14 day Intact Adult Male Assay With Thyroid; and 3. Rodent 20 day Thyroid/ Pubertal Male Assay.

Combinations of the alternative assays, if validated and found to be functionally equivalent, could potentially replace three of the component assays in the proposed T1S battery ( in vitro steroidogenesis assay with testis, 20 day pubertal female assay, and 5 7 day Hershberger EDSTAC Final Report Chapter Five August 1998 5  78 assay) thereby possibly reducing the overall time, cost, and complexity while maintaining equivalent performances of the overall T1S battery. The EDSTAC recognizes that the stateof the science in this area is evolving quickly and strongly encourages the use of new or improved assays for screening as they become available.

4. The EDSTAC recommends that validation/ standardization studies be conducted on all assays in the proposed battery as well as the alternatives.

5. The EDSTAC agrees that EPA should take affirmative steps, in collaboration with industry and other interested parties, to attempt to develop the protocol for a full life cycle ( i. e., with embryonic exposure and evaluation of the adult offspring) developmental exposure screening assay that can be subjected to validation and standardization. The EDSTAC further recommends that, if such an assay were identified, validated, and standardized, the decision on whether it should be included in the T1S battery should include an evaluation of its potential to replace one or more of the recommended T1S assays and its overall impact on the cost effectiveness of the T1S battery.

6. The EDSTAC recommends that all T1S in vitro assays involve multiple dose levels, whether performed by HTPS or bench level methods, so a dose response curve and assessment of relative potencies can be developed. Subject to the results of the validation process, the EDSTAC recommends using one or more dose levels in the performance of the in vivo assays.

7. For assessing receptor binding in vitro, the EDSTAC is recommending that both the cell free receptor binding assays and the transcriptional activation assays for ER and AR be incorporated into the T1S battery, and be subjected to validation and standardization.

8. As noted in Chapter Four, the EDSTAC recommends the use of a high throughput pre screen ( HTPS) for toxicants operating though the ER, AR, and TR using stably transfected cell lines with and without metabolic activation, if available. Substances which have not been assessed in the HTPS should be subject to assays for detection of ER and AR activity performed at the bench. Two types of assays are considered acceptable: cell free receptor binding and transcriptional activation in transfected cells. The latter is preferred. Assays must meet the following characteristics:

· evaluate binding to EAT receptors; · evaluate binding with and without metabolic capability; · distinguish between agonist and antagonist potential; and · yield dose responses to establish relative potency.

9. The EDSTAC is recommending evaluation of antithyroid effects in animals in the longer term rodent screen ( either 14 day or 20 day exposure). Although it is not known whether exposure to xenobiotics for greater than 14 days is required to significantly affect circulating levels of T4, TSH, or thyroid histopathology, the EDSTAC believes these longer periods may be required. The effects of duration of chemical substance and mixture exposure must be quickly evaluated in the validation phase. EDSTAC Final Report Chapter Five August 1998 5  79 B. Principles for Evaluating Tier 1 and Tier 2 Results 10. The EDSTAC recommends that a " weight of evidence" approach be used in evaluating T1S and T2T results and has developed general criteria for applying " weight of evidence" to ensure that decisions are transparent and predictable.

C. Tier 2 Testing 11. The EDSTAC recommends that the following tests be included in the Tier 2 battery:

Mammalian tests · Two generation reproductive toxicity study, or · An alternative less comprehensive test: 1. Alternative mammalian reproductive; and 2. One generation test.

Non mammalian multigeneraton tests · Avian reproduction; · Fish life cycle; · Mysid life cycle; and · Amphibian development and reproduction.

12. The EDSTAC recommends that the " default" action, in absence of any prior information, be to perform all tests in the T2T battery with all endpoints. Further, the EDSTAC recommends that the choice of whether Tier 2 tests will be conducted on all five of the recommend taxa, or a more limited subset of the five taxa, should be based on the physicochemical characteristics and environmental release and exposure information of the chemical substance or mixture to be tested, together with biological data from T1S. The results of T1S or other information may also allow tailoring of T2T such as the inclusion or deletion of certain endpoints ( e. g., thyroid effects) or use of alternative tests.

13. The EDSTAC believes that a project is required to resolve the underlying uncertainties and controversy about issues related to low dose selection and the identification of no observedadverse effect levels ( NOAEL). Further, the EDSTAC recommends that a collaborative group involving government, industry, and appropriate individuals in academia design the study protocols, be kept abreast of the conduct of the studies, evaluate results, and develop overall conclusions and recommendations.

14. The EDSTAC recommends that information used to select doses in the performance of Tier 2 tests include: EDSTAC Final Report Chapter Five August 1998 5  80 · existing information such as that available during priority setting including the results or the HTPS; · results from T1S; · results from other assays or tests; and · results from range finding studies.

15. The EDSTAC recommends including thyroid sensitive endpoints in T2T and that dosing in mammalian tests include fetal and lactational exposure.

D. Validation of the Screening and Testing Batteries 16. The EDSTAC believes the validation and standardization program is of highest priority, and recommends that it proceed on an accelerated schedule. The EDSTAC further recommends that the validation and standardization program be consistent with the principles articulated by the national ( ICCVAM, 1996; Zeiger, 1998) and international ( OECD, 1996) alternative methods validation groups.

17. The EDSTAC recommends that, as individual screens and tests are validated and standardized, they can be utilized in the EDSTP without waiting for all screens and tests in the batteries to be validated.

18. The EDSTAC recommends that a multi stakeholder process, involving government, industry, and academics, be utilized in validating and standardizing the T1S and T2T batteries.

19. The EDSTAC identified other screens and tests which, if available, could have an important utility in the screening and testing program, and recommends that research be conducted to determine whether such assays can be developed, and if so, what purpose the assays could fulfill within the endocrine disruptor screening and testing program.

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Recommendations............................................................................................................... 3 A. Principles to Guide Implementation of a Communications and Outreach Strategy............... 3 B. Basic Features of the Communications and Outreach Strategy............................................ 3 1. What Should be Communicated?.................................................................................... 4 2. To Whom Should Information be Communicated? ....................................................... 11 3. How Should Information be Communicated? ............................................................... 12 4. When Should Information be Communicated? .............................................................. 14 C. Adequacy of Resources Devoted to Communication and Outreach................................... 16 IV. Generalized Schedule for Implementation....................................................................... 16 V. Compilation of Chapter Six Recommendations................................................................ 19 A. Need for Communication ................................................................................................. 19 B. Principles to Guide Implementation of a Communications Strategy................................... 19 C. Basic Features of a Communications and Outreach Strategy............................................. 19 VI. Literature Cited ................................................................................................................ 21 Figures Figure 6.1 Generalized Schedule for Implementation of the Endocrine Disruptor Screening and Testing Program ........................................................................................ 18 Appendices Appendix T: Summary of EPA's September 1997 Outreach Questionnaire Results Appendix U: Summary of Public Comments to the EDSTAC EDSTAC Final Report Chapter Six August 1998 6  1 I. Introduction The EDSTAC recognized early on, that effective communication about the endocrine disruptor screening and testing program and its results, would be critical to the success of the Endocrine Disruptor Screening and Testing Program ( EDSTP) ( Heckler, 1985; Banquet, 1985; Chilton, 1989; NRC, 1989; NRC, 1994; NRC, 1996; NRC, 1983). To address this need, the EDSTAC created the Communications and Outreach Work Group ( COWG), which was charged with three principal tasks:

1. providing advice on the coordination of the overall communications and outreach efforts surrounding the EDSTAC process; 2. developing recommendations to be incorporated into the EDSTAC final report on communication issues regarding key decision points of the Conceptual Framework and implementation of the EDSTP; and 3. improving the understandability of the final report and any other materials distributed by the Committee.

A significant portion of the work completed by the COWG during the EDSTAC process fell under the first task   coordination and input on overall communications and outreach efforts surrounding the EDSTAC plenary meetings. Activities of the work group included: providing feedback to EPA on the public comment period session; developing the Description of the EDSTAC Charge, which was used by EPA to describe the process to the public; recommending to EPA that the Agency coordinate an outreach mailing to interested and potentially interested parties; assisting in the subsequent assembly of materials for the mailing; and discussing additional outreach efforts for EPA and the Committee. Included in the EPA outreach mailing was a questionnaire developed by the COWG and disseminated to over 1,500 addressees. This questionnaire was created in an effort to obtain information as to the public's interest in the EDSTAC and its activities during the Committee's existence, as well as to help in future outreach efforts by the Agency. The information received in response to this questionnaire will assist the Agency in determining the most effective way( s) to communicate with those individuals and organizations interested in the EDSTAC process. A summary of the results of the survey can be found in Appendix T.

The recommendations provided in this chapter focus primarily on the second of these three tasks   developing recommendations to be incorporated into the EDSTAC final report on communication issues regarding key decision points of the Conceptual Framework and implementation of the EDSTP. In some instances, however, communication recommendations regarding key decisions of the Conceptual Framework and the EDSTP are included elsewhere in the report where they are more appropriate.

The work group's efforts surrounding the third task above   improving the understandability of the final report and any other materials distributed by the Committee   included: review of the Priority Setting and Screening and Testing Work Group chapters to ensure communication issues EDSTAC Final Report Chapter Six August 1998 6  2 are addressed where appropriate; development of language appropriate for distribution to the public describing various aspects of the screening and testing program; and development of background materials describing the basic science of the endocrine system, as well as reasons why the EDSTAC was created by EPA, for use in Chapter One of this Report.

II. Need for Communication The EDSTAC Conceptual Framework, which has been described elsewhere in this document, is premised on a phased or tiered approach to decision making regarding screening and testing chemical substances or mixtures for endocrine disruption. Under this approach, increasingly more specific and precise information produced in each tier is used to reach key decisions, which begin with judgments as to how chemicals and mixtures should be selected for movement into the screening and testing stages ( i. e., priority setting). This will lead eventually to judgments about whether a chemical or mixture may or may not interact with the endocrine system ( i. e., T1S) or produce endocrine mediated adverse effects ( i. e., T2T) for the hormone systems currently addressed by the program ( i. e., estrogen, androgen, and thyroid systems ( EAT)).

The first steps of the program utilize broad criteria relating to exposure and effects related information for the purposes of sorting and prioritizing chemicals for T1S. Criteria for moving a chemical into screening are less restrictive than criteria used later in the program to move chemicals from screening into testing or, similarly, from testing into hazard assessment. The purpose of using less restrictive criteria initially is to ensure that chemicals which may cause endocrine activity are not missed in early steps of the program, when information less specific for evaluating interaction with the endocrine system is used to make decisions. Thus, because the information gathered becomes more specific as a chemical moves through the EDSTP, the criteria for progressing through the program need to be more restrictive. Such increasing rigor will focus attention and resources on those chemicals and mixtures most likely to cause endocrine mediated adverse effects.

When little or no effects data on a chemical are available, additional information to guide sorting and priority setting decision making will come from the results of High Throughput Pre Screening ( HTPS), as described in Chapter Four. The T1S battery is intended to identify, through the application of various assays, whether a chemical substance or mixture may interact with the EAT components of the endocrine system and, if so, to forward such compounds to the testing phase of the program. T2T is intended to determine whether a particular compound does or does not produce endocrine mediated adverse effects and whether it should, therefore, be subjected to the hazard assessment phase of decision making.

Communication is most important when decisions are made to move chemicals from one step in the process to the next ( i. e., from initial sorting to priority setting, to screening, to testing). The tiered approach is constructed so the Agency will have increased certainty, with each progressing tier, that a chemical does or does not disrupt the endocrine system for the hormone systems currently addressed by the program. It is important for EPA to clearly communicate the EDSTAC Final Report Chapter Six August 1998 6  3 limitations that must be placed on the interpretation of information from the EDSTP, as well as the meaning and implication of its decisions.

One significant concern identified by the Committee is that information could be misused to label chemicals as " endocrine disruptors" prior to the existence of evidence to support such a claim. Such potential misuse of information could lead to unnecessary and undue concern, along with a failure to focus society's attention on those substances that are most likely to be endocrine disruptors. Such a result could, in the end, create problems serving the interest of no one. This, therefore, necessitates that the public and other interested stakeholders be provided with accurate information about the meaning of the EDSTP results. The recommendations provided in the remainder of this chapter seek to emphasize the importance of communication as EPA moves forward with implementation of the EDSTP.

III. Recommendations A. Principles to Guide Implementation of a Communications and Outreach Strategy EPA should develop and implement an effective communications and outreach strategy for the EDSTP, as this is an element vital to the program's success. EPA should follow a set of principles regarding implementation of the communications and outreach strategy, which include:

· Both the process and results of the EDSTP should be open and transparent. · The results of the EDSTP should be interpreted and communicated within the context set forth in the EDSTAC final report. · The limitations and uncertainties of the available data and the results of EDSTP should be articulated clearly when the screening and testing program is discussed. · As new scientific evidence emerges, the uncertainties and limitations of the data may also change. These changes should be communicated clearly. · EPA should develop quality assurance processes to assure that any database maintained for the public relative to the EDSTP is accurate and current.

B. Basic Features of the Communications and Outreach Strategy It is anticipated that the EDSTP will produce an abundance of information shortly after its initiation, some of which may be preliminary and difficult to interpret. As results of the program are generated, it will be imperative for EPA to make them available to the public in a timely manner and to provide guidance on their interpretation ( while recognizing there may be legitimate disagreement as to the appropriate interpretation). EDSTAC Final Report Chapter Six August 1998 6  4 This program of communication and outreach should consider the following four issues:

1. What should be communicated? 2. To whom should information be communicated? 3. How should information be communicated? 4. When should information be communicated?

The following discussion further addresses these four issues in detail.

1. What Should be Communicated?

The EDSTAC has focused on several aspects of the program, described below, about which EPA should be prepared to provide information. Where appropriate, the Committee has provided suggested language that could be used to communicate such information to those interested in the issues and the outcomes of the EDSTP.

a) Description of the Endocrine Disruptor Screening and Testing Program The EDSTAC determined that one of the central issues for EPA's communication and outreach efforts is the explanation of the screening and testing program itself. Committee members recognized the importance of explicitly describing what information generated by the EDSTP means and does not mean, so as to avoid misinterpretation and misperception of the information. This potential problem was identified as a major area of concern by Committee members.

To address this concern, an explanation of the various components of the EDSTP is provided below in less technical terms than is found throughout the report. This, it is hoped, will help minimize miscommunication about the EDSTP and/ or its results. Each phase of the EDSTP, ( i. e., priority setting, screening, and testing) is briefly described. The Committee envisions such language filling a variety of needs for EPA and others. For example, it could be used in the following ways: to fill requests of the Agency for information about the EDSTP and, more specifically, what it means when chemicals reach certain steps in the process; as background information in the development of booklets or brochures about the screening and testing program; in EPA outreach mailings; and as information placed on EPA's Web site. The language below could also be used more widely, as Committee members and others seek to explain the EDSTP to their constituencies. EDSTAC Final Report Chapter Six August 1998 6  5 Steps of the EDSTP The following examples were developed by the Committee to explain each phase of the EDSTP.

PRIORITY SETTING PROCESS During the priority setting process, existing information is gathered and evaluated on new and existing chemical substances and mixtures to determine their priority to be set aside, screened, tested, or forwarded to hazard assessment. Information on exposure and human health and ecological effects, as well as statutory requirements about chemicals, will be used by EPA to set priorities. The exposure related information and criteria will include: biological sampling data; environmental, occupational, consumer product, and food related data; data on environmental releases; production volume; and fate and transport data and models. The effects related information and criteria will include: toxicological laboratory studies and databases; epidemiological and field studies and databases; predictive biological activity or effects models; and results of high throughput pre screening.

Since most chemicals lack adequate data on human health and ecological effects for purposes of priority setting for endocrine screening and testing, the EDSTAC recommends that chemicals produced in amounts equal to or greater than 10,000 pounds per year, as well as pesticides, be subjected to High Throughput Pre Screening ( HTPS) assays. These assays are intended both to provide a cursory assessment of the chemicals' potential to interact with estrogen, androgen, and thyroid receptor systems and to assist in the effort to set priorities for Tier 1 Screening ( T1S). Using a limited number of assays that are appropriate for automated processing and that rely on robotics technology, HTPS is designed to generate results quickly and inexpensively. HTPS results, by themselves, will not be sufficient to make a determination about whether a chemical may interact with the endocrine system of an intact animal. Such determinations will require additional screening and testing.

In addition, a nominations program which allows citizens and communities to nominate chemicals for EPA's EDSTP will constitute another criterion for consideration by EPA in the priority setting process.

For information on the possible decisions resulting from the priority setting process, see the accompanying information on " Priority Setting Decisions." EDSTAC Final Report Chapter Six August 1998 6  6 PRIORITY SETTING DECISIONS The priority setting process will result in one of four possible decisions:

( 1) Hold. No further analysis required ( at this time). ( 2) Set priorities for Tier 1 Screening ( T1S). ( 3) Sufficient data, or voluntary bypass of T1S, to go to Tier 2 Testing ( T2T). ( 4) Sufficient data to go to hazard assessment.

The first category is for those chemical substances and mixtures that have a low probability of interacting with the endocrine system or exhibiting endocrine mediated adverse effects. The Committee identified one class of chemicals   polymers   that, with some exceptions, falls into this category. A polymer is a chemical compound or mixture of compounds composed of many small units bound together to form a larger compound. Because of their molecular size, most polymers are of low concern, and therefore should be placed into a " hold" status pending a review of their components. For information on how these chemicals can be recalled into the priority setting process, see the accompanying information describing the " hold box."

The second category is for those chemicals with insufficient data to proceed to T2T, which therefore will need to be prioritized for T1S. A combination of exposure and effects data will be used to set these priorities.

The third category is for those chemicals for which sufficient data exist to permit them to go directly to T2T, or for which the owner of the chemical has decided to voluntarily bypass T1S and go directly to T2T, according to the specific recommendations found in Chapter Four of the EDSTAC report. As with T1S, it is important to note that prioritizing a chemical for T2T does not mean the chemical is an endocrine disruptor. It means, simply, that sufficient data exist to indicate the chemical substance or mixture has shown the potential to interact with the specific parts of the endocrine system examined in the EDSTP and should therefore be evaluated in T2T in accordance with the priority it receives.

The fourth category is for those chemicals for which existing data provide equivalent information to the T1S and/ or T2T batteries. Such data demonstrate that a chemical is an endocrine disruptor for the hormone systems addressed by the EDSTP ( i. e., estrogen, androgen, and thyroid). These chemicals will proceed directly to hazard assessment. EDSTAC Final Report Chapter Six August 1998 6  7 TIER 1 SCREENING Tier 1 Screening ( T1S) is defined as the application of assays to determine whether a chemical substance or mixture may interact with the endocrine system for the estrogen, androgen, or thyroid ( EAT) hormone systems. It is intended to provide a fast, cost efficient, and sensitive means of determining which chemicals should be subject to the more comprehensive and specific Tier 2 Testing ( T2T). Screening consists of in vitro and in vivo assays designed to screen for activity in EAT hormone systems. However, it is not designed to quantify such activity ( i. e., to determine doseresponse The screening process can result in one of two decisions:

( 1) No further screening or testing required ( at this time). ( 2) Further analysis requiring T2T.

T1S is designed to provide sensitivity sufficient to minimize the chance that a chemical substance or mixture that may interact with the endocrine system will pass through T1S undetected ( i. e., to minimize false negative results). This, however, is likely to result in an increased number of false positive results ( i. e., chemicals which screen positively in Tier 1 screens without ultimately demonstrating adverse effects on the endocrine system). For this reason, a positive result in screening warrants further investigation in T2T.

Chemicals judged to be positive in T1S will proceed to T2T. Chemicals judged to be negative in T1S, are considered, unlikely to interact with the EAT hormone systems, because of the emphasis on sensitivity. These chemicals will not go on to T2T, but instead will be placed in the " hold box." For information on how chemicals can be recalled into the screening and testing process, see the accompanying information describing the hold box. EDSTAC Final Report Chapter Six August 1998 6  8 TIER 2 TESTING Chemical substances or mixtures enter Tier 2 Testing ( T2T) if: ( 1) existing laboratory, field, or epidemiological data suggest the chemical substance or mixture has shown the potential to interact with the estrogen, androgen, or thyroid hormone systems; ( 2) Tier 1 Screening ( T1S) results are positive; or ( 3) statutory or regulatory mandates require testing. The Tier 2 battery includes both mammalian and non mammalian tests designed to evaluate a variety of adverse reproductive and developmental effects.

The purposes of T2T are: to determine whether chemical substances or mixtures may produce changes in endocrine activity that will likely result in adverse effects; to characterize the nature of the effects; and to evaluate dose response relationships. What constitutes an adverse effect may differ with taxonomic groups and is a matter of scientific judgment that may evolve with new scientific information. The T2T process can result in one of two decisions relating to the hormone systems addressed by the Endocrine Disruptor Screening and Testing Program ( i. e., estrogen, androgen, and thyroid):

( 1) No evidence of endocrine mediated adverse effects for estrogen, androgen, or thyroid hormone systems ( at this time); and ( 2) Evidence of endocrine mediated adverse effects for estrogen, androgen, and/ or thyroid hormone systems in: · mammals; · birds; · fish; · reptiles; · amphibians; and/ or · invertebrates.

Positive T2T results may trigger additional testing and/ or a hazard assessment.

Chemicals that test negative in T2T are generally considered to possess low or no potential to affect the endocrine system, within the scope of endocrine functions addressed by the program. Such chemicals can, however, be recalled into the testing process, even if it has previously received a negative testing result. For information on the criteria used to determine whether a chemical is reentered into the testing process, see the accompanying " hold box" description. EDSTAC Final Report Chapter Six August 1998 6  9 " HOLD BOX"

At three different points in the EDSTP, chemical substances or mixtures are evaluated and may potentially be placed in what is referred to as the " hold box." The first example of this is illustrated in the priority setting phase, where polymers with a number average molecular weight of greater than 1,000 daltons are placed in a " hold" status, pending screening and testing and, if necessary, exposure assessment of their components. Those polymers that are equal to or less than a number average molecular weight of 1,000 daltons will also be prioritized for and subjected to endocrine disruptor screening and testing.

The second situation where chemicals are placed in a " hold box" takes place in the context of Tier 1 Screening ( T1S). If results of a screening battery are deemed negative, the chemical substance or mixture is placed into a " hold box" and no further activity occurs unless certain criteria are met. Specifically, the possibility exists for a chemical substance or mixture to re enter the screening and testing program if:

( 1) existing statutes require periodic review ( e. g., FIFRA re registration); ( 2) new statutory requirements mandate review; ( 3) new screens for endocrine disruption are incorporated into the strategy and it is determined that these new screens may either generate significant new information or they invalidate prior screens and therefore warrant the re screening of chemical substances and mixtures that have already been subjected to T1S; and/ or ( 4) new information on the endocrine disrupting potential of the chemical substance or mixture becomes available which warrants re screening.

The third situation where chemicals are placed in the " hold box" takes place in the context of Tier 2 Testing ( T2T). If results of the T2T battery are deemed negative, the chemical substance or mixture is placed in the " hold box" and no further testing is performed unless certain criteria are met. In addition to ( 1) through ( 4) above, a fifth possibility exists for re entry into the screening and testing program. Specifically a chemical substance or mixture could re enter the screening and testing program if:

( 5) there is a change in the use and expected exposure patterns upon which the selection of tests were made. EDSTAC Final Report Chapter Six August 1998 6  10 A potential outcome of each phase of the screening and testing program, is the development of lists of chemicals. The Committee developed a series of questions EPA should be prepared to address when EDSTP decisions result in the creation of a list of chemicals demonstrating a common decision having been made regarding a chemical's status. The Committee developed these questions as a way to alert EPA to concerns that may arise regarding the results of screening and testing. It will be important for the Agency to clearly communicate about the issues that have been raised to ensure results of the EDSTP are accurately reflected. The questions include:

· What does this list mean? · For what purpose will the list be used? · What are the chemicals on the list? · How was this list derived? · What are the selection criteria for inclusion on the list? · What are the limitations and uncertainties of knowledge associated with the list? · Who compiled the list? · Are there other ways to get a chemical on the list or considered for inclusion? · How can a chemical be removed from the list?

b) Screening and Testing Results Regular EDSTP status reports should be produced and distributed. These documents should include:

· the status of all chemicals and mixtures within the EDSTP; · a list of all chemicals and mixtures whose status within the EDSTP has changed since the last update; and · important EDSTP decisions and developments at decisive points in the program, such as calls for nominations of compounds to be considered in priority setting; lists of chemicals that have been prioritized for T1S; lists of chemicals that have been identified for T2T; lists of chemicals that have produced endocrine mediated adverse effects in T2T and are now subject to hazard assessment; significant scientific advances in the field; the incorporation of new assays into the EDSTP; and expansion of the scope of work ( e. g., looking at additional hormones).

c) Nominations Process As described in Chapter Four, Section IX, of this report, the EDSTAC recommends EPA establish a process that would allow stakeholders, including members of the general public, to nominate chemical substances or mixtures for endocrine disruptor screening and testing. In general, the nominations process is intended to focus on chemical substances or mixtures where exposures are disproportionately experienced by identifiable groups, communities, or ecosystems rather than those where exposures are more broadly experienced by the general population at the regional and/ or national levels. The process should provide a mechanism for prioritizing chemicals unlikely to be considered as having a high priority through the core priority setting process. EDSTAC Final Report Chapter Six August 1998 6  11 It is important for EPA to alert the public about the opportunity to nominate chemicals, as well as to provide accurate and up to date information about the status of all chemicals considered for prioritization. Members of the public should be encouraged to provide comments during the formal public comment period, which is expected to take place after EPA has publicized its proposed list of chemical substances or mixtures prioritized for screening and testing. An opportunity to nominate chemicals will occur at the start of each phase of the EDSTP.

d) Background Information on the EDSTAC Process EPA should communicate information to the public about the EDSTAC, including its purpose, goals, and process, as needed. The language contained in Chapter Two of this report could be used by the Agency for this purpose.

2. To Whom Should Information be Communicated?

a) Members of the Public and Other Stakeholders Throughout the EDSTAC process, an interest in the issue of endocrine disruption and the development of a screening and testing program was evident. This was demonstrated via the public comment sessions held at seven of the nine plenary meetings, where members of the public representing   industry, environmental groups, advocacy organizations, farmers and farm workers, governmental organizations, environmental and health oriented non governmental organizations ( NGOs), trade unions, disease impacted groups, environmental justice networks, students, industries that formulate products but do not manufacture the component chemicals ( i. e., " downstream" industries), and concerned citizens, among others   were given the opportunity to present their comments to the Committee regarding the deliberations of the EDSTAC and its work groups. A compilation of the statements made by members of the public at each of the EDSTAC meetings can be found in Appendix U. Furthermore, each of these stakeholders was also represented either in one of the work groups or on the Committee itself, further demonstrating the variety of interests contributing to this effort.

It is recommended that EPA proactively communicate with groups, such as those listed above, which have clearly demonstrated an interest in the issue, particularly those organizations and individuals who have requested to receive program information directly from EPA. The database of names and organizations already collected by the EDSTAC could be used as a base of contacts for proactive communication to stakeholders. In fact, much of the data entry has already been done. Other stakeholders to include can be found in the list of organizations that received EPA's September 1997 mailing, as well as The Keystone Center's list of interested parties accumulated over the duration of the EDSTAC process.

b) Specific Audiences For some stakeholders, EPA will find it necessary to go beyond the generic EDSTP status reports. A tailored set of messages about the program targeted to specific audiences will be EDSTAC Final Report Chapter Six August 1998 6  12 needed. It is clear that the " public" consists of a variety of people and organizations, each with varying levels of knowledge and interest in endocrine disruptor related issues. In addition, many communities face other challenges such as language barriers and differences in culture or economic viability. Such differences create a need for informational materials to be tailored to such audiences. In particular, EPA should consider this type of communication with environmental justice organizations, " downstream" industries, farm workers, and patient specific groups. To find out more about communicating with such constituencies, the Committee recommends EPA conduct a follow up survey, building on the information gathered from the September 1997 survey described in Section I of this chapter.

3. How Should Information be Communicated?

As EPA carries the important new responsibility of screening and testing chemical substances and mixtures for endocrine disruption, it will be necessary to develop a capacity to quickly respond to requests for information, both about specific chemicals and about the EDSTP in general.

a) Electronic Communication The EDSTAC recommends that EPA create a tracking database with the ability to handle inquiries about the status of specific chemicals and classes of chemicals, as well as summaries for defined sets of chemicals ( e. g., organophosphates). The goal for the creation of such a database is that any member of the public should be able to query and quickly determine the status of a chemical or mixture in the EDSTP. Inquiries might come from within the Agency, from the public, or from industry. As a result, it is important that the database be organized so people can submit inquiries in many different ways and with varying levels of expertise. For example, the inquiry might begin with a chemical name or Chemical Abstracts Service ( CAS) registry number, a chemical structure, or a stage in the EDSTP process.

The tracking database should be compatible with, and fully integrated into, the Endocrine Disruptor Priority Setting Database ( EDPSD), described in Chapter Four. As proposed in Chapter Four, Section X, G, a multi stakeholder group should be created by the Agency to continue development of the EDPSD as a tool for priority setting purposes. In addition, the Committee recommends that the same group assist in development of the tracking database, in order to promote consistency and ensure it meets the needs of the diverse groups likely to use the database in the future. The database should also be compatible with, and integrated into, those being developed elsewhere in the Agency ( e. g., for carcinogens or reproductive toxicants). The EDPSD should not exist in isolation.

In creating this database, several characteristics are desirable if it is to address the needs of a wide range of potential users:

· The database should be useful over the Internet, and a Web site should be established for this purpose. Since it will be integrated with other databases at the Agency, the Web site should be reached through links that begin at several locations ( e. g., the main Agency site, a page dedicated to inquiries about toxic substances in general, a page dedicated to searching for EDSTAC Final Report Chapter Six August 1998 6  13 information on endocrine disruptors, and pages dedicated to searching for other effects such as developmental, reproductive, or carcinogenic).

· The database should include the ability to search by specific chemical names, by classes of chemicals, and, where appropriate, by chemical structure. Searching should be by chemical, not by product name.

· The database should include the ability to search for the place of each chemical in the EDSTP process and subsequent regulatory decisions. This includes the ability to obtain a listing of all chemicals that presently are: ( i) in HTPS; ( ii) undergoing review for priority setting; ( iii) in T1S; ( iv) in T2T; ( v) undergoing hazard assessment; or ( vi) have had a regulatory decision made.

· Whenever the location of a chemical in the system is provided to an inquirer, or a listing of chemicals at particular points in the EDSTP is provided, it is essential that this information have appended to it a brief description of what it means for a chemical to be at that location. This description should be consistent with guidance provided elsewhere in this chapter.

· The database should include the ability to obtain the decision results of each step a chemical has completed to date. The designations for these results should be consistent with those detailed elsewhere in the EDSTAC Report. This should include information describing: ( i) the result of a chemical's priority setting; ( ii) the results of T1S; ( iii) the results of T2T.

· The database should not attempt to summarize the rationale for the Agency's decisions discussed in the previous item and based on specific positives/ negatives for particular screens/ tests. Instead, the database should direct the inquirer to the appropriate documentation, explaining how that documentation can be viewed and/ or obtained.

· To facilitate the utility of the database as a research tool, it would be useful if the database contained information on whether the chemical was positive or negative for each individual screening assay and/ or test, including the results of HTPS. In stating whether the result of a screen or test was positive or negative, it is important that the database also provide information about the criteria by which a result is considered to be a pass or fail for that assay.

In considering the range of questions users might have in directing inquiries to the database, several kinds of information should be available through the database. These include:

· chemical name and CAS registry number; · common synonyms ( but not product names); · chemical structure; · information on the stage in which a chemical currently is found ( priority setting; T1S; T2T; HTPS; hazard assessment; " hold box"); · one sentence descriptions of the purpose and possible outcomes of each of the stages; this description would be provided whenever the inquiry indicates a particular stage has been reached; EDSTAC Final Report Chapter Six August 1998 6  14 · summary of the Agency decision on a chemical at each of the stages through which it has passed ( priority setting; T1S; T2T; HTPS; hazard assessment; " hold box"); · summary of the result obtained from each HTPS screen; · one sentence descriptions of reasonable interpretation( s) of a chemical's having positive or negative results in a particular HTPS screen; · summary of the result obtained from each T1S assay; · one sentence descriptions of reasonable interpretation( s) of a chemical's having positive or negative results for a particular T1S assay; · summary of the result obtained from each T2T test; · one sentence descriptions of reasonable interpretation( s) of a chemical's having positive or negative results of a particular T2T test.

The availability of a tracking system will be a particularly important tool as it relates to the nominations program. Members of the public should be able to rely on this database to provide timely and accurate information about chemicals that have been prioritized for T1S, either through the nominations process or other means. The availability of such information will be imperative as affected communities, in particular, review the list to determine if chemicals of concern to them have been selected for T1S.

b) Telephone, Fax, Mail, and Other Communication For those who do not have access to the Internet, the contents of the EPA Web site should be available by other media through EPA staff support. A centralized, automated telephone system should be developed. In addition, regular EDSTP status reports and important program developments should be posted in: the Federal Register; pesticide registration notices; press releases; and Web announcements. In addition, where appropriate, EPA should provide information about the EDSTP through a variety of media, such as general fact sheets, questionand answer documents, information booklets, EPA newsletters, brochures, pamphlets, trade journals, videotapes, slide presentations, and other publications as appropriate.

EPA should initiate contact with stakeholders, providing them with the address of the Web site and the number of the centralized telephone site. The Agency should maintain proactive communication with these groups until the groups indicate they plan to receive information electronically or are no longer interested.

To be successful, EPA should invest resources into how to effectively manage professional communication efforts.

4. When Should Information be Communicated?

Communication should occur regularly and frequently given the rapid developments in the science of endocrine disruption and the increasing public interest in the issue. There are two kinds of information that EPA should be prepared to communicate at specific points in time. EDSTAC Final Report Chapter Six August 1998 6  15 a) Public Updates About the EDSTP The COWG discussed the means and mechanisms available for disseminating information to the public regarding the progress and results of the EDSTP. One option EPA has used in other programs is a regular bulletin or newsletter that identifies specific actions, events, and program directions taken by EPA staff. The Committee recommends that EPA explore this option for disseminating information to members of the public for whom e mail is either not available or is not an effective means of receiving such information.

The Committee recognizes that this type of informing effort needs to be goal oriented and have some specific parameters in order to provide the best use of Agency funds. Therefore, the following operating conditions should be taken into account in creating an updating bulletin:

· The output should be in the form of a newsletter or bulletin for public review with the purpose of informing the public of the program and its progress. · The publication should be of a limited length and in a desk top format. · Publication should start shortly after EPA initiated the program in late 1998 or mid 1999, and continue for a defined period of time. · The publication should be produced for the duration of the screening phase and into the testing phase, with some predetermined ending time. · The content of the publication could be chemical specific, but more likely would direct interested readers to sources where more detailed information could be found, rather than list volumes of scientific technical information. · The publication should draw heavily on the Web site information, if not duplicate much of what is on the Web site.

The survey conducted by EPA with advice from the COWG indicated that there are members of the public, including individual citizens, organizations, and small businesses, for whom electronic access is not an effective mode of communicating, or is not available. For these constituents, EPA should provide information in an accessible and easy to understand form.

b) Whenever Important EDSTP Developments Warrant Communication Important developments in the EDSTP of a definitive, non preliminary nature should be communicated as soon as that information is available, rather than waiting for the generation of regular public updates. Examples might include: calls for nominations of compounds at the outset of each phase of the EDSTP that are to be considered in priority setting; lists of chemicals that have been prioritized for T1S; lists of chemicals that have identified for T2T; lists of chemicals that have been identified as exhibiting endocrine mediated adverse effects in T2T and are subject to hazard assessment; significant scientific advances in the field; the incorporation of new assays into the EDSTP; expansion of the scope of the EDSTP ( e. g., looking at additional hormone systems); and other key decisions or developments within the EDSTP. EDSTAC Final Report Chapter Six August 1998 6  16 C. Adequacy of Resources Devoted to Communication and Outreach Management of the EDSTP will be a significant new responsibility for EPA, and providing public information on the program will be essential for the full cooperation of affected and interested parties. EPA should allocate sufficient resources with high level responsibility to manage its communications and outreach strategy.

It is important that all information be available through a small number of centralized sites. It is vital that the public and other interested parties be able to obtain information through such a centralized site rather than having to track the material to a specific office in the Agency.

The Committee identified the following tasks that must be provided resources on a continuing basis:

· creation and maintenance of a centralized tracking system in the form of a database, which may be queried for the status of particular chemicals and for summaries of status across classes of compounds; · creation and maintenance of a component of a Web site with an appropriate graphical user interface allowing individuals to make these inquiries; · creation and maintenance of a component of the same Web site allowing individuals to obtain background documents and regular EDSTP status reports; · creation and maintenance of a centralized, automated telephone system allowing individuals to access the tracking system database and to order specific program documents; and · assignment of staff to monitor the above four items, and to disseminate materials that are requested through the automated telephone system or other ways. In addition, this staff resource should proactively send regular EDSTP status reports, as well as important program updates, to stakeholders who have requested such.

Management of the EDSTP should continue to be the responsibility of the EPA Assistant Administrator of the Office of Prevention, Pesticides, and Toxic Substances. Concurrently, coordination across the entire Agency should enable all EPA staff to locate and supply requested information.

IV. Generalized Schedule for Implementation During the EDSTAC process, the importance of communicating EPA's schedule for implementing the EDSTP became evident. To help inform the public of the estimated schedule for implementation, including opportunities to provide public comment on the EDSTP, a generalized schedule was developed. This schedule, while not precise in dates, provides the reader with a sense of the direction that EPA will be taking as they seek to fully implement the EDSTP. It should also be noted that the schedule was developed assuming adequate resources to carry out each activity as scheduled. Lower levels of funding will cause a stretching of various EDSTAC Final Report Chapter Six August 1998 6  17 activities and the other activities that depend on their completion. Specific resources have not yet been approved for EDSTP implementation.

Several fundamental requirements that must be met as set forth in the FQPA will serve as the basis for EPA's implementation plan. These requirements include:

· Using validated assays, EPA must propose a screening program by August 1998. · EPA must implement the proposed screening program by August 1999. · EPA must report to Congress, the progress of the screening and testing program to date by August 2000.

Other key elements of the EDSTP will be implemented according to the attached generalized schedule ( Figure 6.1). The schedule describes the key processes and their relationship to each other. The public will have an opportunity to comment on the report once it is made final and released in the FR Notice.

The key elements of the schedule include:

· EDSTAC and SAB/ SAP peer review processes; · High Throughput Pre Screening feasibility demonstration and utilization; · Final development, utilization, and maintenance of the EDPSD and completion of the priority setting process; · Standardization, validation, and utilization of the T1S battery and newly developed Tier 2 Tests; and · EPA regulatory and administrative processes ( e. g., FQPA Orders, TSCA consent agreements and/ or rulemaking) related to the EDSTP. Final EDSTAC Report Chapter Six August 1998 6  18 Figure 6.1 Generalized Schedule for Implementation of the Endocrine Disruptor Screening & Testing Program ( EDSTP) EDSTAC Final Report Chapter Six August 1998 6  19 V. Compilation of Chapter Six Recommendations A. Need for Communication As described in Chapter Two, Section II, the Communications and Outreach Work Group ( COWG), and then later the full EDSTAC, recognized the importance of communication about the EDSTP to, among other things, prevent misuse of information. Because the EDSTP applies a tiered approach, results become increasingly definitive as chemicals progress through each step of the screening and testing program. This type of system leaves room for interpretation of results, particularly in the early stages of the EDSTP ( i. e., during priority setting or screening), that may or may not be accurate. Therefore, the Committee emphasizes the need for clear and accurate communication to interested stakeholders throughout the development and implementation of the EDSTP. In particular, it is important that EPA clearly communicate about the limitations that must be placed on the interpretation of information and results from the EDSTP, as well as the meaning and implications of its decisions. The recommendations identified in Chapter Six seek to emphasize this point, while providing guidance to EPA as it further develops its communications strategy for the EDSTP.

B. Principles to Guide Implementation of a Communications Strategy 1. The EDSTAC recommends that EPA develop and implement an effective communications and outreach strategy for the EDSTP based on the following set of principles intended to help ensure accurate and open communication to stakeholders:

· Both the process and results of the EDSTP should be open and transparent. · The results of the EDSTP should be interpreted and communicated within the context set forth in the final EDSTAC Report. · The limitations and uncertainties of the available data and the results of EDSTP should be articulated clearly when the screening and testing program is discussed. · As new scientific evidence emerges, the uncertainties and limitations of the data may also change. These changes should be communicated clearly. · EPA should develop quality assurance processes to assure that any database maintained for the public relative to the EDSTP is accurate and current.

C. Basic Features of a Communications and Outreach Strategy 2. The Committee recommends that EPA base their communications and outreach strategy on the following four questions:

· What should be communicated? EDSTAC Final Report Chapter Six August 1998 6  20 · To whom should information be communicated? · How should information be communicated? · When should information be communicated?

Details of the recommendations for each of the four questions are located in Chapter Six, Section III, B. The basic recommendations, however, follow.

3. Under " What should be communicated?," the Committee recommends that EPA be prepared to provide information to interested stakeholders on the EDSTP itself, on screening and testing results, the nominations process, and background information about the EDSTAC process. Suggested language explaining the various components of the EDSTP in less technical terms than is found throughout the report, is included in the chapter.

4. Under " To whom should information be communicated?," the Committee recommends that EPA actively communicate with members of the public and other stakeholders, such as those who have demonstrated interest in the process through their attendance of the public EDSTAC meetings and public comment periods.

5. The Committee recognizes the need for, and recommends EPA develop, tailored information to be relayed through a variety of mechanisms. This would help to ensure that specific audiences   such as environmental justice organizations, " downstream" industries, farm workers, and patient groups   who may not have the ability to access information via traditional means and who have varying levels of knowledge and interest in endocrine disruptor related issues, have the opportunity to learn about the EDSTP and its results.

6. The Committee recommends that EPA conduct a follow up to their September 1997 outreach questionnaire in order to find out more information about how best to communicate with certain groups, such as those listed above in recommendation number five.

7. Under " How should information be communicated?," the Committee recommends that EPA develop a tracking system as part of the priority setting database described in Chapter Four. They recommend that, if possible, such a database be incorporated into existing EPA systems to promote efficiency and cost effectiveness. Several characteristics of a desirable database intended to address the needs of a wide range of potential users have been included. The EDSTAC believes it is important for members of the public to have access to information about the screening and testing program as it progresses, including the ability to query and quickly determine the status of a chemical or mixture in the EDSTP, as well as to access and download relevant EDSTP documents.

8. For those without Internet access, information should be available through a variety of sources, including telephone, fax, mail, Federal Register notices, and other forms of communication, as necessary.

9. Under " When should information be communicated?," the Committee recommends that EPA develop a newsletter or bulletin, as has been done in other EPA programs, that would be made EDSTAC Final Report Chapter Six August 1998 6  21 available on a regular basis. The report should be of a limited length and should be available for a limited duration.

10. The Committee also recommends that information be communicated when warranted by important EDSTP developments, such as a call for nominations, when lists of chemicals have been prioritized for T1S, identified for T2T, or identified as being subjected to hazard assessment after exhibiting endocrine mediated adverse effects in T2T, as well as regarding other key decisions relating directly to the program.

11. As described in Chapter Six, Section III, C, the Committee strongly recommends that EPA commit adequate resources to the communication aspects of this program. Several tasks requiring such support are identified in the report, such as the creation and maintenance of a tracking database, maintenance of a Web site with an appropriate graphical user interface, creation and maintenance of a centralized, automated telephone system, and assignment of staff to monitor such items.

VI. Literature Cited Banquet, C. and K. Ringen, " Cancer Control in Blacks; Epidemiology and NCI Program Plans," Progress in Clinical and Biological Research, 216, 1986, pp. 215 27. Chilton, J. A., ( ed.), " The Cancer Information Service in Jones, LA," Minorities and Cancer, New York: Springer Verlag, 1989, pp. 59 65. Heckler, M., " Report of the Secretary's Task Force on Black & Minority Health," Vol. I: Executive Summary  U. S. Department of Health and Human Services, 1985. National Research Council, " Improving Risk Communication," National Academy Press, 1989, 332 pp. National Research Council, " Risk Assessment in the Federal Government," National Academy Press, 1983, 191 pp. National Research Council, " Science and Judgment in Risk Assessment," National Academy Press, 1994, 651 pp. National Research Council, " Understanding Risk," National Academy Press, 1996, 249 pp. EDSTAC Final Report Chapter Seven August 1998 Chapter Seven Compilation of EDSTAC Recommendations EDSTAC Final Report Chapter Seven August 1998 Table of Contents I. Chapter Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 II. Recommendations: Chapter Three - Conceptual Framework and Principles . . . . . . . . 1 III. Recommendations: Chapter Four - Priority Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 A. Summary and Scope of Effort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 B. The Universe of Chemicals and Initial Sorting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 C. Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 D. Priority Setting Information Categories and Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 E. High Throughput Pre Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 F. Mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 G. Naturally Occurring Non Steroidal Estrogens ( NONEs) . . . . . . . . . . . . . . . . . . . . . . . . . 9 H. Nominations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 I. Endocrine Disruptor Priority Setting Database ( EDPSD) . . . . . . . . . . . . . . . . . . . . . . . . 11 J. Recommended Approach to Priority Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 IV. Recommendations: Chapter Five - Screening and Testing . . . . . . . . . . . . . . . . . . . . . 14 A. Tier 1 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 B. Principles for Evaluating Tier 1 and Tier 2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 C. Tier 2 Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 D. Validation of the Screening and Testing Batteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 V. Recommendations: Chapter Six - Communications and Outreach . . . . . . . . . . . . . . . 18 A. Need for Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 B. Principles to Guide Implementation of a Communications Strategy . . . . . . . . . . . . . . . . 18 C. Basic Features of a Communications and Outreach Strategy . . . . . . . . . . . . . . . . . . . . . 18 EDSTAC Final Report Chapter Seven August 1998 2 1 7  I. Chapter Overview The following chapter provides a summary of the recommendations agreed to, in Chapters Three, Four, Five, and Six, by the EDSTAC regarding establishment of an endocrine disruptor screening and testing program. For more information regarding these recommendations, please see the respective chapters within this report.

II. Recommendations: Chapter Three - Conceptual Framework and Principles 1. The EDSTAC developed a tiered Conceptual Framework that formed the basis for its screening and testing strategy and all subsequent recommendations. The tiered framework consists of the following three major activities:

· Priority setting includes the sorting and prioritization of chemical substances and mixtures based on existing information. The existing information would be used to sort chemicals into four categories. An evaluation and analysis of this information will lead to sorting chemicals into one of four categories:

· Polymers, which are placed into a " hold" status ( with some exceptions) pending a review of their monomers and oligomers. · Chemicals for which there is insufficient data regarding endocrine disruption and will therefore need to be prioritized for Tier 1 Screening. · Chemicals for which sufficient data exists to proceed to Tier 2 Testing. · Chemicals for which sufficient data exists to go to hazard assessment.

· Tier 1 Screening ( T1S) to detect chemical substances and mixtures capable of acting on endocrine systems.

· Tier 2 Testing ( T2T) to determine, characterize, and quantify the nature of the endocrine disrupting properties of the chemical substances and mixtures identified by prior information and/ or T1S.

2. The EDSTAC recommended the adoption of several principles to guide the use of the Conceptual Framework.

· A chemical may bypass one or more tiers when warranted by appropriate information ( e. g., sufficient prioritization data on endocrine disrupting properties to initiate T2T or EDSTAC Final Report Chapter Seven August 1998 2 2 7  hazard assessment). · If information is inadequate to determine if a chemical should move to the next tier, an active process should be developed for generating the needed information to make such a decision. · Criteria and default assumptions for deciding whether chemicals move from one tier to the next should be developed in advance of initiating screening and testing.

3. Within the context of the Conceptual Framework, the EDSTAC recommends that the overall scope of the screening and testing strategy should:

· be relevant to both human health and ecological effects; · initially emphasize identifying and characterizing effects that enhance, mimic, or inhibit estrogenic, androgenic, and thyroid hormone related processes; · consider tests that detect multiple hormone interactions, address endpoints in multiple species, and predict long term or delayed effects; · be periodically revisited to permit inclusion of additional hormone mediated effects or new screens and tests as they become available; · be capable of evaluating the endocrine disrupting properties of chemical substances and common mixtures; and · allow determination of possible additive, synergistic, or antagonistic effects caused by interactions among the components of mixtures.

4. The EDSTAC recommends nine broad principles to guide the implementation of the endocrine disruptor screening and testing program. The screening and testing program should:

· require the minimal number of screens and tests necessary to make sound decisions, thereby reducing the time needed to make these decisions; · examine existing screens and tests for their potential to predict, detect, and/ or characterize endocrine disruptors, ensuring that any modification to existing screens and tests does not compromise their ability to predict other toxicity endpoints; · systematically examine existing screening and testing data not only for adverse endpoints in high dose groups, but also for physiological changes in low dose groups; · not detract from current and new efforts to assess the toxicity of compounds and mixtures through mechanisms other than endocrine disruption; · provide data that can be used for a broad range of management and regulatory programs in a form that supports international harmonization of their use; · include periodic review of new scientific information; · use a performance based approach to the selection of screens, tests, and species, including the use of more appropriate screens, tests, and species as they are developed and validated; · be dynamic in order to stay current with the rapidly evolving science related to the EDSTAC Final Report Chapter Seven August 1998 2 3 7  endocrine system; and · be conducted at the minimum cost necessary to make the decisions within the EDSTAC Conceptual Framework.

5. The EDSTAC also recommended six guiding principles specific to the screens and tests themselves.

· To facilitate making decisions within the EDSTAC Conceptual Framework, all screens and tests should have well defined endpoints. · The use of animals should be reduced to the minimum level needed to obtain scientifically valid results and interpretations. · The results of screens and tests should support further research on effects of endocrine disruptors on populations, communities, and ecosystems. · In interpreting screening and testing results, a " weight of evidence" approach should be used, but should be consistent with a principle of prudence in protecting human health and the environment. In the case of T1S, this means that the strategy will err on the side of false positive identifications rather than false negatives. · Screening and testing results should be reported in a format that facilitates database development and analysis by a broad array of scientific, regulatory, and management organizations. · Decision criteria, such as those for determining statistical significance ( e. g., necessary confidence intervals) and biological plausibility, should be clearly defined.

6. The EDSTAC recommends that T1S provide the minimum, yet valid and reliable, data to detect interactions with the endocrine system. In contrast to Tier 2 tests, T1S assays should:

· be inexpensive, quick, and easy to perform; · be validated and standardized as soon as possible, defining characteristics such as sensitivity and specificity against a " gold standard," once it is identified; · be more " sensitive" than they are " specific," meaning that they should have as their primary objective the minimization of false negative or ( Type II) errors, while permitting an as of yet undetermined, but acceptable, level of false positive or ( Type I) errors; · capture multiple endpoints and reflect as many modes of endocrine action as possible; · be broadly predictive across species, gender, and age; and · yield data capable of being interpreted as either positive or negative for the purpose of determining whether and how to conduct T2T.

7. The EDSTAC recommends that T1S be used to make initial judgments about areas of concern in order to direct the focus of T2T. The interpretation of T1S results should be consistent with best scientific judgment, formed on the basis of considerations such as " weight of evidence," consistency of the data set, and methodological strengths and limitations. EDSTAC Final Report Chapter Seven August 1998 2 4 7  8. The EDSTAC recommends that T2T be based upon T1S results and other relevant information. An underlying principle of T2T is that it should provide information useful for human and ecological hazard assessment. The T2T scheme should be flexible enough to allow for scientific judgment in the selection of the most appropriate tests and endpoints, and costs should be reasonable. Tests should be aimed at determining whether the chemical substance or mixture is an endocrine disruptor and whether the effects are a result of primary or secondary disturbances of endocrine function. In addition, these tests should be designed to establish the relationship between different exposure levels, timing and duration of exposure, and adverse effects, including developmental and reproductive effects on the individual and its progeny.

9. In contrast to T1S, the EDSTAC recommends that T2T should be both sensitive and specific, and designed to minimize false positive ( Type I) and false negative ( Type II) errors. Additionally, this battery of tests should:

· include assessment of endpoints identified as relevant from Tier 1 screens; · include parental/ offspring developmental endpoints ( e. g., two generation studies) in order to adequately evaluate all life stages; · include the life cycle of both viviparous ( live birth) and oviparous ( egg laying) organisms; · be conducted at a range of doses that allow full characterization of the adverse effects of the chemical substance or mixture being tested; · be conducted in accordance with Good Laboratory Practice ( GLP) regulations to the degree consistent with resources and the goal of timely decisions; and · be validated, if need be, as soon as possible against a clearly defined standard.

10. The EDSTAC recommends that a subset of the T1S in vitro assays be conducted with the assistance of automated technology to provide biological effects information to assist in the overall sorting and priority setting process. Because of the role this technology will play in the overall EDSTP, the EDSTAC refers to it as " high throughput pre screening" ( HTPS). The EDSTAC recommends that all chemicals currently produced in an amount equal to or greater than 10,000 pounds per year ( estimated to be about 15,000 chemicals) be subjected to HTPS. Also, it is expected that all pesticides ( i. e., both active ingredients and formulation inerts) will be subjected to HTPS. Any chemicals subjected to the assays conducted in the HTPS step would not be required to repeat the ER binding/ transcriptional activation assay and the AR binding/ transcriptional activation assay as part of T1S. On the other hand, for any chemicals not subjected to HTPS ( e. g., production volumes less than 10,000 pounds per year), the assays in T1S would result in information equivalent to that which would have been provided from HTPS.

11. The EDSTAC recommends that the vast majority of chemicals go through priority setting, T1S, and T2T in a sequential manner. However, the EDSTAC also recognizes there may be individual cases in which T1S is bypassed. Three situations were identified where a chemical may bypass T1S, each with different implications for information requirements in T2T. EDSTAC Final Report Chapter Seven August 1998 2 5 7  · Alternative means to meet T1S information requirements through the generation of data which are " functionally equivalent" to data derived from the recommended screening battery. · Bypassing T1S for chemicals ( e. g., food use pesticides) that have previously been subjected to two generation reproductive toxicity tests. Such chemicals should still be subjected to high throughput pre screening assays. · Bypassing T1S for chemicals for which there is no prior toxicology testing but the owner has voluntarily decided to proceed directly to testing. Such chemicals must be evaluated in the high throughput pre screening assays, and all of the tests in the T2T battery.

III. Recommendations: Chapter Four - Priority Setting A. Summary and Scope of Effort The Priority Setting Work Group based its deliberations on the original Conceptual Framework described in Chapter Three. The work of the group revolved around adapting the Conceptual Framework and included the operational elements necessary for sorting and prioritizing chemicals. The core priority setting process that emerged contained several elements:

· the use of all available existing information; · the development of a relational database to efficiently access and utilize information; · an initial sorting of the universe of chemicals into categories based on an operationalized Conceptual Framework; · the development of high throughput pre screening data and its incorporation into the database; · the use of the database to summarize empirical data and estimate fate and effect parameters where possible; · the use of the database to establish criteria for sorting chemicals where appropriate; and · the use of a compartment based concept to accommodate subjective weighting where appropriate.

The EDSTAC viewed its role within EPA's broader mandate to protect human health and the environment and the broader testing authorities available to EPA. As such, the EDSTAC did not limit itself solely to requirements of the Food Quality Protection Act and the Safe Drinking Water Act Amendments of 1996. The Committee believes it is important to have priorities driven by scientific considerations and explicit value judgments, rather than by existing regulatory requirements.

B. The Universe of Chemicals and Initial Sorting EDSTAC Final Report Chapter Seven August 1998 2 6 7  1. The EDSTAC recommends that pesticides, commodity chemicals, environmental contaminants, naturally occurring non steroidal estrogens ( e. g., phytoestrogens, mycotoxins), food additives, cosmetics, nutritional supplements, and a set of representative mixtures be prioritized for endocrine disruptor screening and testing.

2. The EDSTAC recommends that scientific considerations be used as the primary basis for prioritizing chemicals for endocrine disruptor screening and testing. Statutory authority to protect human health and the environment is embedded in long standing federal legislation, as well as the Food Quality Protection Act and the Safe Drinking Water Act.

3. The EDSTAC recommends that the chemicals under consideration ( approximately 87,000 compounds) be sorted into the following four primary categories based on the operationalized Conceptual Framework:

· Polymers are to be placed on hold ( with some exceptions) pending review of their monomers, oligomers, other components, additives, and degradation products ( approximately 20,000 to 25,000 compounds). · Chemicals to be considered for endocrine disruptor screening ( approximately 62,000 compounds) which lack sufficient data to be placed on hold or to proceed to definitive testing or hazard assessment will be subjected to the priority setting process for T1S. · Chemicals with sufficient data are to bypass screening and proceed directly to testing or hazard assessment ( approximately 500 to 600 compounds). · Chemicals with sufficient data are to go to hazard assessment ( expected to number approximately 50 to 100 compounds)

C. Polymers 4. With some exceptions, the EDSTAC concluded that, due to molecular weight, polymers are less cause for concern than other classes of chemicals with regard to endocrine disruption. However, there is some concern regarding the intestinal absorption capacity of neonates. Because of the lack of information on polymers produced prior to 1979 ( the date of the initial TSCA Inventory), coupled with the low likelihood that polymers themselves are a concern for endocrine disruption, the EDSTAC offers the following recommendations.

· All new polymers with a number average molecular weight ( NAMW) greater than 1,000 daltons and all previously manufactured ( or " existing") polymers ( regardless of NAMW) are to be held from priority setting for endocrine disruptor screening and testing pending the outcome of the screening and testing of their monomer, oligomer, and other components. · The monomers, oligomers, and other components of polymers, as well as " new" polymers ( i. e., those that went into production after 1979) with a NAMW less than 1,000 daltons EDSTAC Final Report Chapter Seven August 1998 2 7 7  are to undergo priority setting, screening, and testing as appropriate. · Chemicals on the EPA SDWA Contaminant Candidate List ( CCL) should be used to identify the potential degradates of polymers which are most likely to present environmental exposure and which should, therefore, be subjected to priority setting, screening, and testing, as appropriate. EDSTAC Final Report Chapter Seven August 1998 2 8 7  · If monomers, oligomers, or other components of a polymer are determined to have endocrine disrupting properties, an exposure assessment should be performed. At this stage, all potential exposure routes for a component would be determined, including the potential for the component to be available from the polymer. · As the Agency gains experience with endocrine disruptor screening and testing of monomers, oligomers, and " new" polymers ( i. e., those that went into production after 1979) with NAMW less than 1,000 daltons, it should apply that experience toward development of an approach to address " existing" polymers ( i. e., those that went into production before 1979).

D. Priority Setting Information Categories and Criteria 5. The EDSTAC recommends using existing exposure related and effects related data and information to establish criteria for accomplishing initial sorting. The Committee identified the following subcategories of information that could be used as the basis for sorting and priority setting and developed principles regarding their use.

Exposure Related Information and Criteria a) Biological sampling data b) Environmental, occupational, consumer product, and food related data c) Environmental releases d) Production volume e) Fate and transport data and models Effects Related Information and Criteria a) Toxicological laboratory studies and databases b) Epidemiological and field studies and databases c) Predictive biological activity or effects models ( e. g., SARs, QSARs) d) Results of high throughput pre screening E. High Throughput Pre Screening 6. The EDSTAC found there was a general lack of endocrine effects data for the vast majority of chemicals. To address this problem, the EDSTAC recommends that, if demonstrated to be feasible, eight in vitro transcriptional activation assays should be conducted in a high throughput pre screening mode ( i. e., with the use of robotics and other automated processes). The objectives for conducting these assays in a high throughput mode is to: EDSTAC Final Report Chapter Seven August 1998 2 9 7  · provide some information about the affinity of chemicals to bind to the estrogen, androgen, and/ or thyroid hormone receptors; · use this information in conjunction with other exposure and effects related information to determine the priority by which chemicals should be advanced to T1S; · improve QSAR models; · provide a source of information to help focus the selection of Tier 2 tests for those chemicals that bypass T1S; and · generate data that can be used to identify chemicals that may be of concern at low doses.

7. The EDSTAC recommends that the high throughput pre screening ( HTPS) transcriptional activation assays be conducted on:

· the estimated 15,000 chemicals that are currently produced in an amount equal to or greater than 10,000 pounds per year; · chemicals that are permitted to bypass T1S and go directly to T2T; · chemicals that are permitted to bypass both T1S and T2T and go directly to hazard assessment; and · all pesticides ( both active ingredients and formulation inerts).

8. The EDSTAC recommends that HTPS results for the " bypass" chemicals not be used to set priorities for T1S, but to improve QSARs and inform dosing considerations, particularly during the interim period when research on low dose is being conducted, and to inform decisions regarding the types of tests that would need to be conducted in T2T.

9. The EDSTAC recommends that existing QSAR models be derived and supplemented with data from the HTPS assays, thereby expanding the predictive ability of these models.

10. The EDSTAC recommends that EPA explore the feasibility of creating an archive of a subset of HTPS project chemicals which can be accessed by researchers interested in studying endocrine mediated toxicity or in validating new screens for endocrine disruptors.

F. Mixtures 11. The EDSTAC recommends that EPA include a limited set of mixtures that span a range of physical and chemical properties in both the feasibility demonstration project for the HTPS assays, as well as the validation effort for the T1S assays.

12. If the screens are shown to be capable of handling a diverse set of mixtures in the HTPS feasibility demonstration project and the T1S validation steps, EPA should use expert judgment, guided by a set of prioritization criteria, to evaluate the literature and to decide on a limited set of mixtures to enter HTPS. EDSTAC Final Report Chapter Seven August 1998 2 10 7  13. The battery of screens validated for use in the screening program should be used to evaluate the mixtures examined in HTPS. If appropriate, screening should be followed by testing.

14. The EDSTAC recommends that a comprehensive literature evaluation be undertaken to identify exposure and effects data on mixtures that do not undergo HTPS. This information would be used to inform the prioritization for Phase II and subsequent phases of the screening and testing program which would use the same prioritization criteria as those used for single chemicals.

15. The EDSTAC recommends that representative sample mixtures be selected from the following categories and be subjected to HTPS ( if feasible) and to T1S:

· contaminants in human breast milk; · phytoestrogens in soy based infant formulas; · mixtures of chemicals most commonly found at hazardous waste sites; · pesticide/ Fertilizer mixtures; · disinfection byproducts; and · gasoline.

G. Naturally Occurring Non Steroidal Estrogens ( NONEs)

16. Naturally occurring non steroidal estrogens include natural products derived by plants ( phytoestrogens) and fungi ( mycotoxins). Due to the ubiquitous presence of these compounds in foods, and due to the potential additive and antagonist effects of NONEs with other endogenous and exogenous hormonally active chemical substances, the EDSTAC recommends that:

· NONEs be included in the endocrine disruptor screening and testing program singly and in complex mixtures; and · the following NONEs be screened and, if necessary, tested.

Representative NONEs:

· Isoflavones: genistein, daidzein, miroestrol, biochanin A, formononetin, equol · Flavones: kaemferol, naringenin · Coumestans: coumesterol · Dihydrochalcones: phoretin · Triterpenes: betulafolienetriol ( ginseng) · Lignans: enterolactone EDSTAC Final Report Chapter Seven August 1998 2 11 7  Representative estrogenic mycotoxins:

· Beta resorcyclic lactones: zearalenone, zearalenol, zearanol H. Nominations 17. The core priority setting process recommended by the EDSTAC focuses on giving high priority to chemicals with widespread exposure at the national level. The EDSTAC recognizes such a process could result in a low priority for chemicals where exposures are disproportionately experienced by identifiable groups, communities, or ecosystems. Therefore, the EDSTAC recommends that EPA establish a nominations process that:

· runs parallel to, but is separate and distinct from, the core priority setting process; · is designed to allow chemical substances and mixtures for which there may not be widespread exposures on a national scale, but for which there are exposures on a smaller scale, to be eligible to receive a priority for T1S; · allows for an early opportunity to submit nominations during each phase of the Endocrine Disruptor Screening and Testing Program; and · draws no less than 5% of the total number of chemical substances or mixtures subjected to T1S from substances receiving nominations but not selected through the main priority setting process.

18. The EDSTAC recommends that any nominated chemical substances and/ or mixtures that becomes a priority for T1S through the core priority setting process be removed from consideration within the list of nominated chemicals in order to ensure that the priorities drawn from the nominations process will compete only against other nominated chemicals.

19. In keeping with the overall purpose of the nominations process, the EDSTAC recommends that a different set of exposure related criteria be used to evaluate the priority for nominated chemicals compared to the exposure related criteria that will be used for the core priority setting process. Specifically, the nominations process should focus on exposures that are disproportionately experienced by identifiable groups, communities, or ecosystems rather than focusing on chemicals for which there is widespread exposure in the aggregate.

20. The EDSTAC recommends that if there are effects data for the nominated chemical, or if the chemical is similar to another chemical substance or mixture for which effects data are available, EPA should utilize those data as a secondary source of information to help set priorities among nominees.

21. The EDSTAC recommends that when the relative priorities of nominated chemical substances or mixtures are evaluated, EPA should consider those that meet the following EDSTAC Final Report Chapter Seven August 1998 2 12 7  criteria to be a higher priority than those that do not:

· chemical substances or mixtures where there is a likelihood of regular exposure, in contrast to those for which exposure occurs only rarely or occasionally; EDSTAC Final Report Chapter Seven August 1998 2 13 7  · chemical substances or mixtures that affect a high proportion of people within a given community or workplace; and · chemical substances or mixtures for which there may be empirical or estimated ( i. e., model derived) effects related data regarding endocrine disrupting potential.

22. The EDSTAC recommends that EPA make use of all available information when evaluating nominations, including anecdotes, and other information gathered as part of the core priority setting process ( e. g., information contained within the Endocrine Disruptor Priority Setting Database).

23. To assist EPA in evaluating nominated chemicals, the EDSTAC recommends that EPA request the following types of information from the public regarding nominations:

· how exposure to the nominated chemical substances or mixtures may be disproportionately experienced by identifiable groups, communities, or ecosystems; · the reasons for the nomination ( which may include both exposure and effects related concerns) and any information that provides a basis for those concerns; and · the degree of support for the nomination from the potentially affected communities and/ or workplaces.

I. Endocrine Disruptor Priority Setting Database ( EDPSD)

24. The EDSTAC identified and evaluated numerous data sources associated with the exposure and effects information categories and criteria ( Appendix G). The Committee endorsed the integration of relevant and useful data sources into a prototype relational database, referred to as the Endocrine Disruptor Priority Setting Database. Although promising, the EDPSD could not be completed within the EDSTAC's time and resource constraints. Consequently, EDSTAC made a number of recommendations regarding continued development and use of the EDPSD.

· EPA should continue to develop and maintain the EDPSD as a tool that can be used to expeditiously sort and prioritize chemicals for endocrine disruption screening and testing. · The process used by EPA in developing the EDPSD, as well as the process by which it is used, should be open and transparent. · EPA should convene a multi stakeholder group prior to the completion of the EDPSD tool to ensure effectiveness, openness, and transparency. · After completion of the HTPS assays, this group should make use of the tool, along with the " compartment based" approach to priority setting described below, in assisting EPA as it develops the final priorities for T1S. · The EDPSD should not be limited to effects data that can be easily placed into a database EDSTAC Final Report Chapter Seven August 1998 2 14 7  format, but should also include data from peer reviewed literature. EDSTAC Final Report Chapter Seven August 1998 2 15 7  · EPA should update the EDPSD at least every six months, and more frequently if time and resources permit.