Although the use of robotic technology will greatly expand the throughput of chemicals over a given period of time for the selected assays, the EDSTAC is not recommending that all chemicals needing to be prioritized for T1S be subjected to HTPS. Rather, the EDSTAC recommends that the set of chemicals currently produced in an amount equal to or greater than 10,000 pounds per year ( estimated to be about 15,000 chemicals) should be subjected to HTPS. Also, it is expected EDSTAC Final Report Chapter Four August 1998 4  33 that all pesticides ( i. e., all pesticide active ingredients and formulation inerts) will be subjected to HTPS. As indicated earlier the EDSTAC makes this recommendation to help EPA avoid an unachievable task that might never be completed. Given the history of TSCA, the EDSTAC believes that 15,000 chemicals is not an insignificant number.

The EDSTAC recommends that chemicals determined to be a high priority for T1S that do not undergo the HTPS assays because they are produced in amounts less than 10,000 pounds per year should still undergo the transcriptional activation assays contained in HTPS. However, rather than using the HTPS process, these lower production volume chemicals should undergo transcriptional activation assays on the bench as part of T1S.

The EDSTAC also recommends that chemicals permitted to bypass T1S and go directly to T2T, as well as those permitted to bypass both T1S and T2T and go directly to hazard assessment ( due to functional equivalency of data), be subjected to HTPS. However, as described more fully below, the results of HTPS from these chemicals would not be used to set priorities for T1S.

G. How Will HTPS Results be Used?

1. For Chemicals That Will be Prioritized for T1S In the context of setting priorities for T1S, the EDSTAC recommends that EPA use the results of HTPS in conjunction with other exposure and effects related priority setting information. In other words, HTPS results should be considered along with any other biological effects information that may be available, as well as information on exposure related considerations ( e. g., biological sampling; environmental, occupation, consumer product, and food related data; releases to the environment; production volumes; and fate and transport models and data).

The HTPS results, by themselves, cannot be regarded as definitively proving or disproving endocrine mediated toxicity in whole animals. Such determinations can only be made with confidence at the end of the entire screening and testing process. There is concern that the results of HTPS will be over interpreted because they may be the first data that will be generated in the endocrine disruptor evaluation process. Therefore, it is important to stress the limitations of these assays. Most importantly, the HTPS assays are very simple in vitro assays. Like any in vitro method, the simplicity that makes the assays attractive for rapid generation of data also limits their reliability as predictors of what might occur in the intact organism. They do not possess all of the complexities of pharmacokinetics, pharmacodynamics, metabolism, and multi system interactions that are inherent in the whole organism. It is rare for an in vitro assay for any toxicity to have better than an 80% concordance with in vivo results. For this reason, most in vitro assays are used only as a preliminary step of a more comprehensive assessment.

HTPS is primarily useful as a pre screen to indicate the need for further evaluation, but will not always predict toxicity in whole animals. The HTPS results, coupled with data from the remainder of the screening and testing program will be useful in interpreting whether a chemical evokes endocrine mediated responses. For these reasons, the EDSTAC strongly recommends EDSTAC Final Report Chapter Four August 1998 4  34 that a negative HTPS result not be used as a basis for placing a chemical into the " hold box." Further, the Committee recommends that a negative HTPS result not be used, in isolation, to decrease the priority of a chemical for screening and testing; nor should a positive HTPS result be the only factor considered in setting priorities for T1S.

2. For Chemicals That Meet the Criteria for Going Directly to T2T or Hazard Assessment Chemicals that meet the criteria for proceeding directly to T2T or hazard assessment would also be subjected to HTPS according to the EDSTP. However, unlike the large number of chemicals that do not meet these criteria, the results of HTPS from this set of chemicals will not be used to help set priorities for T1S.

There are several generic reasons why the EDSTAC recommends conducting HTPS assays on food use pesticides and other chemicals that have previously been subjected to two generation reproductive toxicity tests. These generic reasons include: ( 1) the data generated from the HTPS assays will be valuable in and of themselves, even though they are limited to a single mechanism of action and cannot be used by themselves to determine whether a chemical is or is not an endocrine disruptor; ( 2) as an ancillary benefit, the data can be used to improve and validate QSARs; and ( 3) beyond these generic benefits, in the case of food use pesticides that will complete tolerance reassessments prior to the availability of validated Tier 2 tests, HTPS data can be used, along with other relevant information, to help prioritize whether and, if so, when these chemicals should be subjected to any additional endocrine disruptor testing. The last rationale for recommending food use pesticides complete HTPS assays is further elaborated upon in Chapter Four, Section XI, H.

There may be concern that it is redundant to subject pesticides and other chemicals to HTPS for which substantial two generation reproductive and developmental ( whole animal) toxicity testing data already exist. However, the EDSTAC believes the value of generating HTPS data outweighs the relatively low cost associated with subjecting these chemicals to HTPS.

3. To Improve QSARs The EDSTAC recommends that existing QSAR models be rederived and supplemented with data from the HTPS assays, thereby expanding the predictive ability of these models. Thus, when it comes time to set priorities for the first phase of T1S, HTPS data, as well as improved QSARs, should be used along with other relevant exposure and effects data. It is envisioned that the process of QSAR model expansion and improvement will then continue in a cyclical feedback manner, thus providing the opportunity to validate evolving QSAR models using external data sets for screens and tests of compounds not subjected to HTPS. Eventually, predictions of endocrine disruption potential obtained from validated QSAR models could be used as surrogates for HTPS data in the case of compounds for which effects data are not available. EDSTAC Final Report Chapter Four August 1998 4  35 H. Practical Considerations and Constraints to Be Considered in HTPS Implementation There is widespread agreement that several practical considerations will need to be addressed for HTPS to work as intended. These include:

· Demonstrating the feasibility of HTPS   An important first step in implementing the recommendation of the EDSTAC to incorporate the use of HTPS into the EDSTP is to undertake an effort to demonstrate the feasibility of using this technology for the wide range of chemicals that will need to be considered for endocrine disruptor screening and testing. A detailed discussion of the feasibility demonstration effort that is already underway is contained in Appendix I. · Collecting, handling, and QA/ QC of the chemicals to be tested   The procurement of sufficient quantities of relevant chemical substances, the shipment of these materials, and the assurance of the chemical identity and purity of these chemicals will be the most time consuming phase of HTPS. While these issues are inherent in any of the assays being considered for screening or testing, they must be taken into consideration when planning for HTPS as they are likely to contribute to the cost and time for this step of the program. The EDSTAC recommends that EPA explore the feasibility of creating an archive of a subset of these chemicals, which can be accessed by researchers interested in studying endocrinemediated toxicity or in validating new screens for endocrine disruptors. This may be particularly important for radio labeled compounds that are costly to synthesize. There is precedence for such activities, including the EPA Pesticide Repository, the National Institute of Standards and Technology ( formerly the Bureau of Standards) in the Department of Commerce, and the NTP chemical repository for the validation of in vitro developmental toxicity. · Patent issues   Many or all of the HTPS assays under consideration are patented and the intellectual property issue must be addressed before implementing any endocrine disruptor screening and testing program. This is unlikely to be a critical issue for a massive screening effort because it is almost certain that such work would be done under contract by the holder of the patent. It may, however, be a significant issue for individual investigators or companies who wish to work with the assays on an investigative basis in their own laboratories. Licensing agreements should be worked out before any final decisions are made. · Overall costs and specific cost factors   As with all screening assays, the cost of performing an assay needs to be taken into account in selecting which HTPS assays to recommend, as high cost may limit the number of chemicals that can be evaluated. · Validation of the HTPS assays for the wide range of chemicals that are intended for prescreening   High throughput screening technology has been used in the pharmaceutical and agrochemical industries to find chemicals with novel and relevant biological activity at high potency, as these are the ones that are likely to be candidates for lead optimization. However, environmental chemicals that have been identified so far as having endocrine mediated effects typically have low potency. Issues such as how good the assays will be at detecting such chemicals; the limit of detection; and how easily these assays will accommodate a range of chemical properties ( such as solubility, pH, and high vapor pressure) can be addressed, but doing so may require some research involving a representative group of chemicals before HTPS EDSTAC Final Report Chapter Four August 1998 4  36 can be implemented on a large scale. Based on the results of using HTPS as a tool for identifying discovery leads, one generally should expect a " hit rate" of 1.8 2.0% for a very weak lead ( activity at 100 uM), 0.6% for a weak lead ( activity at 10 uM), and 0.15% for an average lead ( 1 uM) ( Christopher Waller, OSI Pharmaceuticals, Inc., personal communication).

Other implementation issues, such as who will be responsible for conducting various parts of the HTPS process, how much each step will cost, etc., are not addressed in this document. However, it is envisioned that EPA will undertake the coordination ( and, perhaps, expense) of conducting the HTPS step of the program. It is also assumed that implementing the HTPS process will require EPA to work cooperatively with industry to collect what will be a very large number of chemical samples. Moreover, the issue of " orphan chemicals"   those for which there is no current manufacturer or registrant   is an issue that EPA must address.

VI. Recommendations for Handling Polymers A. Introduction This section presents some key issues associated with the prioritization of polymers for endocrine disruptor screening and testing along with several options and a recommended approach for how polymers should be treated.

1. Chemical Nature of Polymers Polymers are defined in 40 Code of Federal Regulations ( CFR) Part 723 as a chemical substance consisting of one or more types of monomer units and comprising a simple weight majority of molecules containing at least three monomer units which are covalently bound to at least one other monomer unit or other reactant and which consists of less than a simple weight majority of molecules of the same molecular weight. Such molecules must be distributed over a range of molecular weights wherein differences in the molecular weight are primarily attributable to differences in the number of monomer units.

Polymers result from chemical reactions that permit varying numbers of monomers or monomer units and other precursors to be chemically incorporated into the products of the reactions. According to 40 CFR Part 723, the term " monomer unit" means " the reacted form of the monomer in a polymer." That is, the monomer must have formed at least one covalent bond with another like or unlike molecule under the conditions of the relevant polymerforming reaction.

Polymer molecules typically vary in their degree of polymerization, or the extent to which they have incorporated varying numbers of monomers, oligomers, and other precursors. However, polymer products might be composed of various other substances that usually are not the EDSTAC Final Report Chapter Four August 1998 4  37 result of the polymerization reaction including:

· Residuals   unreacted polymer precursors, monomers, oligomers, and other reactants · Byproducts   catalyst residues, free radical initiator byproducts, etc. · Impurities   precursor impurities, oxidation products, etc. · Other substances   those that are mixed into the product, such as fire retardants, plasticizers, solvents, inhibitors, fillers, colorants, antioxidants, slip agents, etc.

2. Present Regulatory Status of Polymers The initial TSCA Inventory ( or Initial Inventory), published in 1979, consisted of those chemicals that were manufactured in the U. S. or imported into the U. S. on or after January 1, 1975, and before the end of the initial reporting period ( which varied depending on the chemical and/ or company circumstances). Certain allowances were made for later additions and corrections. The Initial Inventory contained about 60,000 chemicals, approximately half of which were polymers. Chemicals on the Initial Inventory are referred to as " existing chemicals." Chemicals not on the Initial Inventory are considered " new" and are subject to the Pre Manufacture Notification ( PMN) requirements of TSCA. After EPA completes the pre manufacture review of a new chemical and when the manufacturer or importer of the chemical notifies the Agency that manufacture or importation has commenced, EPA adds the new chemical to the Inventory.

The existing chemical polymers are described in the Initial Inventory using a simplified procedure for naming the polymers. Polymers on the Initial Inventory are named as " Polymer of A, B, C, D..." where A, B, C, D... are the monomers which are reacted to form the polymer. The Inventory chemical name does not include any description of the chemical identity of the specific polymer or polymers that are made from these monomers. For example, there is no information about whether the polymer is in the form of a carbamate, amide, isocyanate, or some combination of these functional groups; nor is there any mention of the presence or absence of reactive functional groups, such as isocyanate or epoxy groups. In addition, the number average molecular weight ( NAMW)   which refers to the arithmetic average ( mean) of the molecular weight of all molecules in the polymer   distribution of the polymer or polymers made from the listed monomers is not reported. The Initial Inventory, however, does include a number of low NAMW oligomers ( dimers, trimers, etc.) which are purposefully manufactured as such.

In contrast to the estimated 30,000 polymers reported on the Initial Inventory ( John Walker, U. S. EPA, personal communication), new chemical polymers that are reported to EPA include a chemical description of the polymer containing information on the NAMW distribution, the presence of reactive functional groups, etc. In addition, EPA receives information on the anticipated uses, exposures ( occupational, environmental, consumer, etc.), and environmental releases of the new polymers.

The EPA, under TSCA, first proposed the exemption of certain polymers ( NAMW greater than 20,000 daltons) from PMN in 1982 ( 47 Federal Register ( FR)). The Final Rule for this early exemption was published in 1984. In making its no risk finding, EPA concluded with regard to polymers that: EDSTAC Final Report Chapter Four August 1998 4  38 Molecular weight is clearly the prime determinant of risk. For a chemical to elicit a toxic response within an organism, it must come into direct contact with the biological cells from which it elicits the response. Because all organisms are encased in protective membranes, a chemical must penetrate these membranes and be translocated to various parts of the organism to gain access to its target sites. If a chemical cannot penetrate the protective membranes to access a target site, and it cannot elicit a toxic response, it will not generally present a risk. ( 49 FR 46081, also cited in 60 FR 16328)

EPA operated with this exemption for almost a decade until a proposal to expand the exemption was made in 1993 ( 58 FR). That proposal was published as a final rule in 1995, and it sets out the exemption policy under which the TSCA program now operates ( 60 FR). EPA extensively reviewed over 10,000 polymers from 1980 to 1995 and concluded that:

Of these 10,000, the polymers that would have qualified under the final polymer exemption rule [ 1995] have consistently been characterized as posing low concern for both adverse health and environmental risks by the Agency during the course of PMN review. The characteristics of a significant number of polymers ( i. e., their NAMW and/ or physical/ chemical properties) are such that they are neither absorbed by biological systems nor do they interact with biological systems, as described above. ( 60 FR 16329)

As required by section 5( h)( 4) of TSCA, the current polymer exemption is based wholly on a finding by the EPA that the:

manufacture, processing, distribution in commerce, use, and disposal of new chemical substances meeting the revised polymer exemption criteria will not present an unreasonable risk of injury to human health or the environment under the terms of the exemption. ( 60 FR 16316) EDSTAC Final Report Chapter Four August 1998 4  39 The present regulation ( 60 FR 16333) exempts:

· polymers with average NAMW between 1,000 and 10,000 daltons if they do not contain other than certain specified reactive functional groups ( as well as containing less than 10% oligomers with NAMW less than 500 daltons and less than 25% oligomers with NAMW less than 1,000 daltons); · polymers with average NAMW greater than 10,000 daltons ( and less than 2% oligomers with NAMW less than 500 daltons and less than 5% oligomers with NAMW less than 1,000 daltons); · polyester polymers made with any of a long list of specified reactants; and · polymers produced in quantities less than 10,000 kilograms per year.

Polymers that are ineligible for the exemption include:

· polymers that degrade, decompose, or depolymerize; · polymers that are prepared from monomers or other reactants that are not on the TSCA Inventory; and · water absorbing polymers with NAMW greater than or equal to 10,000 daltons.

B. Key Issues Associated With the Prioritization of Polymers The PSWG originally considered exempting polymers with a NAMW greater than 1,000 daltons from priority setting, similar to the reporting exemption which exists for new chemical polymers under TSCA. All polymers with a NAMW less than 1,000 daltons would be treated like all other chemicals and would be subjected to priority setting. The exempt polymers would be put into a " hold box" pending information on monomers or other low NAMW polymers of potential concern and screening and testing of the monomers themselves. However, concerns surfaced within the PSWG upon further examination.

Bioaccumulation/ Potential Exposure The original proposal to exempt polymers was based on an assumption that molecules larger than 1,000 daltons would not cross biological membranes and barriers. If a neonate is orally exposed to a polymer with a NAMW greater than 1,000 daltons, some of the polymer could enter the body and interact with cells. Such an interaction is unlikely to occur in a more mature animal but could occur in neonates due to delayed intestinal closure. Gastrointestinal absorption is dependent on factors such as lipophilicity, molecular weight, particle size, and metabolism of chemicals in the gastrointestinal tract ( Baintner, 1986; Kleinman and Walker, 1984; Lecce and Broughton, 1973; Walker, 1978; Westrom and Tagesson, 1989; Westrom, Svendsen, and Tagesson, 1984; Weaver, Laker, et al., 1987; Westrom, Tagesson, et al., 1989).

The potential for gastrointestinal absorption of high molecular weight substances was taken into consideration by the EPA as early as 1982. The Agency concluded that: EDSTAC Final Report Chapter Four August 1998 4  40 · Substances with NAMW greater than 1,000 daltons are generally not readily absorbed through the intact gastrointestinal tract. ( 49 FR 46081); · " For a chemical to elicit a toxic response within an organism, it must come into direct contact with the biological cells from which it elicits the response. Because all organisms are encased in protective membranes, a chemical must penetrate these membranes and be translocated to various parts of the organism to gain access to its target sites. If a chemical cannot penetrate the protective membranes to access a target site, and it cannot elicit a toxic response, it will not generally present a risk." ( 49 FR 46081, also cited in 60 FR 16328) · Dermal exposure, rather than inhalation or ingestion, is the major route of exposure for most polymers. ( 47 FR 33930)

Based on the available data, EPA was able to proceed in making its no risk finding as a basis for the polymer exemption. The physical properties of a polymer affect not only its functional ability, but its fate and transport in the environment. Generally, as the molecular weight and degree of polymerization increase, the affinity for adsorption to solids ( soil and sediment) increases and the potential for biodegradation and bioaccumulation decreases.

Polymer Complexity Polymers are complex substances consisting of additives such as fire retardants, antioxidants, slip agents, colorants, residual monomers, catalysts, additive reaction products, catalyst residues and reaction products, byproducts, low molecular weight polymer chains, etc. Although additives, monomers, catalysts, many oligomers, and many other substances will be included in the priority setting scheme, some of the other polymer components may not be. Concern about their toxicity arose on the part of the PSWG after reviewing some work done in the early 1970' s on a complex polymer fluid showing that the fluid's polysiloxane dimers and trimers were more toxic components of the mixture than were the monomers. Although the issue was not one of incomplete breakdown products, but rather of intentionally made dimers and trimers, the work highlighted the fact that by only studying the monomer, it is conceivable that one might miss a higher order of toxicity reached in the dimers, trimers, etc. The toxicity of these other polymer components may not be the same as the toxicity of the monomers. Thus, testing data from the monomers and additives may not provide complete guidance as to the toxicity of the entire polymer.

Composition of Copolymers Most polymers, for regulatory purposes, are described and assigned Chemical Abstracts Service Registry Numbers ( CASRNs) on the basis of the monomers used in their manufacture. For polymers having multiple monomers ( or copolymers, as opposed to homopolymers), the relative concentrations of the various monomers can vary widely, but the polymers can still be assigned the same CASRN. For example, poly( A/ B) with an A/ B ratio of 95/ 5 or 5/ 95 is still described by the same CASRN. Consequently, for purposes of prioritizing polymers for testing, the CASRN does not represent a unique chemical composition. EDSTAC Final Report Chapter Four August 1998 4  41 In addition, for many condensation polymers, chemically identical polymers can be made from slightly different monomers. In this instance, the CASRN would be different, even though the polymers are compositionally indistinguishable.

The variable compositions within a CASRN listing, and identical compositions for different CASRN listings, are problematic for both new polymers, as well as for those nominated to the original Inventory.

Testing of Polymers Many polymer components do not have an identity apart from their role as a component of a polymer. Hence, they do not exist independently and, in general, cannot be readily synthesized or purified for screening and testing. If such components were to be tested, they would have to be extracted from the polymer matrix in which they exist. Such an extraction would be a highly complex undertaking, requiring the identification of a long list of parameters such as:

· solvent for the extraction; · time for the extraction; · temperature for the extraction; · surface area of the polymer to be extracted; and · volume of the extracting solvent.

Varying any of these parameters would affect which polymer components are extracted and how much of any component is extracted. Variation in these parameters can reflect different use conditions of the polymer, different potential exposure conditions, different properties of the polymer, and different components which one desires to extract. In addition, any extraction would yield an extract which is a mixture consisting of the polymer components, primarily the smaller monomer and additive compounds. Thus, any test will yield a result which does not describe the endocrine behavior of the polymer components by themselves. Further, since the conditions of the extraction determine the composition of the extract and the concentration of the components in the extract, the test may not necessarily yield useful information regarding the potential toxicity of the polymer.

Once the polymer components are extracted, the extract may need to be concentrated, for example, to obtain an appropriate concentration for testing or to remove extracting solvents. This " concentration" step must be very carefully conducted so as to ensure that no part of the extract is lost or altered. In most cases, validation of this step would be very difficult. EDSTAC Final Report Chapter Four August 1998 4  42 Migration of Polymer Components Two types of components are of interest: ( 1) the lower molecular weight monomers and oligomers that may be present in the matrix of high NAMW polymers; and ( 2) the additives, catalysts, etc. Because essentially all of these components are on the TSCA Inventory, they will be considered individually along with other chemicals during prioritization and will receive due consideration for screening and testing.

Degradation Products of Polymers The EDSTAC considered the issue of the potential for polymers to degrade in the environment and therefore pose risk of organismic exposure to substances which would not be captured under the priority setting scheme. Most polymers are chemically designed to be used in applications where stability is essential to their functional and commercial success. Although most polymers would not be expected to degrade in the environment, data are not complete for all polymer classes. However, concern about the ability of chemical degradates to enter the environment, especially water, is not limited to the potential degradates of polymers alone, but includes essentially all chemicals which are released to the environment. The EDSTAC does not consider it necessary to give special consideration to the potential degradates of polymers. These issues will be considered for polymers as well as other chemicals in the priority setting scheme in the context of the exposure criteria.

C. Options Considered by the PSWG 1. Include all Polymers ( Regardless of NAMW) From Priority Setting This option would ensure, in theory, that no molecules are overlooked in priority setting. The polymers would be subject to the same exposure and effects related criteria as are the smaller molecules. From a practical standpoint, however, exposure data would be the primary driver in this application, and such data would be hard to obtain for most of the polymers.

For most polymers, the likelihood is small when humans and other animals come in contact with polymers that a significant bioavailable dose would be received. Therefore, the public health value of including all polymers in the prioritization exercise would be negligible. This needs to be balanced in light of the significant resources that would be required to actually characterize the polymeric substance, obtain and evaluate the available exposure and effects data, and make a prioritization decision for thousands of polymers. EDSTAC Final Report Chapter Four August 1998 4  43 2. Include Polymers With NAMW Greater Than 1,000 Daltons to Which Neonates are Likely to be Exposed; Put the Others in Hold Criteria would need to be developed to identify those polymers which are used in materials most likely to come in contact with neonates. It must be acknowledged that such criteria are most workable for humans and less readily ascertainable for fish and wildlife. Examples of the kinds of polymers that would need to be considered relevant to human neonates include those used in food contact materials, infant toys, etc. A significant advantage of such an effort over option number 1 would be to focus the priority setting on those molecules most likely to present a potential exposure to the sensitive population. The technical difficulties associated with screening and testing polymers, which are described above, would still remain.

3. Hold Polymers With NAMW Greater Than 1,000 Daltons From Priority Setting No priority setting of the polymer would occur unless data indicate leachable monomers or oligomers have endocrine disruption potential. This option focuses resources on the polymers that contain or might release monomers or oligomers of concern. This still entails a significant technical investment to determine the nature and amount of leachable " other components" from the polymer. Priority setting would initially take place on the monomers under the same criteria as other single chemicals.

4. Exempt all Polymers With NAMW Greater Than 1,000 Daltons; Concentrate on Monomers This option obviates the resource intensive step of considering the " other" chemicals present in a typical polymer mixture. Priority setting would take place on the monomers and the appropriate ones would be screened and tested. This is the least resource intensive option ( at the priority setting stage, at least) and focuses on identification of monomers of concern. Concerns about a monomer's use in a polymer arise not during priority setting but after screening and testing is completed. At this point, the results of screens and tests of the monomer, along with the proper dose response analysis, would be considered with exposure assessment ( including use and migration from polymers) to assess risk. This option would still require detailed consideration of polymers, but at a later stage in the program and only for polymers where screening and testing of the monomer and other components indicate a concern.

5. Modified Option 4   Treat Polymers as Mixtures and Consider Them Along With Other Mixtures The issues that complicate the consideration of polymers are similar, if not identical, to those faced by mixtures in general. These include often broadly defined composition, wide range of chemicals present in one CASRN ( chemical nature and NAMWs), etc. By considering polymers along with mixtures, the consideration of exposure and effects related criteria would be similar for both. EDSTAC Final Report Chapter Four August 1998 4  44 D. Recommendation for Handling Polymers The EDSTAC prefers option number 4. In particular, the EDSTAC recommends that existing and new chemical monomers and oligomers, as well as new chemical polymers with a NAMW of less than 1,000 daltons, should be considered within the broader priority setting scheme and undergo screening and testing as appropriate. The priority setting scheme will consider the potential for sensitive populations to be exposed ( e. g., the exposure of neonates). Existing chemical polymers, regardless of NAMW, are viewed as presenting a lower priority for initial action because of the unavailability of critical information such as NAMW and explicit information about the chemical nature of the polymer. In addition, many of the existing polymers are very large molecules ( NAMW greater than 50,000 daltons). As such, potential exposure to residual monomers and low molecular weight oligomers contained in existing polymers is limited.

Thus, the EDSTAC recommends:

1. All monomer and oligomer components of polymers should be prioritized for and subjected to endocrine disruptor screening and testing.

2. All " new" polymers ( i. e., those produced after the Initial TSCA Inventory, which was published in 1979) with number average molecular weight ( NAMW) less than 1,000 daltons should also be prioritized for and subjected to endocrine disruptor screening and testing. Throughout this document, the term " number average molecular weight," or " NAMW," of polymers is utilized. This term indicates a numerical mean, with the actual MW of the polymers ranging about this mean. The EDSTAC recommends embracing the language in the 1995 Final TSCA Polymer Rule ( 60 FR 16333) which uses a NAMW cutoff of 1,000 daltons, provided that the polymer does not contain other than certain specified reactive functional groups and that the polymer contains less than 10% oligomers with MW less than 500 daltons and less than 25% oligomers with a MW of less than 1,000 daltons.

3. All previously manufactured polymers ( regardless of NAMW) and all " new" polymers with a NAMW greater than 1,000 daltons should be set aside pending the outcome of the screening and testing of their monomer and oligomer components.

4. If the component is determined to have endocrine disrupting properties, the component should proceed to hazard assessment.

5. As with any chemical shown 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. EDSTAC Final Report Chapter Four August 1998 4  45 Finally, the EDSTAC recommends that EPA gain experience with monomers, oligomers, and new polymers with NAMW less than 1,000 daltons and learn how to apply that experience toward the development of an approach to address existing polymers. This would focus the EDSTP on the polymers about which the best information is available and on those most biologically relevant to the endpoints of concern. To the extent that data generated during implementation of the EDSTP on new chemical polymers indicate a problem, EPA should obtain information on molecular weight, production volume, chemical identity, and any other appropriate information needed to identify and evaluate existing chemical polymers in the priority setting step of the EDSTP. This could be done through the TSCA Inventory Update Rule.

VII. Recommendations for Handling Mixtures A. Introduction The EDSTAC has acknowledged the importance of considering mixtures, and public comment at plenary meetings reinforced the Committee's concern over mixtures. This section discusses several of the key issues relating to the screening and testing of chemical mixtures for endocrine disruption and presents: a scheme for organizing the various mixtures, recommended priority setting criteria, and recommendations for initial action.

B. Definition Quite simply, a mixture is any combination of two or more chemicals. The number of chemical mixtures present in the environment is practically infinite. In addition to the approximately 87,000 chemicals considered for priority setting, many other metabolites, degradates, and combustion products may also occur in the environment. Given this huge array of possible mixtures, the EDSTAC focused on grouping mixtures into general classes.

C. Categorization Scheme for Mixtures Mixtures can be sorted on where they are found in the environment, their source, and their chemical makeup. The EDSTAC proposes a simple categorization approach to mixtures focused on the range of mixtures found in products, the environment, and human tissues and fluids. The proposed scheme for organizing mixtures, along with examples of categories of data that fit, is outlined below:

1. Products commonly containing mixtures a. Pesticide formulations b. Cosmetics, toiletries, cleaners, and other consumer products c. Petroleum derived products   gasoline, solvents, metalworking fluids d. Food   including additives, contaminants, and phytoestrogens EDSTAC Final Report Chapter Four August 1998 4  46 e. Pharmaceuticals/ Over the counter drugs f. Other commercial, formulated products For products commonly containing mixtures, a further three part distinction can be made between:

· Formulated products   These are products mixed to contain a specified proportion of chemicals necessary for product function. Examples include pesticides, cosmetics, medicines, etc. · Commercial non formulated products   These are products which are blended to attain certain performance criteria. In contrast to the formulated products, the proportion of ingredients is generally not fixed. Although knowledge about the precise identity or proportion of the chemicals contained therein is limited, some information about the chemical nature ( e. g., aliphatic/ aromatic) is available. Examples include fuels, solvents, and lubricants. · Industrial chemicals   For the purposes of priority setting, these will be considered as single chemicals. However, even though one chemical predominates, other chemical impurities may be present as well. The potential activity of impurities must be considered in the screening and testing of these " single chemicals." Commodity chemicals such as styrene, propylene, and toluene are examples of such " single chemicals."

2. Environmental media commonly containing mixtures ( including, but not limited to, TSCA and FIFRA chemicals, metabolites, degradates, and combustion products)

a. Contaminated media at Superfund sites b. Toxic chemicals in urban air c. Contaminated drinking water i. Pesticides/ Fertilizers ii. Disinfection byproducts iii. Chemicals commonly found in drinking water d. Surface water and groundwater i. Effluents e. Indoor air f. Sediments/ Sludge g. Occupational media ( e. g., welding fumes, coke oven emissions, etc.)

3. Tissues and media from humans and other animals ( including animals produced for food, fish, and wildlife) commonly containing mixtures ( including, but not limited to, TSCA and FIFRA chemicals, metabolites, degradates, and combustion products) from:

a. Blood b. Breast milk c. Exhaled breath d. Fat EDSTAC Final Report Chapter Four August 1998 4  47 e. Urine f. Miscellaneous tissues ( e. g., finfish, shellfish, meat, poultry, etc.)

D. Determining the Composition of Mixtures to be Considered Determining the precise composition of mixtures to be considered for prioritization is challenging given the large number of possibilities. This task is somewhat easier for mixtures found in products because the basic formulations are usually well defined and are not likely to drift widely over time. However, the composition of mixtures found in environmental and biological samples is highly variable with respect to specific components present and their relative amounts. In such cases, higher priority should be given to mixture combinations typically or frequently found in environmental and biological media.

E. Criteria for Prioritizing Mixtures The following are some recommended criteria for prioritizing mixtures for the purpose of endocrine disruptor screening and testing:

1. Exposure data on mixtures ( same criteria as with single chemicals) · Biological sampling ( human and other biota) data for components of mixtures · Environmental, occupational, consumer product, and food related data · Environmental releases · Production volume · Fate and transport data and models 2. Toxic effects associated with the mixture in question ( same criteria as with single chemicals) · Toxicological laboratory studies and databases · Epidemiological and field studies and databases ( populations affected) · Predictive biological activity or effects models ( e. g., SARs, QSARs)

3. Toxic effects data on major components · Use the ranking developed for individual components by the EDSTAC to rank mixtures based on the relative ranking of the components they contain · This approach is especially useful for: · mixtures for which there are no toxic effects data on the mixture itself. If toxic effects data are available on the mixture, those data should be given primary consideration in priority setting for the mixture. EDSTAC Final Report Chapter Four August 1998 4  48 · environmental contaminants and complex product mixtures, especially if the mixture contains a component with a high priority for screening and testing.

F. Recommendations The EDSTAC and EPA are, in many ways, entering uncharted territory. The evaluation ( including the design, implementation, and interpretation of screens and tests) of the potential for endocrine disruption of single compounds is still emerging and fraught with much scientific uncertainty. Nonetheless, the Committee urges EPA to rigorously address the science of mixture toxicology in their research efforts, and recognizes the need, under the auspices of the EDSTP, to begin to confront mixtures.

The science of evaluating mixtures remains complex and unclear for any toxic endpoint. Given the potentially overwhelming task of establishing priorities for endocrine disruptor screening and testing of mixtures, the Committee recommends a well considered, step wise approach to the inclusion and prioritization of mixtures in the EDSTP. The EDSTAC urges EPA to identify the challenges it faces early in this endeavor, and to address these issues in a transparent fashion.

The recommendations that follow are based on the assumption that, prior to undertaking the T1S step of the program, the following will occur:

· Demonstration/ Validation ( D/ V) of both HTPS and the T1S battery   a limited number of chemicals will be selected and evaluated in the battery of screens recommended by the EDSTAC. The purpose of this D/ V phase is to show the utility and validity of the screens to be used in both HTPS and T1S.

· HTPS   a series of transcriptional activation assays will be selected for utilization in the high throughput mode.

Specific recommendations for mixtures:

1. D/ V   Include a limited set of mixtures in the D/ V phase of screening, including those to be included in HTPS. For the purpose of this phase, a set of mixtures should be selected that spans a range of physical and chemical properties. The goal here is to challenge HTPS and T1S with a variety of chemicals to ensure feasibility and robustness before evaluating other mixtures. Clearly, the mixtures chosen for validation may be drawn from mixtures found in the environment and may include " known" endocrine disruptors, but the primary selection criterion should be chemical diversity. This component of the D/ V phase is in addition to any D/ V efforts done for individual chemicals, as described above.

2. HTPS   If the screens are shown to be capable of handling single components as well as a diverse set of mixtures in the D/ V phase, expert judgment ( e. g., EDSTAC consensus), guided by a set of prioritization criteria, should be used to evaluate the literature and to decide on a EDSTAC Final Report Chapter Four August 1998 4  49 limited set of mixtures to enter HTPS. Rather than focusing on chemical diversity as in the initial D/ V phase, these mixtures should be representative of those found in environmental media or biological tissues. For each mixture, a set of chemicals should be identified that are deemed representative of the chemicals and their proportions found in the selected mixture. The EDSTAC recommended that the PSWG develop prioritization criteria for mixtures and identify a set of mixtures to enter HTPS. These criteria and the set of mixtures are described in Chapter Four, Section VII, E, and Section VII, F, 4, respectively.

3. Screening and Testing   The battery of assays 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. Additionally, a comprehensive literature evaluation should be undertaken to identify exposure and effects data on mixtures that have not already undergone HTPS. This information should be used to inform the prioritization for Phase II and subsequent phases. During the time it would take to accomplish this, data could be gathered from the screening and testing of single compounds during Phase I and from a limited number of mixtures to help inform the prioritization of other candidate mixtures. The prioritization of mixtures for Phase II and subsequent phases would use the same prioritization criteria as those used for single chemicals.

4. Highest Priority Mixtures for Screening and Testing   The EDSTAC is concerned that the sheer complexity of the mixtures issue could produce " paralysis by analysis" and result in no meaningful progress. To overcome this potential inertia, the EDSTAC urges EPA to focus initially on six types of mixtures. These six types of mixtures have been identified by applying the exposure and effects criteria for priority setting outlined earlier in this chapter. In suggesting that EPA focus its initial attention on these six types of mixtures, by no means does the EDSTAC underestimate the enormous challenge of addressing just these six. However, the EDSTAC believes a systematic approach that focuses initially on these six types of mixtures could shed light on a wide range of technical challenges, help validate screens and tests, and promote development of decision making protocols for screening and testing other types of mixtures. Thus, the EDSTAC recommends that EPA focus its initial efforts on identifying a relatively small number of representative samples of mixtures ( i. e., more than one and fewer than ten) from the following six types of mixtures; and second whether it is technically feasible to run these representative samples through the HTPS, T1S, and T2T. If such steps are determined to be technically feasible, the EDSTAC recommends that the selected representative samples of mixtures be subjected to HTPS, T1S, and, if necessary, T2T. In presenting the six candidate types of mixtures, in several instances the EDSTAC identifies some data sources that EPA might use to initiate the first step of this activity ( i. e., to identify a small number of representative samples):

a) Contaminants in human breast milk   The contaminants in human breast milk are recommended for immediate attention because infants are directly exposed to them. Existing literature demonstrates that human breast milk in the United States and elsewhere is contaminated with a sizable number of chemicals that tend to exist in common proportions ( Jensen and Slorach, 1990). Scientific opinion favors breast feeding over reliance on infant formulas and cows' milk in most cases. Therefore, the results of testing EDSTAC Final Report Chapter Four August 1998 4  50 contaminants in human breast milk must be communicated with great sensitivity.

The EDSTAC acknowledges that if hazards are recognized in breast milk, no techniques exist for reducing immediately the hazards to those exposed. But women have a right to know the extent to which they have been exposed to endocrine disrupting chemicals and are entitled to know the hazards to which they are subjecting their infants. Over the longterm the evidence from analysis of contaminants in breast milk can be an impetus to the evaluation of policies for reducing further exposure to such chemicals.

b) Phytoestrogens in soy based infant formulas   Soy based infant formulas contain a complex mixture of plant derived NONEs   often referred to as " phytoestrogens." In particular, the formulas contain a category of phytoestrogens called isoflavones, specifically genistein and daidzein. But the formulas also contain a wide array of other isoflavones, present as minor components, which also possess estrogenic characteristics ( Chapter Four, Section VIII).

c) Mixtures of chemicals most commonly found at hazardous waste sites   ATSDR has published a summary of the combinations of chemicals most commonly found at hazardous waste sites ( Johnson and De Rosa, 1995). These mixtures pose a potential hazard to the communities in which these sites are located and, to the extent that such sites are located in lower income areas, their presence raises issues of environmental justice. Such sites are distributed broadly across the United States.

d) Pesticide/ Fertilizer mixtures   Pesticides and fertilizers have commonly been detected in surface water and groundwater across the United States. The National Toxicology Program ( NTP) of the National Institute for Environmental Health Sciences ( NIEHS) has conducted tests for traditional reproductive and developmental toxicological endpoints of the most commonly occurring mixtures in California and Iowa, two heavily agricultural states ( Heindel et al., 1994). Screening and testing these mixtures will provide an opportunity to compare results to the toxicological data already available.

e) Disinfection byproducts   Some of the chemicals used for purifying drinking water supplies produce byproducts that, ironically, may themselves pose a hazard to human health. EPA currently is reviewing monitoring data on disinfection byproducts, with the objective of setting priorities for screening and testing. EPA is whittling down a list of several hundred such byproducts and anticipates, in the short run, NIEHS/ NTP initiating testing on approximately ten of these chemicals for carcinogenicity, immunotoxicity, and reproductive effects. Based on whatever results are available from this review and testing, and subject to technical feasibility, the EDSTAC recommends subjecting representative mixtures of the most commonly occurring disinfection byproducts to screening and possible testing for endocrine disruption.

f) Gasoline   Gasoline is a complex mixture of volatile organic compounds to which large numbers of the population are exposed by inhalation. Dermal exposure can also occur, particularly in occupational settings. Subject to technical feasibility, the EDSTAC EDSTAC Final Report Chapter Four August 1998 4  51 recommends that representative samples of this mixture be subjected to screening and, if necessary, testing. The EDSTAC did not have time to identify potential data sources for determining whether it is possible and, if so, what might constitute, representative samples of gasoline.

VIII. Recommendation to Screen Naturally Occurring Non Steroidal Estrogens A. Background Naturally occurring non steroidal estrogens ( NONEs) include natural products derived from plants ( phytoestrogens) and fungi ( mycotoxins). NONEs are less active than estradiol and diethylstilbestrol ( DES) in in vitro and in vivo assays, but the ubiquitous presence of these compounds in foods indicate that NONEs cannot be ignored ( e. g., Cassidy, 1996; Clarke et al., 1996; Gavaler et al., 1995; Sheehan and Medlock, 1995). Moreover, the potential additive, antagonist, and synergistic effects of NONEs with other endogenous and exogenous hormonally active chemical substances are issues that warrant investigation. Significant research on NONEs is being conducted in the United States and other countries to better characterize the benefits and potential hazards ( effects) of, as well as the levels of exposure to, these estrogenic compounds.

NONEs are commonly perceived as safe, generally beneficial, and overall innocuous to humans. For example, the low incidence of breast cancer in women within Asia has been attributed to the beneficial effects of the phytoestrogen genistein. Genistein is a major component in soybeans, which comprise a large part of some Asian diets. Moreover, phytoestrogens are recommended as safer, natural alternatives to steroidal estrogens for hormone replacement therapy. However, over the last 40 years, adverse effects of naturally occurring non steroidal estrogenic compounds have been well documented in wildlife ( range livestock) and laboratory animals. In humans, there are reports that phytoestrogens prolong the menstrual cycle and cause ( weak) proliferation of reproductive epithelial cells.

Exposure to NONEs through food sources can occur throughout one's lifetime ( i. e., in utero, infancy, childhood, and adulthood). Significant quantities of a complex mixture of isoflavone phytoestrogens ( predominately genistein and daidzein) are present in various soy based foods. Soybean infant formulas are widely used in the U. S. and abroad, and there is research under way to determine the effects of these compounds on male infants. Additionally, the exposure and uptake of NONEs in adults is evident because phytoestrogens have also been detected in human breast milk and urine.

The potential effects of NONEs, beneficial and detrimental, should not be dismissed or assumed to be non existent because organisms have the ability to rapidly metabolize these compounds. Many of the endocrine disruption issues and concerns for pesticides and industrial chemicals may be just as relevant for NONEs. There is substantial evidence to justify a designation of high priority for screening and testing of these compounds based on the exposure to and potential effects of NONEs to both wildlife and human populations. While there is an abundant amount of EDSTAC Final Report Chapter Four August 1998 4  52 in vitro and in vivo screening data ( mainly uterotrophic and estrogen receptor binding assays) on NONEs, broad based mechanistic screening and two generation reproductive/ developmental toxicity testing ( according to current guideline standards for pesticides and chemicals) is lacking. A review of the literature indicates that:

· Estrogenic plant and fungal natural products are ubiquitous in nature and occur in significant quantities in at least 20 fruits and vegetables including legumes, coffee, beer, wine, and bourbon whiskey and forage clover. ( Cassidy, 1996; Clarke et al., 1996; Gavaler et al., 1995; Richard and Thompson, 1997; Thomas, 1998; Verdeal and Ryan, 1979; Wiese and Kelce, 1997). · NONE levels vastly exceed pesticide residues in food. The typical daily intake of isoflavones by humans, estimated to be 0.6 mg/ kg/ day, can prolong a human female's menstrual cycle. The daily intake of a vegetarian who consumes very large quantities of soy derived nutrients could be much higher. ( Adams, 1996; Cassidy, 1996; Clarke et al., 1996; Wiese and Kelce, 1997). · Coumesterol is uterotrophic in female rats fed over a 90 hour period at dose levels within the range reported in human foods. Exposure of newborn rats to 100 ug/ day of coumesterol accelerates the onset of puberty, increases the incidence of persistent vaginal keratinisation and induces bloody ovarian follicles. ( Clarke, 1996; Sheehan and Medlock, 1995; Verdeal and Ryan, 1979; Wiese and Kelce, 1997). · The deleterious effects of clover phytoestrogens on grazing sheep is well documented. Effects range from temporary and permanent infertility to permanent abnormalities in their reproductive organs. ( Adams, 1996; Thomas, 1997; Verdeal and Ryan, 1979). · At doses up to 50 mg/ day by oral administration, zearalenone, a corn mycotoxin, produces effects on the vulva, uterus, ovary, cervix, and mammary glands of swine. Sows receiving 5 mg of purified zearalenone daily throughout the last month of pregnancy produced litters with stillborn pigs or pigs with a " splayleg" incoordination of hind limbs. ( Adams, 1996; Wiese and Kelce, 1997; Verdeal and Ryan, 1979). · Phytoestrogens ( genistein) can be both tumor promoters and inhibitors depending on the target organ and the dose. Genistein has been observed to inhibit both tyrosine kinase and topoisomerase II. The latter is the target site of action for taxol, a drug currently used to treat breast cancer. ( Clarke et al., 1996; Lien and Lien, 1996; Markovits, 1989). · NONEs may produce various biological responses in vivo. NONEs may act as estrogen agonists or antagonists ( anti estrogenic effects). These effects could either be beneficial or deleterious depending on the target tissue and dose. Additionally, NONEs may cause other responses through other mechanisms that do not involve the estrogen receptor, for example genistein. Additionally, it is reported that some phytoestrogens may alter the concentration of sex hormone bonding globulin which, in turn, alters the bioavailability of endogenous hormones. ( Adams, 1996; Cassidy, 1996; Clarke et al., 1996; Safe and Gaido, 1998; Sheehan and Medlock, 1995; Wiese and Kelce, 1997; Wiseman, 1996).

B. Recommendation The EDSTAC therefore recommends screening and, if necessary, testing: ( 1) representative EDSTAC Final Report Chapter Four August 1998 4  53 NONEs singularly; and ( 2) a complex mixture of NONEs ( e. g., soy based infant formulas as discussed in Section VII of this chapter). Data from the representative compounds should be compared to hormones and synthetic chemicals. The representative compounds should come from the major chemical classes of estrogenic natural products. Testing soy based infant formulas should be made part of the initial investigation to evaluate mixtures.

The following NONEs were chosen from the literature based on their reported effects ( beneficial and deleterious) to wildlife and/ or humans and on their widespread occurrence in nature. These NONEs should be screened and, if necessary, tested.

Representative NONEs: 1. Isoflavones: genistein, daidzein, miroestrol, biochanin A, formononetin, equol 2. Flavones: kaemferol, naringenin 3. Coumestans: coumesterol 4. Dihydrochalcones: phoretin 5. Triterpenes: betulafolienetriol ( ginseng) 6. Lignans: enterolactone Representative estrogenic mycotoxin: 7. Beta resorcyclic lactones: zearalenone, zearalenol, zearanol IX. Recommendation for a Nominations Process A. Introduction The EDSTAC recommends that EPA establish a process that would allow affected citizens to nominate chemical substances or mixtures for endocrine disruptor screening and testing. In general, the nominations process recommended by the EDSTAC is intended to focus on chemical substances or mixtures where exposures are disproportionately experienced by identifiable groups, communities, or ecosystems rather than on chemical substances or mixtures where exposures are more broadly experienced by the general population at the regional and/ or national levels. As such, the nominations process is intended to provide a mechanism for prioritizing chemical substances or mixtures that are unlikely to be considered as high priority through the core priority setting process. For this reason, the EDSTAC recommends that the nominations process should run parallel to, but be separate and distinct from, the core priority setting process described earlier in this chapter. EDSTAC Final Report Chapter Four August 1998 4  54 B. Description of the Nominations Process Consistent with the overall philosophy of the core priority setting process, as described in Section XI of this chapter, chemical substances and mixtures that are nominated will, in effect, be placed in one of the " compartments" of the overall compartment based approach to priority setting ( Chapter Four, Section XI). The EDSTAC recommends a goal for each phase of the EDSTP of no less than 5% of the total number of chemical substances or mixtures subjected to T1S drawn from substances receiving nominations but not selected through the main priority setting process. The EDSTAC recognizes that the total number of nominations or their quality may be such that this goal cannot be met in specific phases. For each phase of the EDSTP, the nominated chemicals should be evaluated against the specialized criteria described below. Priorities for the nominated chemicals should be established in accordance with these specialized criteria on a separate track, rather than attempting to integrate the prioritization of the nominated chemicals with the chemicals that are selected for T1S through the core priority setting process. Any nominated chemical substance or mixture that becomes a priority for T1S through the core priority setting process should 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.

The nominations process should allow for an early opportunity to submit nominations during each phase of the EDSTP. A call for nominations should be made via a public notice specifying both the criteria by which nominations will be evaluated and the deadline for submitting nominations. The time period for submitting nominations should end prior to the expected Federal Register ( FR) notice announcing EPA's formal proposal for T1S priorities. As a part of the public comment period following such an announcement, members of the public should be given an opportunity to comment on all chemicals that are proposed for T1S. Chemicals not included in the priority list for each phase of the EDSTP could be nominated at the start of the next phase. However, the public comment period following the FR notice should not be considered a second opportunity to nominate chemicals for the current phase of the program.

C. Criteria for Evaluating Nominated Chemicals As noted above, the EDSTAC recommends that the nominations process should utilize a different set of criteria than will be used for the core priority setting steps of the EDSTP, particularly with respect to exposure. The exposure related criteria for the nominations process should be designed to allow for 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 status for T1S. Thus, the nominations process should be designed to focus on exposures that are disproportionately experienced by identifiable groups, communities, or ecosystems. EDSTAC Final Report Chapter Four August 1998 4  55 After exposure related criteria have been considered in the evaluation of nominated chemical substances and mixtures, it is likely that effects related information will need to be considered to help further set priorities among nominations. This is potentially problematic because there is likely to be a lack of effects related information. In fact, the lack of effects data may be the very reason for public concern. That is, communities may be regularly exposed to a chemical substance or mixture that has not undergone meaningful toxicological evaluation. Nevertheless, if there are effects data, or if the chemical substance or mixture is chemically similar to another chemical substance or mixture for which effects data are available, the Committee recommends that EPA utilize those data as a secondary source of information to help set priorities among nominees.

In summary, when evaluating nominations, EPA should consider nominated chemical substances and mixtures that meet the following criteria to be a higher priority than those that do not meet these criteria:

· chemical substances and mixtures for which there is a likelihood of a regularly completed exposure pathway as compared to chemical substances and mixtures for which the exposure pathway is likely to be completed only rarely or occasionally; · chemical substances and mixtures that affect a high proportion of people within a given community or workplace; and · chemical substances and mixtures for which there may be direct or indirect ( i. e., model derived) effects related data regarding the endocrine disrupting potential of the nominated chemical substance or mixture.

D. Submission of Nominations Members of the public should be encouraged to submit nominations with as much information as possible, but it should still be permissible to do so without data or evidence as it relates to the specialized criteria. Lack of such information should not preclude EPA from evaluating a nominated chemical on par with nominated chemicals for which data have been submitted. EPA should make use of all information available to the Agency, including anecdotal information that may be submitted, as well as information gathered as part of the core priority setting process ( e. g., information contained within the EDPSD recommended in Section X of this chapter). Recognizing that the nominations process may be vulnerable to misuse for various reasons, the EDSTAC recommends that the Agency design a nominations process that protects nominators, workers, communities, registrants, manufacturers, etc., as appropriate. Recognizing that misuse could significantly detract from its intended purpose, the EDSTAC recommends that the nominations process be as transparent as possible and that EPA provide the list of nominations with any appropriate supporting information in appropriate publications, such as the Federal Register Notice and/ or the Internet.

The identity of nominating organizations should be made public. The identity of individual nominators should be kept confidential by EPA upon written request. In order to assist EPA in its evaluation of nominated chemicals, the Committee recommends that nominations should include EDSTAC Final Report Chapter Four August 1998 4  56 the following types of information:

· how exposure to the nominated chemical substance or mixture 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.

E. Mixtures in the Context of the Nominations Process The EDSTAC expects nominations of chemical mixtures as well as individual chemical substances. However, as with the broader discussion of mixtures contained in Section VII of this chapter, the EDSTAC recognizes there are difficult technical and policy issues surrounding the issue of screening and testing mixtures. The EDSTAC is particularly concerned that EPA and other governmental agencies, in anticipation of the nominations process raising expectations for action, be prepared to take whatever steps may be appropriate to address potential public health and environmental impacts that are identified through the EDSTP. Similarly, the EDSTAC recommends that the communication and outreach effort that will accompany the nominations process should address the capabilities, as well as the limitations, which EPA and other governmental agencies are likely to face in any effort subsequent to the screening and testing stage of the process.

F. Ability to Track Nominations As recommended in Chapter Six of this report, members of the public should be able to track and locate the progress of all chemicals in the EDSTP through a centralized, on line database run by EPA. This on line database will provide an opportunity, in addition to the FR notice, for members of the public to determine the status of chemicals that may be of concern to them.

X. The Endocrine Disruptor Priority Setting Database A. Introduction As described in other sections of this chapter, the PSWG began its work by describing exposureand effects related information categories and criteria to be used for sorting and prioritizing chemicals for endocrine disruptor screening and testing. The PSWG also identified and evaluated data sources associated with these categories and criteria. These data sources are listed in matrices contained in Appendix G.

After identifying these data sources, the PSWG grappled with how to use them to sort and EDSTAC Final Report Chapter Four August 1998 4  57 prioritize chemicals for endocrine disruptor screening and testing. Over time it became clear that there was much value and utility in assembling the relevant and useful data sources into a single relational database, which is referred to as the Endocrine Disruptor Priority Setting Database ( EDPSD). The PSWG had contemplated developing and using the EDPSD to assist in the EDSTAC's deliberations and, in particular, to help the work group and the Committee understand the implications of alternative approaches to priority setting. After making significant progress on the prototype EDPSD, the PSWG and the EDSTAC came to realize that the tool could not be completed given time and resource constraints.

This section presents recommendations on the further development, utilization, and maintenance of the prototype EDPSD. The recommended approach to priority setting contained in Section XI of this chapter builds upon the recommendations contained in this section.

B. Recommendation and Principles to Guide the Continued Development, Utilization, and Maintenance of the Prototype EDPSD The EDSTAC recommends that EPA continue to develop and maintain the EDPSD as a tool that can be used to expeditiously sort and prioritize chemicals for endocrine disruptor screening and testing. The EDSTAC identified several principles that should guide EPA's use of the EDPSD, along with the process EPA should follow in conjunction with use of the EDPSD.

Most importantly, the EDPSD itself, as well as the process by which it is utilized, should be open and transparent. As described in more detail below, EPA should convene a multi stakeholder group prior to the completion of the tool. This group would serve to help ensure that the tool was developed and ultimately used according to the guidelines suggested by the EDSTAC. EPA and the multi stakeholder group should develop ground rules to prevent the use of the EDPSD to confirm a priori assumptions regarding the priority for screening specific chemicals or as a means to hide or obfuscate the basis for priority setting decisions. Furthermore, EPA should provide notice and opportunity to comment on the proposed database tool before it is used by the Agency. This will allow an opportunity for additional chemical specific data that might not otherwise be included in the identified data sources to be incorporated into the EDPSD.

C. Description of the Prototype EDPSD The prototype EDPSD is a relational database that ( as of December 1997) contains records for approximately 87,000 chemicals with Chemical Abstracts Service Registry Numbers ( CASRNs) from data sources related to the information categories and criteria described in Sections III and IV of this document. It was created using Molecular Design Limited Information Systems' Integrated Scientific Information System. The CASRNs of discrete organic chemicals, polymers, and inorganic chemicals from each data source were entered in a multi field format. The number of chemical records in the EDPSD is determined by the cumulative number of chemical records contained in each data field. EDSTAC Final Report Chapter Four August 1998 4  58 The data fields included in the prototype EDPSD were used to develop a form that appears on the computer screen during operation of the EDPSD ( Figure 4.2). When queried using particular scenarios ( e. g., how many TRI chemicals produced between 10,000 and one million pounds appear in Great Lakes fish ( GLC Fish) and also occur in the ATSDR database, etc.), the EDPSD provides the number of chemicals meeting the criteria used. Any number of scenarios can be developed depending upon user interests. The prototype EDPSD showed great promise in providing numbers of chemicals that displayed certain criteria, and also has potential to develop algorithms combining different criteria. However, early queries using different scenarios occasionally resulted in numbers that were known to be inaccurate. It was assumed that the inaccuracies were resolvable by adequately cross referencing the different data fields and conducting appropriate QA/ QC corrections to the data included in the fields. However, the QA/ QC exercise could not be completed in the tight time frame of the EDSTAC schedule. As such, final development, demonstration, and validation of the EDPSD was viewed as a high priority, post EDSTAC task for EPA with multi stakeholder involvement. A more detailed description of the EDPSD follows.

All data fields in the EDPSD ( Figure 4.2, Tables 4.1, and 4.2) are linked by CASRNs, and there are no duplicate records for any chemical. For most discrete organic chemicals, chemical formulas, molecular weights, and Simplified Molecular Input Line Entry System ( SMILES) notations and chemical structures were entered into the EDPSD.

There are two types of fields in the EDPSD   logical and numerical. Logical fields are binary in nature ( i. e., +/, yes/ no, true/ false, etc.). For example, a chemical either is present or absent in a particular data source that is included in the EDPSD. Numerical fields, by contrast, are quantitative. They provide an actual measured value or, alternatively, an estimated number associated with a particular data source or environmental fate parameter ( e. g., an estimated hydrolysis half life of two hours).

As a relational database, the EDPSD may be queried in a wide variety of ways to answer questions in minutes that would otherwise take hours, days, or weeks to answer. As noted earlier, the EDPSD can be used to rapidly estimate the numbers and types of chemicals in different data sources that meet different criteria ( e. g., the number of chemicals with annual production/ importation volumes greater than one million pounds per year and log octanol water partition coefficients ( LogP) > 6 that are measured in Great Lakes fish and identified by California's Proposition 65 as reproductive toxicants).

The EDPSD is a very powerful tool for exploring alternative approaches to the application of the criteria described in Sections III and IV in this document. As described more fully in Chapter Four, Section X, G, the EDSTAC recommends that EPA and the multi stakeholder group make full use of the EDPSD in an effort to advise the Agency on its final decisions for priority setting for T1S. However, the EDSTAC recommends that EPA and the multi stakeholder group not be EDSTAC Final Report Chapter Four August 1998 4  59 limited to data that can easily be placed into a database format such as the EDPSD when providing advice and making final decisions on priorities for T1S ( Chapter Four, Section X, E).

D. Preliminary Recommendation for Data Fields to be Included in the EDPSD As noted above, significant progress was made in developing the EDPSD, but the tool was not completed given the time period and resources available to the EDSTAC. During the course of its work, the PSWG spent time grappling with the question of what data sources should be considered for inclusion in the EDPSD. This section outlines some of the PSWG's preliminary conclusions, which should be a starting point for the recommended development and implementation of the EDPSD to be completed by EPA and the proposed multi stakeholder group. The following data sources should be included, but are not considered to comprise a final comprehensive list. Rather, they illustrate the kinds of data sources that might be included in the final version of the EDPSD. The data field examples ( Figure 4.2, Tables 4.1, and 4.2) are categorized by type, and each data field example is further described in Appendix G.

E. Special Handling of Effects Data in the Context of the EDPSD The proposed EDPSD is a relational database tool that the EDSTAC recommends be used to assist in prioritizing chemicals for endocrine disruptor screening and testing. The prototype EDPSD has purposely been designed to be user friendly, transparent, and flexible. However, these very qualities make it difficult, if not impossible, to include information from the general scientific literature that is not organized into accessible numerical or logical databases. Though this represents a significant shortcoming, the EDSTAC believes the EDPSD is sufficiently versatile to justify its use. However, the EDPSD should not be used in isolation from other " tools," nor should it be used to perform functions that do not lend themselves to its design.

There are numerous data sources that provide toxicological, epidemiological, or field study data that may be useful in prioritizing chemicals for endocrine disruptor screening and testing. Although far from comprehensive, published studies can be identified through widely available scientific literature databases such as Medline, Toxline, and NIOSHTIC.

Substance specific reports are also widely available that include summarized data reviewed by the authors. Such reports are prepared by various organizations and agencies such as the International Agency for Research on Cancer ( IARC), NIOSH ( Criteria Documents), ATSDR ( Toxicologic Profiles), to name a few. Other sources of compiled data exist in the substancespecific rules and rule making dockets of regulatory agencies such as OSHA, EPA, CPSC, or online data summaries such as the EPA IRIS system. Less exhaustive reviews are also found in agency investigative reports such as the NIOSH Health Hazard Evaluation reports or ATSDR hazardous site evaluations. Research grant progress and final reports submitted to NIH, EPA, private foundations, etc., on the other hand, are not widely available. Lastly, some companies EDSTAC Final Report Chapter Four August 1998 4  60 Figure 4.2. Example of data fields arranged into a form as they might appear on a computer screen CASRN MW Formula Name SMILES Exposure Related Criteria:

Biological Sampling Environmental Sampling Release to the Environment Invertebrates, Fish, and Wildlife GLC Fish ATSDR/ PL Chemical Production or Importation < 10,000 lbs. > 10,000 < million lbs. > million < billion lbs. > billion lbs. Site limited intermediates Polymers Inorganics Fate and Transport LogP Hydrolysis half life ( d) Atmospheric ( OH radical) half life ( d) HLC ( atm/ cum / mole) VP ( mm/ Hg) Water solubility ( mg/ l) KOC BCF Effects Related Criteria:

Predicted Biological Activity/ Effect Laboratory Studies Epidemiology/ Field Studies RTECS TSCATS 8( e) HE RTOX TSCATS 8( e) EE RTOX Prop 65 Statutory Related Criteria:

FQPA SDWA Active Ingredients Inert Ingredients NHATS TRI ER QSAR SDWA CCL EDSTAC Final Report Chapter Four August 1998 4  61 Table 4.1. Existing files ( and field type) in the Endocrine Disruptor Priority Setting Database More information on the existing and proposed data fields recommended for inclusion in the EDPSD may be found in Appendix G of this report.

Generic and Notation Files:

1. Descriptive ( all textual)   CASRN, Chemical name, Chemical formula, and SMILES 2. Quantitative ( numerical)   Molecular weight Exposure Related Criteria Files:

1. Biological Sampling Data ( logical)   NHATS*

2. Environmental, Occupational, Food, and Consumer Product Data ( logical)   Great Lakes Fish, Invertebrates, Fish, and Wildlife, ATSDR/ PL 3. Environmental Release Data ( logical)   Toxics Release Inventory*

4. Production/ Importation Volume Data ( logical)   Annual production volume categories* for discrete organic chemicals ( x < 10,000 lbs.; 10,000 < x < 1,000,000 lbs.; 1,000,000 < x < 1,000,000,000 lbs.; x > 1,000,000,000); Site limited intermediates, Polymers, and Inorganics 5. Fate and Transport Data and Models ( all numerical )   Estimated LogP ( based on QSARs); Hydrolysis half life, Atmospheric half life, Henry's Law Constant, Vapor pressure, KOC, Water solubility, and Bioconcentration factor Effects Related Criteria Files:

1. Toxicology Laboratory Studies & Epidemiology and Field Studies and Databases ( all logical)   RTECS, TSCATS 8( e), HE RTOX, EE RTOX, and Proposition 65 2. Predictive Biological Activity or Effects Models ( numerical)   Hologram QSAR for estrogen receptor binding Statutory Related Criteria Files:

1. FQPA ( logical)   Pesticide active ingredients, Inerts*

2. SDWA ( logical)   Contaminant Candidate List*

(*) Indicates data files that are currently logical, but could be changed to numerical with appropriate quality control and analysis. EDSTAC Final Report Chapter Four August 1998 4  62 Table 4.2. Examples of file types that could be placed in the Endocrine Disruptor Priority Setting Database Exposure Related Criteria Files:

1. Biological Sampling Data   NHANES, TEAM, NHEXAS ( when available)

2. Environmental, Occupational, Consumer Product, and Food Related Data   Published data on measured concentrations of industrial chemicals, pesticide active ingredients and inerts in air, drinking water, ground water, surface water, sediment, and soil ( e. g., ACGIH/ TLV, FDA/ GRAS, OSHA/ PEL, FDA/ PAFA)

3. Environmental Release Data ( logical or numerical )   ATSDR/ HSEES ( logical numerical), USGS Pesticide Monitoring Program 4. Production/ Importation Volume Data ( logical or numerical )   Non CBI individual production volumes for industrial chemicals, discrete organic chemicals, polymers, inorganics, pesticide active ingredients, and inerts 5. Fate and Transport Data and Models ( all numerical )   Measured data for LogP, Hydrolysis half life, Atmospheric half life, Henry's Law Constant, Vapor pressure, KOC, Water solubility, and Bioconcentration factor, Estimated and measured biodegradation rate data Effects Related Criteria Files:

1. Laboratory Toxicology Studies & Epidemiology and Field Studies and Databases* ( all logical)   RTECS, TSCATS 8( e), HE RTOX, EE RTOX, and Proposition 65 2. Predictive Biological Activity or Effects Models ( numerical)   Hologram QSAR for estrogen receptor binding Statutory Related Criteria Files:

1. FQPA ( logical)   Pesticide active ingredients and inerts*

2. SDWA ( logical)   Contaminant Candidate List*

(*) Indicates data files that are currently logical, but could be changed to numerical with appropriate quality control and analysis. EDSTAC Final Report Chapter Four August 1998 4  63 maintain published literature databases relevant to their products as well as epidemiological data on the health experience of their work force. Unfortunately, for any given chemical substance or mixture, the process of collecting and assessing most of these data is extraordinarily time consuming and resource intensive.

For these reasons, the EDSTAC recommends that EPA make use of the potentially valuable information contained in the scientific literature in an efficient and cost effective manner. In particular, EPA should make use of all of the data that is available to it in a step wise fashion, starting first with data that lends itself for inclusion in the EDPSD. This will include data from databases such as RTECS and TSCATS, which are limited to positive findings from the literature. Other databases that contain abstracts of studies but are not limited to positive findings could be searched next for those chemicals that either have positive findings in RTECS or TSCATS or that warrant further review due to the application of other effects related information or criteria ( e. g., positive HTPS or QSAR results). Finally, if necessary and helpful to the process of either making or justifying the basis for final priority setting decisions, EPA could review the literature available on a particular chemical.

F. Continued Development of the EDPSD In order to complete data collection in anticipation of the use of the EDPSD, data from additional files need to be included in the database, and the relevance of those files to priority setting for endocrine disruptor screening and testing needs to be provided as part of the justification for their addition. All new chemicals from each additional file must include, at a minimum, CASRNs and molecular weights. All new discrete organic chemicals from each additional file must also include SMILES notations and chemical structures.

The EDSTAC recommends that EPA provide resources to complete the QA/ QC investigations of files that are currently in the EDPSD. The EDSTAC further recommends that EPA provide resources to add new files to the EDPSD in stages. These files and the stages for their addition could include:

1st stage: EPA and other databases that provide data on use for industrial chemicals and pesticides; information from pesticide ecotoxicity, fate, and toxicity one liners; chemicals that are non food use pesticide active ingredients and non food use other pesticide ingredients; chemicals on the Generally Regarded As Safe ( GRAS) list; and chemicals in the Priority Assessment of Food Additives ( PAFA) database. 2nd stage: Data on chemical use that were not readily available in databases; chemicals and concentrations of chemicals in National Health and Nutrition Examination Survey ( NHANES), Total Exposure Assessment Methodology ( TEAM), and ATSDR's Hazardous Substances Emergency Events Surveillance ( HSEES) files; measured chemical fate data; and additional QSARs for endocrine disruptors. 3rd stage: Inclusion of HTPS data and improved QSARs.

The EDSTAC recognizes that the time and resources required to add new files will depend upon a EDSTAC Final Report Chapter Four August 1998 4  64 number of factors, including: when pending files are received, the format of received files, the determination of whether to use files as sources of numerical or logical data, conversion of logical files to numerical files, completion of QA/ QC investigations of the files and data, and expediency of the input process.

G. Use by Multi Stakeholder Group The EPA should convene a multi stakeholder group prior to completion of the tool. This group would serve to ensure that the tool was developed and ultimately used according to the guidelines provided by the EDSTAC. This multi stakeholder group should provide input and assistance to EPA in completing the development of this tool. Once the tool is completed, the multistakeholder group should be provided an opportunity to make use of the tool to provide input on the priorities for T1S. However, EPA would ultimately be responsible for setting priorities for T1S. Presumably, the group would follow the approach to priority setting recommended in Section XI of this chapter. Specifically, the group should make use of the EDPSD to understand the implications of its recommendations to EPA regarding the number and types of chemicals that should be included on the list of priority chemicals for T1S in Phase I of the program.

The EDSTAC recommends that the multi stakeholder group convened for this purpose be approximately half the size of the EDSTAC, but with the same degree of balance and diversity of interests. EPA should establish ground rules for the multi stakeholder group that encourage the group to stay focused on the development of a fair and scientifically sound set of final recommendations of priorities for T1S. As indicated earlier, the ground rules should encourage the assembled group not to use the EDPSD as a tool that simply confirms or justifies a set of a priori assumptions.

Finally, the EDSTAC recommends that the Agency provide an opportunity for public comment on the content and structure of the database tool, as well as on the approach or way in which the Agency intends to use the tool. Among other things, this will allow an opportunity for submission of additional chemical specific data to be incorporated into the database tool. The EDSTAC also recommends that, after receiving comment on the tool itself, EPA propose for public comment its T1S priorities. EDSTAC Final Report Chapter Four August 1998 4  65 H. Maintenance In order for the EDPSD to remain a timely and viable tool, the EDSTAC recommends that EPA update the database every six months at a minimum, and more frequently if time and resources permit. If maintained properly, the EDSTAC believes the tool will not only provide the capability to understand the " real world" implications of alternative approaches to priority setting, but the tool will also have broad application and pertinence, once knowledge of the existence of the tool spreads.

XI. Recommended Approach to Priority Setting A. Introduction The EDSTAC's recommended approach to priority setting establishes an initial sorting step to separate the universe of chemicals that need to be considered for endocrine disruptor screening and testing into four distinct categories:

1. polymers that will be placed into a " hold" status ( with some exceptions) pending a review of their monomers and oligomers; 2. chemicals for which there are insufficient data to proceed to either T2T or hazard assessment and will therefore need to be prioritized for T1S; 3. chemicals for which sufficient data exists to go to T2T; and 4. chemicals for which sufficient data exists to go to hazard assessment.

In this concluding section of the Priority Setting chapter, a number of issues are presented which the PSWG considered in developing its recommendations, followed by the EDSTAC's recommended approach to setting priorities for T1S. Also included is the EDSTAC's rationale for its recommendation to rely on EPA's schedule for tolerance reassessments under the FQPA as the basis for setting priorities for food use pesticides that will be permitted to bypass T1S and go directly to T2T.

B. Obstacles to an Ideal Priority Setting System In an ideal world, EPA would have sufficient information on exposures to and effects from candidate chemicals to provide a basis for priority setting. In reality, existing data sets are uneven in quality and quantity. The EDSTAC's review of available data, contained in Sections III and IV of this chapter and in Appendix G, attests to these problems. Major characteristics of this unevenness include the following:

· Many more data are available on the effects of the relatively small number of active ingredients in pesticides ( approximately 900) than on the thousands of industrial chemicals EDSTAC Final Report Chapter Four August 1998 4  66 produced in much larger quantities. · Biological monitoring data for humans are scarce. A relatively small number of chemicals ( on the order of 100 or less) have been routinely sampled in human blood and urine in the United States, and the major U. S. national program for sampling concentrations in human tissues was discontinued in 1990. · Monitoring data for other organisms, while more numerous than human data, still focus on a relatively small number of chemicals. · Data on routine chemical releases to the environment, while markedly better than they were prior to the creation of the Toxic Release Inventory about 10 years ago, still encompass only 528 industrial chemicals and pesticides and frequently rely on engineering estimates rather than on actual releases.

C. Principles for Setting Priorities The EDSTAC's report could have been designed primarily to assist EPA in implementing the screening program provisions of the FQPA and the SDWA. But, as noted earlier, the EDSTAC saw its charge as reaching beyond these specific statutes and EPA's regulatory authority. The EDSTAC acknowledges that EPA's implementation of these priority setting recommendations will be influenced most heavily by its statutory authorities. Nevertheless, the EDSTAC hopes its broad, scientifically derived approach will encourage voluntary testing behavior within the private sector and new screening and testing initiatives by other agencies.

The proposed priority setting system for T1S is based on the following three principles:

1. The system should be " transparent."

Environmental health concerns in the United States are usually addressed in decisions that represent a mix of scientific judgment and individual and shared values. Priority setting for endocrine active chemicals is especially value laden, because necessary knowledge of effects and exposures is so lacking. There are many different, reasonable, and not obviously wrong ways of deciding how to apply the information categories and criteria identified by the EDSTAC. The manner in which these are used should identify as clearly as possible the weights assigned to various categories and the rationales underlying those weights.

2. The system should reflect guiding principles derived from the EDSTAC's review of existing data on effects and exposures.

Sections III and IV of this chapter present the EDSTAC's major conclusions about the strengths and limitations of the information included in each exposure and effects related information category, as well as on a set of guiding principles for how to use the information in setting priorities. These guiding principles are principles for weighting data. A nonexhaustive list includes, for example: EDSTAC Final Report Chapter Four August 1998 4  67 · The greater the relevance of a biological sampling data set to large populations, disproportionately exposed subpopulations, or particularly susceptible subpopulations, the more weight the data set should be given. · The more likely a chemical is to be internalized by an organism from its environment, the greater weight it should be given. · The more likely environmental releases are to lead to organism exposure, the greater weight the release data should be given. · Production volume should not be used to prioritize between existing industrial chemicals and pesticides, because production volumes for high volume industrial chemicals are several orders of magnitude higher than those for pesticides.

3. The system should rely heavily on empirical data, but the highest priority should not be assigned solely to those chemicals for which the most empirical information on exposures and effects has been gathered.

The most solid evidence of exposures comes from monitoring of organisms, including humans. Chemicals detected in organisms should be weighted heavily in the priority setting system. However, the number of chemicals monitored in this fashion is limited. Therefore, chemicals that may not be widely monitored in organisms or environmental media, yet are of potential concern, should not be excluded completely from the highest priority rankings. Existing empirical data on selected chemicals can and should be used to improve the predictive capacity of models for chemicals lacking empirical data.

The EDSTAC also prefers weighting heavily empirical evidence of effects, at least until it is learned how to develop better models for use in the assessment process. The EDSTAC recognizes that there is a risk that heavily weighting those chemicals about which the most is known may penalize those chemical producers who have evaluated the potential effects of their products. The Committee acknowledges this possibility, but it should be kept in perspective. It applies mainly to active ingredients in pesticides. Since the food use pesticides ( approximately 500 of almost 900 currently registered active ingredients) may go directly to T2T anyway, thereby skipping T1S, the availability of large amounts of data on these pesticides will not raise their priority for T1S higher.

D. Recommended Strategy for Setting Priorities for Tier 1 Screening The EDSTAC advocates adoption of a " compartment based priority setting strategy." This strategy builds directly upon the several distinct exposure and effects related information categories and criteria found in Sections III and IV, respectively, as well as several specially targeted priorities identified elsewhere in this chapter, including: mixtures ( Section VII), naturally occurring non steroidal estrogens ( Section VIII), and nominations ( Section IX). The basic premise of a compartment based priority setting strategy is to establish separate priorities for a limited number of separate compartments. The term " compartment" simply refers to the particular information category or criterion or combinations of information categories or criteria that define each set of priorities. Such compartments can be defined by the integration of EDSTAC Final Report Chapter Four August 1998 4  68 exposure and effects data, the consideration of exposure data on their own, effects data on their own, or specially targeted priorities, as described below.

A compartment based approach can be contrasted with approaches that strive to develop a single rank ordered priority list that integrates all exposure and effects related information categories and criteria. The Committee believes the proposed compartmentalized approach best accommodates its principles for priority setting and the real world situation of uneven data.

E. Examples of Compartments for the Recommended Priority Setting Strategy While the EDSTAC endorses the general framework of a " compartment based priority setting strategy," the specific compartments and the weights and/ or order in which they should be utilized have not yet been agreed upon. Thus, the compartments described immediately below are intended solely as examples.

Where the EDSTAC was confident of the data that are pertinent to a particular compartment, the number of chemicals estimated to fall within each compartment are indicated below. For some of the example compartments, the EDSTAC did not have sufficient data to provide estimates. The compartments are not listed in order of agreed upon priority.

As noted above, the following examples of compartments fall within four major categories:

· Integrated Exposure/ Effects   Each of these compartments draws first from databases containing information on exposures. Within each compartment, priorities are set on the basis of effects data. For purposes of illustration only, these data on effects are presumed to come from TSCATS, RTECS, HTPS, and QSAR models. These are the databases currently projected for inclusion in the EDPSD. Elsewhere in this chapter, the challenge of readily assessing effects data, and the desirability of taking a " tiered approach" to such assessments that goes more deeply into or beyond databases such as those mentioned specifically above are described. It is anticipated that most of the chemicals in Phase I will be prioritized based on integrated exposure and effects data.

· Exposure Only   Compartments in this category would prioritize chemicals based on exposure data only, without using effects data. It is anticipated that chemicals in these compartments would be relatively few compared to those taken from integrated compartments. These compartments would focus on identifying chemicals with high production volumes. Special attention should be paid to chemicals for which there is evidence of embryonic, post partum or post hatch, early life stage, and pre maturation exposures.

· Effects Only   Compartments in this category would prioritize chemicals based on effects data only, without using exposure data. It is anticipated that chemicals prioritized in these compartments taken for screening in any one phase would be relatively few compared to those taken from integrated compartments. These compartments would focus on identifying chemicals with noteworthy effects data. EDSTAC Final Report Chapter Four August 1998 4  69 · Specially Targeted Categories   These categories   which presume widespread exposure and the possibility of widespread effects   include mixtures, nominations, and non steroidal estrogens. The nominations category can include less widespread, yet elevated exposures and can be driven by reported effects that might be associated with exposures to chemicals.

1. Examples of Integrated Exposure/ Effects Compartments a) Chemicals found in human biological samples These are the most solid indicators of human exposure. They number approximately 100 chemicals and include chemicals from the NHATS, NHANES, and TEAM studies described earlier in this chapter and in Appendix G, Table 1. Some of these substances may bypass T1S and go directly to T2T. Priorities for screening among the remaining substances can be established based on effects data, with the highest priority given to chemicals on this list for which there is some indication of possible biological effects. The EDSTAC acknowledges that some of the human sampling data are not current, but believes they are nevertheless worthwhile to use.

b) Chemicals found in wildlife samples These are the most solid indicators of wildlife exposure. U. S. Fish and Wildlife Service's Environmental Contaminant Data Management System lists 625 compounds and the Great Lakes Fish Monitoring Program lists over 550 compounds. ( See Appendix G, Table 1.) Priorities among these chemicals can be set based on effects.

c) Highest volume chemical releases from industrial sites This component draws on the Toxic Release Inventory, which includes 528 chemicals. Priorities within the compartment would be based on evaluation of effects data.

d) Commonly occurring chemicals at hazardous waste sites ATSDR has published a list of the most commonly occurring chemicals at hazardous waste sites ( Johnson and De Rosa, 1995). These pose a potential hazard to the communities in which these sites are located and, to the extent that such sites are located in lower income areas, the presence of these sites raises profound issues of environmental justice. These sites are distributed broadly across the United States. Priorities within this compartment would be based on evaluation in Environmental Fate and Transport models and assessment of pertinent effects data. EDSTAC Final Report Chapter Four August 1998 4  70 e) Cosmetics, food additives, and related substances within FDA jurisdiction This compartment includes substances like cosmetics and food additives which are eaten or are intended to be put on the skin of humans. Therefore, exposure is widespread. Priorities for screening within this compartment would be based on evaluation of data on effects, to the extent that such data are readily available.

f) Chemicals to which there is significant occupational exposure Occupational exposures can be orders of magnitude higher than environmental exposures. This compartment includes workplace chemicals: ( 1) to which large numbers of workers are exposed, or ( 2) that are present in large quantities/ high concentrations and therefore represent a disproportionately high risk to workers. EPA regulates occupational exposures to pesticides and pesticide products. OSHA regulates approximately 400 chemicals in the workplace; however, the majority of occupational exposures are unregulated. Integrating chemicals identified in this category with effects information will yield a group of chemicals which pose a high risk to worker populations.

g) Chemicals to which there is widespread environmental exposure An example, because of the potentially large number of people exposed, would be consumer exposure. The EDSTAC believes that chemicals in consumer products for which there is evidence of endocrine disrupting effects should be given a high priority for screening and testing. In the environmental realm, chemicals for which there is evidence of their presence in environmental media and for which there is evidence of endocrine disrupting effects should, likewise, be given a high priority for screening and testing.

2. Examples of Exposures Only Compartments a) High production volume chemicals A limited number of chemicals would be drawn from this compartment. These chemicals would have very high production or import volumes and would be included unless there were clear reasons to believe that exposures would not be likely ( e. g., a chemical is site limited and not stable). This category would identify chemicals with high exposure potential that are unlikely to be selected in an exposure/ effects integrated approach because of few or no effects data.

b) Chemicals to which there is widespread or significant environmental, occupational, consumer, or food related exposure but no effects data:

Evidence of widespread or significant human exposure ( in the environment, workplace, consumer products, or food) should be sufficient to put a chemical on EDSTAC Final Report Chapter Four August 1998 4  71 the priority list for screening and testing. The rationale is that the majority of commercial chemicals have not been tested for endocrine disrupting effects, and therefore a proactive approach is needed for chemicals that entail significant human exposure.

3. Examples of Effects Only Compartments a) Results of HTPS A relatively small number of chemicals is expected in this category. HTPS is designed to increase available knowledge on effects of chemicals, especially for those chemicals about which little is known. The results of HTPS can assist in setting priorities within other compartments, but can also be used on a " standalone basis, as indicated in Section V of this chapter. Alternatively, this compartment could contain any chemicals that have a positive result in the HTPS assays, but are not otherwise identified as a priority under any of the compartments described above. Chemicals in this compartment could be ranked based on HTPS determinations regarding their potency, while acknowledging that HTPS does not address the full range of endocrine disrupting mechanisms.

b) Results of Epidemiology Assessments Epidemiological analyses may or may not provide useful information about human exposures to chemicals. Epidemiological studies can provide evidence of health effects related to chemicals. The strength of a causal association between exposure and health effects will vary depending on study design and quality. In general, the weight of evidence is greatest for a randomized controlled trial and weakest for simple case reports. Cohort studies, case control studies, ecological analyses, and simple demographic or temporal analyses of disease fall in between randomized control trials and case reports, providing decreasing weight ofevidence for a causal association between exposure and disease.

c) Results of Laboratory and Field Studies This compartment would include chemicals that were identified by laboratory or field studies as having the potential to cause effects in humans or wildlife. However, these chemicals would have either no or inadequate exposure data. EDSTAC Final Report Chapter Four August 1998 4  72 4. Specially Targeted Compartments a) Mixtures People and other living organisms are continually exposed to mixtures. The EDSTAC does not underestimate the difficulty of addressing these mixtures. Nevertheless, initial steps must be taken to understand the implications of these exposures. In Section VII, the EDSTAC identified six types of mixtures from which representative samples of mixtures should be selected as a priority for T1S. It is the Committee's belief that its recommendations represent a reasonable and prudent approach.

b) Naturally occurring non steroidal estrogens ( NONEs)

As described in Section VIII, humans and other living organisms are broadly exposed to a wide range of naturally occurring chemicals that affect hormones. These substances are ubiquitous in food. Individuals exposed to them should be made aware of the benefits and hazards that may be associated with their consumption. Based on such information, consumers may be able to voluntarily alter their diets. As indicated in Section VIII, twelve such substances should be addressed in Phase I.

c) Nominations The EDSTAC recommends EPA establish a process to allow citizens to nominate chemicals for endocrine disruptor screening and testing. The purpose, criteria, and principles that should guide EPA in developing and implementing the recommended process are described in Section IX of this chapter.

F. Numbers of Chemicals Prioritized and Associated Weightings of Compartments EPA has not provided the EDSTAC with a target for the number of chemicals the Agency believes should go through T1S in either Phase I, subsequent phases, or for the life of the program. The PSWG of the EDSTAC exchanged views about potential targets for the number of chemicals for each phase of the program but did not attempt to reach consensus on this matter in the hopes of using the EDPSD as a tool that could be used to explore alternative scenarios and targets. The PSWG and the EDSTAC had hoped to use the tool to develop precise recommendations on how to structure the compartments ( i. e., how many compartments there should be and how many chemicals should be drawn from each compartment). However, because the EDPSD was not completed before the drafting of the EDSTAC's final report, the EDSTAC ( and, in particular, the PSWG that conducted this work on the EDSTAC's behalf) was unable to conduct a " reality check" on how the illustrative compartments might work in practice.

In the absence of having a tool that could be used to both ground its recommendations in the most EDSTAC Final Report Chapter Four August 1998 4  73 up to date and relevant data available and to test out alternative priority setting scenarios, the EDSTAC was reluctant to develop recommendations on such questions as how many compartments there should be, how many chemicals should be drawn from each compartment, and how many chemicals should be screened and/ or tested in each phase of the program. Additional uncertainties that made it difficult to develop such recommendations include unknown results of the validation and standardization process, laboratory capacity to conduct screens and tests, and the feasibility of conducting screens and tests on chemical substances and/ or mixtures with certain physical properties ( e. g., gases).

Thus, the number of chemicals to be selected for T1S is a major unknown in achieving greater specificity at this time on how the system should work in practice. For example, if only a small number of chemicals can be screened in Phase I, this dramatically reduces the number of chemicals that can be selected from each compartment, and may dictate the selection of a smaller number of compartments. On the other hand, if the number of chemicals to be screened is relatively large, this provides somewhat greater flexibility in selecting chemicals and could alter the weights assigned to different compartments. Factors such as laboratory capacity, private sector testing response, and the universe of eligible chemicals are variables that may be considered in the determination of the number of chemicals to be screened in Phase I.

Whatever number is chosen, it should encompass chemicals most widely found in biological samples, produced at highest volumes, released in greatest amounts, and most likely to be of environmental concern, and several mixtures to which there is widespread exposure. Moreover, should a decision be made to raise the priority for screening of those chemicals that rank highest in multiple compartments, this will provide increased assurance that screening resources are being directed where they can be most helpful. Beyond the chemicals that rise to the top because of their high rankings in multiple compartments, the question of how many chemicals should be selected from each compartment is a heavily value driven exercise. For example and for illustrative purposes only, one could take all or almost all of the chemicals from a compartment ( e. g., measured concentrations in tissues and fluids of living organisms) that is deemed highly important relative to other compartments.

For example and for illustrative purposes only, if the number of chemicals chosen is relatively large, chemicals could be prioritized by:

· Selecting 72% from the integrated exposure/ effects compartments; · Selecting 10% from the exposure only compartment( s); · Selecting 10% from the effects only compartment( s); and · Selecting 8% from the specially targeted compartments.

Conversely, and again for example and for illustrative purposes only, if the number of chemicals chosen is relatively small, chemicals could be prioritized by:

· Selecting 60% from the integrated exposure/ effects compartments; · Selecting 15% from the exposure only compartment( s); EDSTAC Final Report Chapter Four August 1998 4  74 · Selecting 15% from the effects only compartment( s); and · Selecting 10% from the specially targeted compartments.

G. Next Steps ( Reaching Closure) on Phase I Priorities for Screening and Testing The EDSTAC believes it has created a strong, logical, transparent basis for setting priorities for T1S. The Committee recommends that the multi stakeholder group, described in Section X, G, use the EDPSD tool to experiment with the above categories and compartments to determine more finely the numbers of chemicals that emerge for T1S. The experiment can encompass including or excluding different quantitative thresholds for guiding decisions on the larger categories of priority chemicals, including parameters related to environmental fate and transport and parameters related to reported effects data.

H. Recommended Approach to Setting Priorities for Tier 2 Testing During Phase I of the EDSTP As described in Chapter Three, the EDSTAC is recommending that the owners/ producers of chemicals should be permitted to bypass T1S under two alternative scenarios. " Scenario 1" covers chemicals for which two generation reproductive toxicity studies are either required by statute ( i. e., FIFRA), or where such studies have been completed in the past, but in both cases the studies did not include the additional T2T endocrine disruptor endpoints recommended by the EDSTAC. " Scenario 2" covers chemicals where the owner/ producer has decided to voluntarily complete T2T without having completed the full T1S battery or any prior two generation reproductive toxicity testing.

This section focuses primarily on the need to set priorities for food use pesticides regulated under FQPA, which is a subset of chemicals covered under Scenario 1, during the first phase of implementing the EDSTP. As discussed below, the EDSTAC recommends that priorities for conducting T2T on food use pesticides should be based on the FIFRA/ FQPA re registration and tolerance reassessment processes.

Priority setting for T2T for chemicals other than food use pesticides for which two generation reproductive toxicity tests have been completed in the past but where the chemical is not regulated under FIFRA/ FFDCA, as well as chemicals that bypass T1S under Scenario 2, will generally be driven by the same priorities set during the priority setting phase for T1S unless the producer/ owner of the chemical wishes to voluntarily expedite testing. In other words, the EDSTAC recommends that a chemical which receives a high priority ranking for T1S should retain that high priority ranking for T2T even when the owner wishes to voluntarily bypass T1S. Food use pesticides that bypass T1S under Scenario 1 are likely to be the prime candidates for the alternative approaches to completing the information requirements for T2T described in Chapter Five, Section V. It is also assumed that it may be necessary to assess endocrine mediated endpoints that had not been adequately assessed in past two generation reproductive toxicity tests on these compounds. The determination of which alternative tests and/ or additional endpoints EDSTAC Final Report Chapter Four August 1998 4  75 need to be conducted will be made on a case specific basis.

The EDSTAC recognizes that it may be necessary to conduct a limited number of assays that are similar, if not identical, to those that would have been conducted during T1S for chemicals which are permitted to bypass the T1S battery. The purpose of conducting these assays as part of T2T is to gain knowledge about specific mechanisms of action necessary to complete the hazard assessment step and/ or to determine whether any adverse effects observed in T2T are in fact endocrine mediated.

The decision to consider pesticides separately for priority setting was based on practical realities associated with scheduling in EPA's Office of Pesticide Programs. These include ongoing reregistration activities, which have been in progress for more than a decade, and new requirements for tolerance reassessment and registration renewal mandated under the Food Quality Protection Act. These represent the primary scheduling priorities in the Pesticides Program for the foreseeable future.

Under the re registration program mandated in 1988, EPA reviews older pesticides to ensure compliance with current scientific and regulatory policies. Re registration is intended to update test data requirements and standards for approval which change over time. During re registration the Agency issues Data Call Ins ( DCIs). The interval between issuance of the DCI and receipt of data is dependent upon the number and the kind of studies requested. Presently, re registration is being conducted on compounds for which DCIs were issued en masse shortly after passage of the 1988 amendments to FIFRA or on a case specific basis thereafter. For the most part, these data have been received by the Agency. Data were requested for 436 active ingredients, and Registration Eligibility Decisions ( REDs) have been issued for approximately 200 of the 436 pesticide ingredients ( John Housenger, U. S. EPA, personal communication). Generally, neither the DCIs nor REDs issued to date have systematically dealt with endpoints acknowledged to be endocrine mediated.

In addition to the re registration process, food use pesticides represent a category of pesticides for which EPA has already undertaken a hazard based priority setting exercise. The food use pesticides are being reviewed with an eye to tightening regulatory treatment in light of new scientific data and statutory requirements. This priority setting exercise was mandated by Congress under Section 408( q)( 3) of the FQPA. EPA is required to reassess all existing tolerances for pesticide residues in or on raw and processed foods for both active and inert ingredients by August 2006. EPA is directed to give priority review to pesticides that appear to present risk concerns based on existing data. In reassessing tolerances, EPA must consider:

· aggregate exposure to the pesticide; · cumulative effects from other substances with a common mode of toxicity; · whether there is an increased susceptibility to the pesticide for infants and children; and EDSTAC Final Report Chapter Four August 1998 4  76 · whether the pesticide produces an effect in humans similar to an effect produced by a naturally occurring estrogen and other endocrine effects.

The FQPA requires EPA to review, within ten years, all tolerances and exemptions established prior to FQPA's enactment on August 3, 1996. EPA is required to review 33% of applicable tolerances and exemptions by August 1999, 66% by August 2002, and 100% by August 2006. FQPA also required EPA to publish its review schedule within one year of the law's enactment, which EPA did on August 4, 1997 ( 62 FR 42019 42030). This general schedule developed by EPA for tolerance reassessment, along with re registration and registration renewal, are the primary driving forces in scheduling regulatory actions for pesticides and their formulations and inert ingredients. With respect to tolerance reassessment, EPA has divided the pesticide reevaluation process into three categories, which will be reviewed in chronological order over ten years:

· Group 1, the highest priority class, includes organophosphate, carbamate, and organochlorine pesticides. It also includes pesticides classified by EPA as probable human carcinogens ( Groups B1 and B2 in EPA's carcinogen ranking system), and possible human carcinogens for which EPA has quantified a cancer potency ( Group CQ* in EPA's carcinogen ranking system). Group 1 also includes high hazard inert ingredients and any pesticides that appear to exceed their reference dose ( RfD). [ Note that RfD is defined as the daily exposure level of a pesticide which, during the entire 70 year human lifetime, appears to be without appreciable risk of non cancer effects on the basis of all of the facts known at the time. It is expressed in milligrams of the pesticides as it appears in the diet, per kilogram of body weight per day ( mg/ kg/ day).] The exposure must not exceed 100% of the RfD to meet the reasonablecertainty of no harm health based standard in the FQPA. The inclusion of certain pesticides in Group 1 is also driven by EPA's need to complete their re registration by 2002, even though their tolerances may not appear to pose the greatest risk to public health. Also in Group 1 are pesticides for which tolerances and exemptions are in the process of being proposed for revocation. · Group 2 includes possible human carcinogens not included in Group 1. Group 2 also includes remaining pesticides for which re registration must be completed by 2002, and other pesticides included for other scheduling reasons. · Group 3 includes biological pesticides, those inert ingredients not identified as high hazard, and selected other pesticides. It should be noted that biopesticides, mainly the pathogenic microorganisms, are probably not amenable to endocrine disruption screening and testing.

At the time of the FQPA's enactment, there were 9,728 tolerances and exemptions for active and formulation inert ingredients subject to the reassessment requirement. According to the EPA, 8,190 of these are tolerances for active ingredients, 712 are exemptions for active ingredients, and 826 are exemptions for inert ingredients ( John Housenger, U. S. EPA, personal communication). The total number of all active pesticide ingredients and inerts currently registered by EPA is approximately 3,400 ( Penny Fenner Crisp, U. S. EPA, personal communication). This includes approximately 900 active ingredients and approximately 2,500 inerts. ( Some of the inerts are also listed in the TSCA Inventory.) Of these 3,400, 469 active ingredients are scheduled to be EDSTAC Final Report Chapter Four August 1998 4  77 addressed through the tolerance reassessment process. This includes 228 in Group 1 ( scheduled for review by August 1999), 93 in Group 2 ( scheduled for review by August 2002), and 148 in Group 3 ( scheduled for review by August 2006). There are an additional 823 inert ingredient exemptions that will be dealt with as part of Group 3.

There are both advantages and limitations to using the re registration and tolerance reassessment processes as the basis for setting priorities for endocrine disruption screening and testing: · Re registration and tolerance reassessment priorities were not established specifically with endocrine disruption endpoints in mind. On the other hand, registration renewal, which has yet to begin, could take them into consideration. The current database on reproduction and developmental toxicity for most food use pesticides reflects the application of the 1985 test guidelines. Non food use pesticides may or may not have reproductive or complete developmental toxicity data, depending on their specific use patterns. · The priority setting process for food use pesticides is driven by human health considerations, so the entire set of non human, ecosystem protection concerns of EDSTAC is not explicitly incorporated. However, most of the food use pesticides with ecological concerns to nontarget organisms appear on the Group 1 and Group 2 lists. · Tolerance reassessment for Group 1 pesticides is likely to be completed prior to the completion of the validation and standardization of all EDSTAC recommended screens and tests.

Even though the tolerance reassessment process may be complete for Group 1 chemicals before the screening and testing program is fully operational, other opportunities will arise during which the human health risk assessments done for the ten year tolerance reassessment exercise will be revisited. One of those opportunities will be during the fifteen year registration renewal cycle. Other opportunities may arise sooner than that, for example during the course of periodic modifications to the registration status of a specific active and/ or other product ingredient( s). For instance, requests may be submitted for emergency exemptions ( Section 18' s), new uses, and/ or modifications to existing uses. Each of these actions requires an updating of the previous risk assessment. If the pesticide under evaluation has been shown to share a common mechanism of action with other pesticides, the other pesticides will have to be revisited, as well. Also, when test guidelines are updated, the program will assess whether or not additional data might be needed to upgrade the database on all pesticides for which that test guideline is appropriate. ( Such an assessment will need to be done soon in light of the recent upgrading of the multigeneration reproductive toxicity and developmental toxicity test guidelines.) In light of these possibilities, the EDSTAC recommends that HTPS data be used, along with other relevant information, to help prioritize whether and, if so, when these pesticides should be subjected to any additional endocrine disruptor testing prior to the next mandated fifteen year registration renewal cycle.

Notwithstanding these disadvantages, the EDSTAC recommends that the priorities EPA has established for the re registration and tolerance reassessment processes be used as the basis for the priorities for subjecting food use pesticides to T2T. When planning for the registration renewal process begins, the FQPA requirement for endocrine disruptor screening and testing should be designated as a criterion for priority setting. EPA's priority scheme for tolerance reassessment and exemption reviews encompasses many pesticides of potential concern for EDSTAC Final Report Chapter Four August 1998 4  78 endocrine disruption. However, it leaves out several hundred non food use active and inert ingredients. These will be addressed using the recommended process for setting priorities for T1S as described above.

XII. Compilation of Chapter Four Recommendations 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: