Use of High Throughput Assays and Computational Tools; Endocrine Disruptor Screening Program; Notice of Availability and Opportunity for Comment, 35350-35355 [2015-15182]

Download as PDF 35350 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices asabaliauskas on DSK5VPTVN1PROD with NOTICES may claim all or part of a response confidential. EPA will disclose information that is covered by a claim of confidentiality only to the extent permitted by, and in accordance with, the procedures in TSCA section 14 and 40 CFR part 2. Burden statement: The annual public reporting and recordkeeping burden for this collection of information is estimated to average 31.5 hours per response. Burden is defined in 5 CFR 1320.3(b). The ICR, which is available in the docket along with other related materials, provides a detailed explanation of the collection activities and the burden estimate that is only briefly summarized here: Respondents/Affected Entities: Entities potentially affected by this ICR are companies that manufacture, process or import chemical substances, mixtures or categories. Estimated total number of potential respondents: 1. Frequency of response: On occasion. Estimated total average number of responses for each respondent: 1. Estimated total annual burden hours: 31.5 hours. Estimated total annual costs: $2,388. This includes an estimated burden cost of $2,388 and an estimated cost of $0 for capital investment or maintenance and operational costs. III. Are There Changes in the Estimates from the Last Approval? There is a decrease of 916 hours in the total estimated respondent burden compared with that identified in the ICR currently approved by OMB. This decrease reflects additional both adjustment changes from a reduction in the assumed number of PAIR reports filed annually, and program changes resulting from mandatory electronic submissions of PAIR reports. In recent years (FY 2011–FY 2014), EPA has received no PAIR submissions and, for the purposes of this analysis, EPA assumes an annual rate of one submission per year. At the time OMB last renewed this ICR, EPA estimated an average of 33 reports from 14.8 submitters based on fiscal year 2006– 2010 data. The ICR supporting statement provides a detailed analysis of the change in burden estimate. This change is both an adjustment and a program change. IV. What is the Next Step in the Process for this ICR? EPA will consider the comments received and amend the ICR as appropriate. The final ICR package will then be submitted to OMB for review VerDate Sep<11>2014 19:33 Jun 18, 2015 Jkt 235001 and approval pursuant to 5 CFR 1320.12. EPA will issue another Federal Register document pursuant to 5 CFR 1320.5(a)(1)(iv) to announce the submission of the ICR to OMB and the opportunity to submit additional comments to OMB. If you have any questions about this ICR or the approval process, please contact the technical person listed under FOR FURTHER INFORMATION CONTACT. Authority: 44 U.S.C. 3501 et seq. Dated: June 10, 2015. James Jones, Assistant Administrator, Office of Chemical Safety and Pollution Prevention. [FR Doc. 2015–14946 Filed 6–18–15; 8:45 am] BILLING CODE 6560–50–P ENVIRONMENTAL PROTECTION AGENCY [EPA–HQ–OPPT–2015–0305; FRL–9928–69] Use of High Throughput Assays and Computational Tools; Endocrine Disruptor Screening Program; Notice of Availability and Opportunity for Comment Environmental Protection Agency (EPA). ACTION: Notice. AGENCY: This document describes how EPA is planning to incorporate an alternative scientific approach to screen chemicals for their ability to interact with the endocrine system. This will improve the Agency’s ability to fulfill its statutory mandate to screen pesticide chemicals and other substances for their ability to cause adverse effects by their interaction with the endocrine system. The approach incorporates validated high throughput assays and a computational model and, based on current research, can serve as an alternative for some of the current assays in the Endocrine Disruptor Screening Program (EDSP) Tier 1 battery. EPA has partial screening results for over 1800 chemicals that have been evaluated using high throughput assays and a computational model for the estrogen receptor pathway. In the future, EPA anticipates that additional alternative methods will be available for EDSP chemical screening based on further advancements of high throughput assays and computational models for other endocrine pathways. Use of these alternative methods will accelerate the pace of screening, decrease costs, and reduce animal testing. In addition, this approach advances the goal of providing sensitive, specific, quantitative, and SUMMARY: PO 00000 Frm 00052 Fmt 4703 Sfmt 4703 efficient screening using alternative test methods to some assays in the Tier 1 battery to protect human health and the environment. DATES: Comments must be received on or before August 18, 2015. ADDRESSES: Submit your comments, identified by docket identification (ID) number EPA–HQ–OPPT–2015–0305, by one of the following methods: • Federal eRulemaking Portal: http:// www.regulations.gov. Follow the online instructions for submitting comments. Do not submit electronically any information you consider to be Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. • Mail: Document Control Office (7407M), Office of Pollution Prevention and Toxics (OPPT), Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460–0001. • Hand Delivery: To make special arrangements for hand delivery or delivery of boxed information, please follow the instructions at http:// www.epa.gov/dockets/contacts.html. Additional instructions on commenting or visiting the docket, along with more information about dockets generally, is available at http:// www.epa.gov/dockets. FOR FURTHER INFORMATION CONTACT: For technical information contact: Jane Robbins, Office of Science Coordination and Policy (OSCP), Office of Chemical Safety and Pollution Prevention, Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460–0001; telephone number: (202) 564–6625; email address: robbins.jane@epa.gov. For general information contact: The TSCA-Hotline, ABVI-Goodwill, 422 South Clinton Ave., Rochester, NY 14620; telephone number: (202) 554– 1404; email address: TSCA-Hotline@ epa.gov. SUPPLEMENTARY INFORMATION: I. General Information A. Does this action apply to me? This action is directed to the public in general, and may be of interest to a wide range of stakeholders including those interested in endocrine testing of chemicals (including pesticides), and the EDSP in general. Since others also may be interested, the Agency has not attempted to describe all the specific entities that may be affected by this action. B. What is the agency authority for taking this action? The EDSP is established under section 408(p) of the Federal Food, Drug and E:\FR\FM\19JNN1.SGM 19JNN1 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices asabaliauskas on DSK5VPTVN1PROD with NOTICES Cosmetic Act (FFDCA), 21 U.S.C. 346a(p). Section 408(p)(1) requires EPA ‘‘to develop a screening program, using appropriate validated test systems and other scientifically relevant information to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other effects as [EPA] may designate.’’ [21 U.S.C. 346a(p)(1)]. Section 408(p)(2) requires that the screening program be implemented ‘‘after obtaining public comment and review . . . by the scientific advisory panel established under section 25(d) of the Federal Insecticide, Fungicide, and Rodenticide Act. . .’’ [21 U.S.C. 346a(p)(2)]. This document describes the new scientific methods that are available as alternatives to some of the current EDSP Tier 1 screening assays and solicits public comment on EPA’s plan to use these alternative approaches to screen chemicals for their ability to interact with the endocrine system. The approach described in this document is not binding on either EPA or any outside parties, and EPA may depart from the approach presented in this document where circumstances warrant and without prior notice. C. What action is the agency taking? This document describes and solicits comments on how EPA is planning to incorporate scientific advancements and tools into the EDSP. The adoption of scientific advancements into the EDSP has been underway and part of the public dialogue about EDSP for several years. As EPA has consistently indicated, the Agency intends to continue to incorporate in the EDSP new methods involving high throughput assays and computational toxicology. Also, EPA has identified a universe of approximately 10,000 chemicals as potential candidates for screening and testing under the EDSP (Ref. 1). This approach is expected to accelerate the pace of screening, add efficiencies, decrease costs, and reduce animal testing. EPA is planning to incorporate the partial screening results from validated high throughput assays and computational models as an alternative to data from some of the current assays in the EDSP Tier 1 screening battery. Currently, EPA has partial screening results for over 1800 chemicals that have been evaluated using the high throughput assays and computational model for the estrogen receptor pathway. The use of high-throughput assays and computational models for EDSP screening is an initial step in EPA’s VerDate Sep<11>2014 19:33 Jun 18, 2015 Jkt 235001 integration of 21st-century integrated assessment and testing approaches broadly, beyond EDSP, across a wide range of chemicals related to regulatory and non-regulatory decisions made in programs under the Agency’s purview (Ref. 2). Much of the knowledge gained in using these approaches for EDSP screening will be useful in applying high throughput assays and computational models to thousands of chemicals across many toxicological endpoints and exposure scenarios. D. What should I consider as I prepare my Comments for EPA? 1. Submitting CBI. Do not submit this information to EPA through regulations.gov or email. Clearly mark the part or all of the information that you claim to be CBI. For CBI information in a disk or CD–ROM that you mail to EPA, mark the outside of the disk or CD–ROM as CBI and then identify electronically within the disk or CD–ROM the specific information that is claimed as CBI. In addition to one complete version of the comment that includes information claimed as CBI, a copy of the comment that does not contain the information claimed as CBI must be submitted for inclusion in the public docket. Information so marked will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. 2. Tips for preparing your comments. When preparing and submitting your comments, see the commenting tips at http://www.epa.gov/dockets/ comments.html. II. Background A. What is the Endocrine Disruptor Screening Program (EDSP)? The Food Quality Protection Act (FQPA) of 1996 amended FFDCA to require EPA ‘‘to develop a screening program, using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other effects as [EPA] may designate’’ (21 U.S.C. 346a(p)(1)). Also in 1996, the Agency chartered the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), under the provisions of the Federal Advisory Committee Act (FACA) (5 U.S.C. App. 2, section 9(c)), to provide advice on developing an endocrine disruptor screening program (Ref. 3). The EDSTAC was comprised of members representing the commercial chemical and pesticides industries, Federal and State agencies, worker PO 00000 Frm 00053 Fmt 4703 Sfmt 4703 35351 protection and labor organizations, environmental and public health groups, and research scientists. EDSTAC recommended that EPA’s program address both potential human and wildlife effects; examine effects on estrogen, androgen, and thyroid hormone-related processes; and include non-pesticide chemicals, contaminants, and mixtures in addition to pesticide chemicals (Ref. 2). In 1998, based on the EDSTAC recommendations, EPA established the EDSP using a two-tiered approach (Ref. 4). The purpose of Tier 1 (referred to as ‘‘screening’’) is to identify substances that have potential biological activity (‘‘bioactivity’’) in the estrogen, androgen, or thyroid hormone pathways using a battery of assays. The purpose of Tier 2 (referred to as ‘‘testing’’) is to identify and establish a dose-response relationship for any adverse effects that might result from the endocrine bioactivity identified through the Tier 1 assays. The ultimate purpose of the EDSP is to provide information to the Agency that will allow the Agency to evaluate any possible endocrine effects associated with the use of a chemical and take appropriate steps to mitigate any related risks to ensure protection of public health. In 2009, the Agency issued test orders requiring Tier 1 screening for 67 chemicals (‘‘List 1’’) (Ref. 5). Between the time needed to review the substantial volume of ‘‘other scientifically relevant information’’ submitted by test order recipients to satisfy selected screening assays, the time and resources of industry spent generating data, the time spent by the Agency reviewing the information, and the delays resulting from the limited laboratory capacity for conducting many of the Tier 1 assays and corresponding time extension requests, the review of the initial List 1 chemicals has taken over four years and has imposed significant burdens on test order recipients and the agency. The Agency is still finalizing the data evaluation records and determinations concerning which of the List 1 chemicals need further Tier 2 testing. More information on the EDSP history and the status of current activities is available at http:// www.epa.gov/endo. B. What is meant by ‘‘high throughput assays and computational model’’? High throughput assays are automated methods that allow for a large number of chemicals to be rapidly evaluated for a specific type of bioactivity at the molecular or cellular level. This approach, which can help identify compounds that may modulate specific E:\FR\FM\19JNN1.SGM 19JNN1 35352 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices asabaliauskas on DSK5VPTVN1PROD with NOTICES biological pathways, was initially developed by pharmaceutical companies for drug discovery. The results of these methods provide an initial understanding of a biochemical interaction or possible role of a chemical in a given biological process. In vitro high throughput assays are usually conducted using a microtiter plate: a plate containing a grid with a large number of small divots called ‘‘wells.’’ The wells contain chemical and/or biological substrate (e.g., living cells or proteins). Depending on the nature of the experiment, changes can be detected (e.g., color, fluorescence, etc.) when the chemical is added to indicate whether there is bioactivity. High throughput microtiter plates typically come in multiples of 96 wells (96, 384, or 1536), so that through the use of robotics, data processing and control software, liquid handling devices, and sensitive detection methods, an extremely large number of chemicals can be evaluated very efficiently. High throughput assays can be run for a range of test chemical concentrations and produce concentration-response information representing the relationship between chemical concentration and bioactivity. The concentration-response data from multiple assays can be mathematically integrated in a computational model of a biological pathway, providing values representative of a chemical’s bioactivity in that pathway (e.g., estrogen receptor pathway). To reduce non-specific results, the computational model can use results from multiple assays and technologies to predict whether a chemical is truly bioactive in the pathway being evaluated. The most prominent cause of non-specific results (activity in an assay that is likely not due to bioactivity of the chemical in the pathways) is cytotoxicity in cell-based assays. In other cases, chemicals influence the assays through a manner dependent on the physics and chemistry of the technology platform (i.e., ‘‘assay interference’’). C. What is ToxCastTM? To improve efficiencies in screening and testing chemicals, EPA scientists are harnessing advances in molecular and systems biology, chemistry, toxicology, mathematics, and computer technology. In doing this, they are helping to revolutionize chemical screening and safety testing based on advances in computational toxicology. A major part of this effort is the Agency’s Toxicity Forecaster, or ToxCastTM, which uses automated, robotics-assisted high throughput assays VerDate Sep<11>2014 19:33 Jun 18, 2015 Jkt 235001 to expose living cells or proteins to chemicals and measure the results. The high throughput assays produce concentration-response information representing the relationship between chemical concentration and bioactivity. These innovative methods have the potential to quickly and efficiently screen large numbers of chemicals and other substances. ToxCastTM is part of EPA’s contribution to a federal research collaboration called ‘‘Toxicity Testing in the 21st Century’’, or ‘‘Tox21,’’ pooling resources and expertise from EPA, the National Institutes of Health and the U.S. Food and Drug Administration to use robotics for screening thousands of chemicals for potential bioactivity (Ref. 6). As part of EPA’s commitment to gather and share its chemical data openly and clearly, all ToxCastTM chemical data are publicly available through user-friendly web applications called the interactive Chemical Safety for Sustainability (iCSS) and EDSP21 dashboards (Refs. 7 and 8). The EDSP21 and iCSS dashboards provide accessible portals for users to search and query the ToxCastTM chemical data. Users can review chemicals and data of interest, as well as export the information. Making ToxCastTM data available through the dashboards creates an environment that encourages external stakeholder interactions identifying potential issues, concerns, and suggesting improvements. D. What is meant by the ToxCastTM ER Model for bioactivity? The ToxCastTM ER Model for bioactivity (‘‘ER Model’’) includes data from 18 estrogen receptor (ER) high throughput assays from ToxCastTM that detect multiple events in the receptor pathway. The ER Model also includes a computational module that integrates the assay data to produce a value for ER agonist and antagonist bioactivity for each chemical (Ref. 9). An ER agonist binds and activates the receptor, and an antagonist binds and blocks activation. These 18 high throughput assays measure bioactivity at different sites along the ER pathway including receptor binding, receptor dimerization, chromatin binding of the mature transcription factor, gene transcription and changes in estrogen-receptor growth kinetics. Bioactivity (i.e., response) is measured using various detection methods (e.g., fluorescence, etc.) across a range of concentrations to examine potential concentration-response relationships, including no change across concentrations indicating no bioactivity. Concentration-response relationships for each assay are mathematically integrated in the ‘‘ER PO 00000 Frm 00054 Fmt 4703 Sfmt 4703 Model’’ to quantify bioactivity from multiple assays. The computational model integrates the results of each of the 18 ER assays as an area under the curve (AUC) for ER agonist or antagonist bioactivity for each chemical. The bioactivity values generally range from 0 to 1 for each chemical, with 0 indicating no bioactivity and 1 approximating the positive reference chemical (e.g., estradiol for ER agonism). In order to validate the ER Model, ToxCastTM data have been collected and reviewed on over 1800 chemicals, including ER reference agonists and antagonists (Ref. 10). ER agonist and antagonist bioactivity scores from the ‘‘ER Model’’ compare very well with reported bioactivity of reference chemicals across a range of structures and potencies. Of the over 1800 chemicals tested, over 1700 chemicals had very low or no detectable ER bioactivity (Ref. 10). The ‘‘ER Model’’ bioactivity scores were validated by comparing the scores to 45 reference chemicals, equivalent to a performancebased approach to validation. EPA also compared ‘‘ER Model’’ results to a database of curated uterotrophic studies published in peer-reviewed literature. ER agonist bioactivity scores accurately predicted in vivo ER agonist activity for a large set (∼150) of chemicals with uterotrophic data (Refs. 9 and 11). The validation of the ‘‘ER Model’’ as an alternative screening method for three current Tier 1 assays (ER binding, ER transcriptional activation (ERTA), and uterotrophic) was peer reviewed by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2014 (Refs. 9 and 11). The FIFRA SAP fully endorsed the use of these alternatives for the ER binding and ERTA assays; however, there was not consensus among panel members on the use of the ‘‘ER Model’’ as an alternative for the uterotrophic assay (Ref. 11). In response to the concerns raised by the FIFRA SAP, EPA has published a paper clarifying the relationship between ‘‘ER Model’’ bioactivity and uterotrophic results, and illustrating that a uterotrophic assay would provide no added value if ‘‘ER Model’’ data are available (Ref. 12). Based on these findings, EPA concludes that ‘‘ER Model’’ data are sufficient to satisfy the Tier 1 ER binding, ERTA and uterotrophic assay requirements. The Agency intends to build on the performance-based validation approach presented at the December 2014 FIFRA SAP expanding this approach to include E:\FR\FM\19JNN1.SGM 19JNN1 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices other key events in the estrogen pathway. asabaliauskas on DSK5VPTVN1PROD with NOTICES III. Using High Throughput Assays and Computational Models for Screening A. How Will ToxCastTM data be used for screening in the EDSP? The ability to screen chemicals rapidly for bioactivity in several endocrine pathways, and reducing the use of animals in testing, have been EDSP goals since 1998, when the program was first adopted (Ref. 4). As previously noted, when the first Tier 1 orders (for List 1 chemicals) were issued in 2009, EPA had not confirmed the reliability and relevance of the ToxCastTM results so that they could be cited as ‘‘other scientifically relevant information’’ to satisfy the Tier 1 ER binding, ERTA, and uterotrophic assays (Ref. 13). However, since that time, EPA has reached a critical juncture, determining that the science has progressed such that reevaluation of EPA’s earlier position is warranted. Based on scientific advances, EPA intends to implement the use of high throughput assays and computational models to evaluate, and to a significant extent, screen chemicals. The in vitro high throughput and computational model alternatives provide an accurate quantitative measure of specific endocrine pathway bioactivity and mechanisms. The current Tier 1 battery includes animal-based assays that do not clearly identify or differentiate pathways and mechanisms. Specifically, the current Tier 1 ER binding, ERTA and uterotrophic assays do not provide both estrogen agonist and antagonist activity and animals are required to conduct the ER binding and uterotrophic assays. EPA is planning to adopt in vitro high throughput assays and computational models for detecting and measuring ER agonist and antagonist bioactivity as an alternative for three current Tier 1 assays: 1) ER binding in vitro assay (Ref. 14); 2) ER transcriptional activation in vitro assay (ERTA) (Ref. 15); and 3) in vivo uterotrophic assay (Refs. 16 and 17). EPA is also planning to accept existing results for chemicals that have been evaluated using the ToxCastTM ‘‘ER Model’’ for bioactivity. The accompanying database contains the ER agonist bioactivity and ER antagonist bioactivity for over 1800 chemicals and identifies those chemicals that are pesticide active ingredients, pesticide inert ingredients, and on EDSP Lists 1 or 2 (Ref. 10). This is a ‘‘living’’ database that will continue to incorporate bioactivity results for chemicals as they become available. This database is available at http://www.epa.gov/endo and in the docket identified for this document in a format that can be easily reviewed and manipulated electronically (Ref. 10). It is important, however, not to equate a determination of a chemical’s bioactivity from the ‘‘ER Model’’ with a determination that a chemical causes endocrine disruption. The World Health Organization (WHO)/ International Programme on Chemical Safety (IPCS) defines endocrine disruption as being caused by ‘‘an exogenous substance or mixture that alters function(s) of the endocrine system . . . and . . .consequently causes adverse health effects in an intact organism or its progeny, or (sub)populations’’ (Ref. 18). Bioactivity is an indicator that a chemical has the potential to alter endocrine function, but (1) whether the chemical actually alters endocrine function and (2) whether that altered function produces an adverse outcome in an intact animal cannot be determined without further testing (i.e., Tier 2 testing). The EDSP has been developed over the past 19 years, and has demonstrated that the current screening process may take upwards of 5 years before a Tier 1 decision is available or Tier 2 test orders are issued. In light of recent advances in high throughput assays and computational models, and advances likely to come in the next two years, it is prudent for the Agency to consider new, rapid screening methods. The availability of additional alternative high throughput assays and computational models in the near term will allow EPA to screen more chemicals in less time, involve fewer animals, and cost less for everyone. Furthermore, reconsideration of the EDSP List 2 chemicals may be appropriate since ‘‘ER Model’’ data are available for many List 2 and other chemicals (Refs. 10 and 19). Ongoing use of high throughput assays and computational models will address thousands of chemicals in the future. These advancements in the EDSP screening program will not affect the Estrogen Receptor (ER) Binding .............................................................. Estrogen Receptor Transactivation (ERTA) ............................................. Uterotrophic .............................................................................................. Female Rat Pubertal ................................................................................ 19:33 Jun 18, 2015 Jkt 235001 PO 00000 Frm 00055 overall framework—i.e., the Tier 1 screening battery and Tier 2 testing approach focused on estrogen, androgen and thyroid pathways in humans and wildlife remains unaffected. Instead, as discussed above, EPA is planning to adopt sensitive, specific, quantitative, and efficient screening methods that will rapidly screen many chemicals and substantially decrease costs and animal use and may be used as an alternative to some EDSP Tier 1 screening assays. Accordingly, EPA intends a future recipient of an EDSP test order to be able to satisfy the screening requirement for ER, ERTA, and uterotrophic in one of three ways: (1) cite existing ToxCastTM ‘‘ER Model’’ for bioactivity data as ‘‘other scientifically relevant information’’ (where available); (2) generate new data relying on the 18 ER high throughput assays and the ToxCastTM ‘‘ER Model’’ for bioactivity; or (3) generate their own data using the current Tier 1 ER binding, ERTA, and uterotrophic assays. B. How Does EPA intend to use high throughput assays and computational models for the EDSP in the future? EPA believes that ongoing adoption of alternative methods and technologies will continue to advance EDSP screening of chemicals for bioactivity in the estrogen, androgen, and thyroid pathways. EPA is continuing research on the ‘‘ER Model’’ to determine if ToxCastTM assays can provide comparable information as that of the Female Rat Pubertal and the Fish Short Term Reproduction assays. In addition, research continues on the ToxCastTM ‘‘AR Model’’ for bioactivity which, if fully validated, may be considered as an alternative (alone or with the ‘‘ER Model’’) for the following current Tier 1 assays: AR binding, Male Rat Pubertal, Hershberger, and Fish Short Term Reproduction. Research is also underway to develop steroidogenesis ToxCastTM (STR) and thyroid (THY) bioactivity models. Over time, the Agency’s goal is to develop a set of ‘‘non-animal’’ high throughput assays and computational bioactivity models as an alternative to all of the assays in the current Tier 1 screening battery. The following table is intended to illustrate the evolution of screening in the EDSP: Alternative high throughput assays and computational model for EDSP Tier 1 battery Current EDSP Tier 1 battery of assays VerDate Sep<11>2014 35353 Fmt 4703 ER Model (alternative). ER Model (alternative). ER Model (alternative). ER, STR , and thyroid (THY) Models (Future). Sfmt 4703 E:\FR\FM\19JNN1.SGM 19JNN1 35354 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices Alternative high throughput assays and computational model for EDSP Tier 1 battery Current EDSP Tier 1 battery of assays Male Rat Pubertal ..................................................................................... Androgen Receptor (AR) Binding ............................................................. Hershberger .............................................................................................. Aromatase ................................................................................................ Steroidogenesis (STR) ............................................................................. Fish Short Term Reproduction ................................................................. Amphibian Metamorphosis ....................................................................... The table indicates combinations of various alternative assays and models that might overlap for evaluating potential endocrine bioactivity of chemicals. The in vitro high throughput and computational model alternatives provide a focused evaluation of the mechanistic aspects of endocrine pathways, thereby providing specific and quantitative measures of bioactivity. Several assays in the Tier 1 battery rely on intact animals and identify bioactivity in the multiple biological pathways present. For this reason, the specificity of the in vitro high throughput and computational model alternatives may be more informative of specific endocrine pathway bioactivity. The annual EDSP Comprehensive Management Plan and future FIFRA SAP meetings are opportunities for staying informed on EPA’s scientific progress on the evolution of Tier 1 screening in the EDSP. For information, visit EPA’s Web site (http:// www.epa.gov/endo) or sign-up to receive announcements go to (http:// www.epa.gov/endo/pubs/ assayvalidation/listserv.htm). asabaliauskas on DSK5VPTVN1PROD with NOTICES IV. Issues for Comment In connection with EPA’s stated intention to use the scientific tools discussed in this Notice as alternatives to some of the current EDSP Tier 1 screening assays, EPA is specifically seeking public comment on the following: 1. The use of the ToxCastTM ‘‘ER Model’’ for bioactivity as an alternative method for the current ER binding and ERTA Tier 1 screening assays. 2. The use of the ToxCastTM ‘‘ER Model’’ for bioactivity as an alternative method for the current uterotrophic Tier 1 screening assay. 3. The use of results from the ToxCastTM ‘‘ER Model’’ for bioactivity on over 1800 chemicals as partial screening for the estrogen receptor pathway. V. References The following is a listing of the documents that are specifically referenced in this document. The docket includes these documents and other VerDate Sep<11>2014 19:33 Jun 18, 2015 Jkt 235001 AR, STR, and THY Models (Future). AR Model (Future). AR Model (Future). STR Model (Future). STR Model (Future). ER, AR, and STR Models (Future). THY Model (Future). information considered by EPA, including documents that are referenced within the documents that are included in the docket, even if the referenced document is not physically located in the docket. For assistance in locating these other documents, please consult the technical person listed under FOR FURTHER INFORMATION CONTACT. 1. U.S. EPA. Endocrine Disruptor Screening Program; Universe of Chemicals and General Validation Principles. November 2012. Available at http://www.epa.gov/ endo/pubs/edsp_chemical_universe_ and_general_validations_white_paper_ 11_12.pdf. 2. U.S. EPA. Endocrine Disruptor Screening Program for the 21st Century: (EDSP21 Work Plan); The Incorporation of In Silico Models and In Vitro High Throughput Assays in the Endocrine Disruptor Screening Program (EDSP) for Prioritization and Screening; Summary Overview. A Part of the EDSP Comprehensive Management Plan. September 30, 2011. Available at http:// www.epa.gov/endo/pubs/edsp21_work_ plan_summary%20_overview_final.pdf. 3. U.S. EPA. Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC); Final Report. August 1998. Available at http://www.epa.gov/endo/ pubs/edspoverview/finalrpt.htm. 4. U.S. EPA. Endocrine Disruptor Screening Program; Proposed Statement of Policy; Notice. Federal Register (63 FR 71542, December 28, 1998) (FRL–6052–9). 5. U.S. EPA. Endocrine Disruptor Screening Program; Tier 1 Screening Order Issuance Announcement; Notice. Federal Register (74 FR 54422, October 21, 2009) (FRL–8434–8). 6. U.S. EPA. Office of Research and Development (ORD); Description of Computational Toxicology Research Program. Available at http://epa.gov/ ncct. 7. U.S. EPA. Interactive Chemical Safety for Sustainability (iCSS) Dashboard, Version 0.5. Available at http://actor.epa.gov/ dashboard. 8. U.S. EPA. EDSP21 Dashboard. Available at http://actor.epa.gov/edsp21. 9. U.S. EPA. Integrated Bioactivity and Exposure Ranking: A Computational Approach for the Prioritization and Screening of Chemicals in the Endocrine Disruptor Screening Program. December 2014. Docket ID No. EPA–HQ–OPP– 2014–0614–0003. Available at http:// www.regulations.gov/ #!documentDetail;D=EPA–HQ–OPP– PO 00000 Frm 00056 Fmt 4703 Sfmt 4703 2014–0614–0003. 10. U.S. EPA. Endocrine Disruptor Screening Program (EDSP); Estrogen Receptor Bioactivity Based on ToxCa TM ‘‘ER Model.’’ June 1, 2015. Available at http:// www.epa.gov/endo. 11. U.S. EPA. FIFRA SAP Minutes No. 2015– 01. FIFRA SAP Meeting on the Integrated Bioactivity and Exposure-Based Prioritization and Screening, held December 2–4, 2014. Docket ID No. EPA–HQ–OPP–2014–0614–0029. March 2, 2015. Available at http:// www.epa.gov/scipoly/sap/meetings/ 2014/december/120214minutes.pdf. 12. Browne, P., Judson, R.S., Casey, W., Kleinstreuer, N., Thomas, R.S. Screening Chemicals For Estrogen Receptor Bioactivity Using A Computational Model. Manuscript accepted for publication. Environ. Sci. Technol. June 12, 2015. Available in the docket and electronically at http://pubs.acs.org/ journal/esthag. 13. U.S. EPA. Endocrine Disruptor Screening Program; Policies and Procedures for Initial Screening; Notice. Federal Register (74 FR 17560, April 15, 2009) (FRL–8399–9). Note: the status and progress of all List 1 Tier 1 orders are available at http://www.epa.gov/endo/ pubs/toresources/index.htm. 14. U.S. EPA. Endocrine Disruptor Screening Program Test Guidelines; OPPTS 890.1250: Estrogen Receptor Binding Assay Using Rat Uterine Cytosol (ER– RUC). October 2009. EPA 740–C–09–005. Available at http://www.epa.gov/ocspp/ pubs/frs/publications/Test_Guidelines/ series890.htm. 15.U.S.EPA. Endocrine Disruptor Screening Program Test Guidelines; OPPTS 890.1300: Estrogen Receptor Transcriptional Activation (Human Cell Line (HeLa-9903)). October 2009. EPA 740–C–09–006. Available at http:// www.epa.gov/ocspp/pubs/frs/ publications/Test_Guidelines/ series890.htm. 16.U.S.EPA. Endocrine Disruptor Screening Program Test Guidelines; OPPTS 890.1600: Uterotrophic Assay. October 2009. EPA 740–C–09–0010. Available at http://www.epa.gov/ocspp/pubs/frs/ publications/Test_Guidelines/ series890.htm. 17. Organization of Economic Co-operation and Development (OECD). Test Guideline No. 440:Uterotrophic Bioassay in Rodents: A short-term screening test for oestrogenic properties. OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. DOI: http://dx.doi.org/10.1787/ E:\FR\FM\19JNN1.SGM 19JNN1 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices 9789264067417-en. 18. World Health Organization (WHO)/ International Programme on Chemical Safety (IPCS). Global Assessment of the State-of-the-Science of Endocrine Disruptors. WHO/IPCS/EDC/02.2. 2002. Available at http://www.who.int/ipcs/ publications/new_issues/endocrine_ disruptors/en. 19. U.S. EPA. Endocrine Disruptor Screening Program; Final Second List of Chemicals and Substances for Tier 1 Screening; Notice. Federal Register (78 FR 35922, June 14, 2013) (FRL–9375–8). Available at http://www.gpo.gov/fdsys/pkg/FR– 2013–06–14/pdf/2013–14232.pdf. Authority: 21 U.S.C. 346a(p). Dated: June 11, 2015. James J. Jones, Assistant Administrator, Office of Chemical Safety and Pollution Prevention. [FR Doc. 2015–15182 Filed 6–18–15; 8:45 am] BILLING CODE 6560–50–P ENVIRONMENTAL PROTECTION AGENCY [EPA–HQ–SFUND–2006–0361; FRL—9929– 32–OSWER] Proposed Information Collection Request; Comment Request; Trade Secret Claim Submissions under the Emergency Planning and Community Right-to-Know Act. Environmental Protection Agency (EPA). ACTION: Notice. AGENCY: The Environmental Protection Agency (EPA) is planning to submit an information collection request (ICR), ‘‘Trade Secret Claims Submitted under the Emergency Planning and Community Right-to-Know Act.’’ (EPA ICR No. 1428.10, OMB Control No. 2050–0078) to the Office of Management and Budget (OMB) for review and approval in accordance with the Paperwork Reduction Act. Before doing so, EPA is soliciting public comments on specific aspects of the proposed information collection as described below. This is a proposed extension of the ICR, which is currently approved through December 31, 2015. An Agency may not conduct or sponsor and a person is not required to respond to a collection of information unless it displays a currently valid OMB control number. DATES: Comments must be submitted on or before August 18, 2015. ADDRESSES: Submit your comments, referencing Docket ID No. EPA–HQ– SFUND–2006–0361, online using www.regulations.gov (our preferred method), by email to asabaliauskas on DSK5VPTVN1PROD with NOTICES SUMMARY: VerDate Sep<11>2014 19:33 Jun 18, 2015 Jkt 235001 superfund.docket@epa.gov, or by mail to: EPA Docket Center, Environmental Protection Agency, Mail Code 28221T, 1200 Pennsylvania Ave. NW., Washington, DC 20460. EPA’s policy is that all comments received will be included in the public docket without change including any personal information provided, unless the comment includes profanity, threats, information claimed to be Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. FOR FURTHER INFORMATION CONTACT: Sicy Jacob, Office of Emergency Management, Mail Code 5104A, Environmental Protection Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460; telephone number: (202) 564–8019; fax number: (202) 564–2620; email address: jacob.sicy@epa.gov. SUPPLEMENTARY INFORMATION: Supporting documents which explain in detail the information that the EPA will be collecting are available in the public docket for this ICR. The docket can be viewed online at www.regulations.gov or in person at the EPA Docket Center, WJC West, Room 3334, 1301 Constitution Ave. NW., Washington, DC. The telephone number for the Docket Center is 202–566–1744. For additional information about EPA’s public docket, visit http://www.epa.gov/ dockets. Pursuant to section 3506(c)(2)(A) of the PRA, EPA is soliciting comments and information to enable it to: (i) evaluate whether the proposed collection of information is necessary for the proper performance of the functions of the Agency, including whether the information will have practical utility; (ii) evaluate the accuracy of the Agency’s estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (iii) enhance the quality, utility, and clarity of the information to be collected; and (iv) minimize the burden of the collection of information on those who are to respond, including through the use of appropriate automated electronic, mechanical, or other technological collection techniques or other forms of information technology, e.g., permitting electronic submission of responses. EPA will consider the comments received and amend the ICR as appropriate. The final ICR package will then be submitted to OMB for review and approval. At that time, EPA will issue another Federal Register notice to announce the submission of the ICR to OMB and the opportunity to submit additional comments to OMB. PO 00000 Frm 00057 Fmt 4703 Sfmt 4703 35355 Abstract: This information collection request pertains to trade secrecy claims submitted under Section 322 of the Emergency Planning and Community Right-to-Know Act of 1986 (EPCRA). EPCRA contains provisions requiring facilities to report to State and local authorities, and EPA, the presence of extremely hazardous substances (Section 302), inventory of hazardous chemicals (Sections 311 and 312) and manufacture, process and use of toxic chemicals (Section 313). Section 322 of EPCRA allows a facility to withhold the specific chemical identity from these EPCRA reports if the facility asserts a claim of trade secrecy for that chemical identity. The provisions in Section 322 establish the requirements and procedures that facilities must follow to request trade secrecy treatment of chemical identities, as well as the procedures for submitting public petitions to the Agency for review of the ‘‘sufficiency’’ of trade secrecy claims. Trade secrecy protection is provided for specific chemical identities contained in reports submitted under each of the following: (1) Section 303 (d)(2)- Facility notification of changes that have or are about to occur, (2) Section 303 (d)(3)—Local Emergency Planning Committee (LEPC) requests for facility information to develop or implement emergency plans, (3) Section 311—Material Safety Data Sheets (MSDSs) submitted by facilities, or lists of those chemicals submitted in place of the MSDSs, (4) Section 312—Emergency and hazardous chemical inventory forms (Tier I and Tier II), and (5) Section 313 Toxic chemical release inventory form. Form Number: EPA Form 9510–1. Respondents/affected entities: Entities potentially affected by this action are manufacturers or non-manufacturers subject to reporting under Sections 303, 311/312 or 313 of the Emergency Planning and Community Right-toKnow Act (EPCRA). Respondent’s obligation to respond: Mandatory if the respondents would like to claim the chemical identity for any of the chemicals as trade secret in any of the reports required to be submitted under EPCRA. Estimated number of respondents: 332 (total). Frequency of response: Annual for claims submitted under EPCRA Sections 312 and 313. Total estimated burden: 3,154 hours (per year). Burden is defined at 5 CFR 1320.03(b). Total estimated cost: $206,155 (per year). No capital and operation and E:\FR\FM\19JNN1.SGM 19JNN1

Agencies

[Federal Register Volume 80, Number 118 (Friday, June 19, 2015)]
[Notices]
[Pages 35350-35355]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-15182]


-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPPT-2015-0305; FRL-9928-69]


Use of High Throughput Assays and Computational Tools; Endocrine 
Disruptor Screening Program; Notice of Availability and Opportunity for 
Comment

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: This document describes how EPA is planning to incorporate an 
alternative scientific approach to screen chemicals for their ability 
to interact with the endocrine system. This will improve the Agency's 
ability to fulfill its statutory mandate to screen pesticide chemicals 
and other substances for their ability to cause adverse effects by 
their interaction with the endocrine system. The approach incorporates 
validated high throughput assays and a computational model and, based 
on current research, can serve as an alternative for some of the 
current assays in the Endocrine Disruptor Screening Program (EDSP) Tier 
1 battery. EPA has partial screening results for over 1800 chemicals 
that have been evaluated using high throughput assays and a 
computational model for the estrogen receptor pathway. In the future, 
EPA anticipates that additional alternative methods will be available 
for EDSP chemical screening based on further advancements of high 
throughput assays and computational models for other endocrine 
pathways. Use of these alternative methods will accelerate the pace of 
screening, decrease costs, and reduce animal testing. In addition, this 
approach advances the goal of providing sensitive, specific, 
quantitative, and efficient screening using alternative test methods to 
some assays in the Tier 1 battery to protect human health and the 
environment.

DATES: Comments must be received on or before August 18, 2015.

ADDRESSES: Submit your comments, identified by docket identification 
(ID) number EPA-HQ-OPPT-2015-0305, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the online instructions for submitting comments. Do not submit 
electronically any information you consider to be Confidential Business 
Information (CBI) or other information whose disclosure is restricted 
by statute.
     Mail: Document Control Office (7407M), Office of Pollution 
Prevention and Toxics (OPPT), Environmental Protection Agency, 1200 
Pennsylvania Ave. NW., Washington, DC 20460-0001.
     Hand Delivery: To make special arrangements for hand 
delivery or delivery of boxed information, please follow the 
instructions at http://www.epa.gov/dockets/contacts.html.
    Additional instructions on commenting or visiting the docket, along 
with more information about dockets generally, is available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: For technical information contact: 
Jane Robbins, Office of Science Coordination and Policy (OSCP), Office 
of Chemical Safety and Pollution Prevention, Environmental Protection 
Agency, 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; 
telephone number: (202) 564-6625; email address: robbins.jane@epa.gov.
    For general information contact: The TSCA-Hotline, ABVI-Goodwill, 
422 South Clinton Ave., Rochester, NY 14620; telephone number: (202) 
554-1404; email address: TSCA-Hotline@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    This action is directed to the public in general, and may be of 
interest to a wide range of stakeholders including those interested in 
endocrine testing of chemicals (including pesticides), and the EDSP in 
general. Since others also may be interested, the Agency has not 
attempted to describe all the specific entities that may be affected by 
this action.

B. What is the agency authority for taking this action?

    The EDSP is established under section 408(p) of the Federal Food, 
Drug and

[[Page 35351]]

Cosmetic Act (FFDCA), 21 U.S.C. 346a(p). Section 408(p)(1) requires EPA 
``to develop a screening program, using appropriate validated test 
systems and other scientifically relevant information to determine 
whether certain substances may have an effect in humans that is similar 
to an effect produced by a naturally occurring estrogen, or such other 
effects as [EPA] may designate.'' [21 U.S.C. 346a(p)(1)]. Section 
408(p)(2) requires that the screening program be implemented ``after 
obtaining public comment and review . . . by the scientific advisory 
panel established under section 25(d) of the Federal Insecticide, 
Fungicide, and Rodenticide Act. . .'' [21 U.S.C. 346a(p)(2)].
    This document describes the new scientific methods that are 
available as alternatives to some of the current EDSP Tier 1 screening 
assays and solicits public comment on EPA's plan to use these 
alternative approaches to screen chemicals for their ability to 
interact with the endocrine system. The approach described in this 
document is not binding on either EPA or any outside parties, and EPA 
may depart from the approach presented in this document where 
circumstances warrant and without prior notice.

C. What action is the agency taking?

    This document describes and solicits comments on how EPA is 
planning to incorporate scientific advancements and tools into the 
EDSP. The adoption of scientific advancements into the EDSP has been 
underway and part of the public dialogue about EDSP for several years. 
As EPA has consistently indicated, the Agency intends to continue to 
incorporate in the EDSP new methods involving high throughput assays 
and computational toxicology. Also, EPA has identified a universe of 
approximately 10,000 chemicals as potential candidates for screening 
and testing under the EDSP (Ref. 1). This approach is expected to 
accelerate the pace of screening, add efficiencies, decrease costs, and 
reduce animal testing.
    EPA is planning to incorporate the partial screening results from 
validated high throughput assays and computational models as an 
alternative to data from some of the current assays in the EDSP Tier 1 
screening battery. Currently, EPA has partial screening results for 
over 1800 chemicals that have been evaluated using the high throughput 
assays and computational model for the estrogen receptor pathway.
    The use of high-throughput assays and computational models for EDSP 
screening is an initial step in EPA's integration of 21st-century 
integrated assessment and testing approaches broadly, beyond EDSP, 
across a wide range of chemicals related to regulatory and non-
regulatory decisions made in programs under the Agency's purview (Ref. 
2). Much of the knowledge gained in using these approaches for EDSP 
screening will be useful in applying high throughput assays and 
computational models to thousands of chemicals across many 
toxicological endpoints and exposure scenarios.

D. What should I consider as I prepare my Comments for EPA?

    1. Submitting CBI. Do not submit this information to EPA through 
regulations.gov or email. Clearly mark the part or all of the 
information that you claim to be CBI. For CBI information in a disk or 
CD-ROM that you mail to EPA, mark the outside of the disk or CD-ROM as 
CBI and then identify electronically within the disk or CD-ROM the 
specific information that is claimed as CBI. In addition to one 
complete version of the comment that includes information claimed as 
CBI, a copy of the comment that does not contain the information 
claimed as CBI must be submitted for inclusion in the public docket. 
Information so marked will not be disclosed except in accordance with 
procedures set forth in 40 CFR part 2.
    2. Tips for preparing your comments. When preparing and submitting 
your comments, see the commenting tips at http://www.epa.gov/dockets/comments.html.

II. Background

A. What is the Endocrine Disruptor Screening Program (EDSP)?

    The Food Quality Protection Act (FQPA) of 1996 amended FFDCA to 
require EPA ``to develop a screening program, using appropriate 
validated test systems and other scientifically relevant information, 
to determine whether certain substances may have an effect in humans 
that is similar to an effect produced by a naturally occurring 
estrogen, or such other effects as [EPA] may designate'' (21 U.S.C. 
346a(p)(1)). Also in 1996, the Agency chartered the Endocrine Disruptor 
Screening and Testing Advisory Committee (EDSTAC), under the provisions 
of the Federal Advisory Committee Act (FACA) (5 U.S.C. App. 2, section 
9(c)), to provide advice on developing an endocrine disruptor screening 
program (Ref. 3). The EDSTAC was comprised of members representing the 
commercial chemical and pesticides industries, Federal and State 
agencies, worker protection and labor organizations, environmental and 
public health groups, and research scientists. EDSTAC recommended that 
EPA's program address both potential human and wildlife effects; 
examine effects on estrogen, androgen, and thyroid hormone-related 
processes; and include non-pesticide chemicals, contaminants, and 
mixtures in addition to pesticide chemicals (Ref. 2).
    In 1998, based on the EDSTAC recommendations, EPA established the 
EDSP using a two-tiered approach (Ref. 4). The purpose of Tier 1 
(referred to as ``screening'') is to identify substances that have 
potential biological activity (``bioactivity'') in the estrogen, 
androgen, or thyroid hormone pathways using a battery of assays. The 
purpose of Tier 2 (referred to as ``testing'') is to identify and 
establish a dose-response relationship for any adverse effects that 
might result from the endocrine bioactivity identified through the Tier 
1 assays. The ultimate purpose of the EDSP is to provide information to 
the Agency that will allow the Agency to evaluate any possible 
endocrine effects associated with the use of a chemical and take 
appropriate steps to mitigate any related risks to ensure protection of 
public health.
    In 2009, the Agency issued test orders requiring Tier 1 screening 
for 67 chemicals (``List 1'') (Ref. 5). Between the time needed to 
review the substantial volume of ``other scientifically relevant 
information'' submitted by test order recipients to satisfy selected 
screening assays, the time and resources of industry spent generating 
data, the time spent by the Agency reviewing the information, and the 
delays resulting from the limited laboratory capacity for conducting 
many of the Tier 1 assays and corresponding time extension requests, 
the review of the initial List 1 chemicals has taken over four years 
and has imposed significant burdens on test order recipients and the 
agency. The Agency is still finalizing the data evaluation records and 
determinations concerning which of the List 1 chemicals need further 
Tier 2 testing. More information on the EDSP history and the status of 
current activities is available at http://www.epa.gov/endo.

B. What is meant by ``high throughput assays and computational model''?

    High throughput assays are automated methods that allow for a large 
number of chemicals to be rapidly evaluated for a specific type of 
bioactivity at the molecular or cellular level. This approach, which 
can help identify compounds that may modulate specific

[[Page 35352]]

biological pathways, was initially developed by pharmaceutical 
companies for drug discovery. The results of these methods provide an 
initial understanding of a biochemical interaction or possible role of 
a chemical in a given biological process. In vitro high throughput 
assays are usually conducted using a microtiter plate: a plate 
containing a grid with a large number of small divots called ``wells.'' 
The wells contain chemical and/or biological substrate (e.g., living 
cells or proteins). Depending on the nature of the experiment, changes 
can be detected (e.g., color, fluorescence, etc.) when the chemical is 
added to indicate whether there is bioactivity. High throughput 
microtiter plates typically come in multiples of 96 wells (96, 384, or 
1536), so that through the use of robotics, data processing and control 
software, liquid handling devices, and sensitive detection methods, an 
extremely large number of chemicals can be evaluated very efficiently.
    High throughput assays can be run for a range of test chemical 
concentrations and produce concentration-response information 
representing the relationship between chemical concentration and 
bioactivity. The concentration-response data from multiple assays can 
be mathematically integrated in a computational model of a biological 
pathway, providing values representative of a chemical's bioactivity in 
that pathway (e.g., estrogen receptor pathway). To reduce non-specific 
results, the computational model can use results from multiple assays 
and technologies to predict whether a chemical is truly bioactive in 
the pathway being evaluated. The most prominent cause of non-specific 
results (activity in an assay that is likely not due to bioactivity of 
the chemical in the pathways) is cytotoxicity in cell-based assays. In 
other cases, chemicals influence the assays through a manner dependent 
on the physics and chemistry of the technology platform (i.e., ``assay 
interference'').

C. What is ToxCast\TM\?

    To improve efficiencies in screening and testing chemicals, EPA 
scientists are harnessing advances in molecular and systems biology, 
chemistry, toxicology, mathematics, and computer technology. In doing 
this, they are helping to revolutionize chemical screening and safety 
testing based on advances in computational toxicology. A major part of 
this effort is the Agency's Toxicity Forecaster, or ToxCast\TM\, which 
uses automated, robotics-assisted high throughput assays to expose 
living cells or proteins to chemicals and measure the results. The high 
throughput assays produce concentration-response information 
representing the relationship between chemical concentration and 
bioactivity. These innovative methods have the potential to quickly and 
efficiently screen large numbers of chemicals and other substances. 
ToxCast\TM\ is part of EPA's contribution to a federal research 
collaboration called ``Toxicity Testing in the 21st Century'', or 
``Tox21,'' pooling resources and expertise from EPA, the National 
Institutes of Health and the U.S. Food and Drug Administration to use 
robotics for screening thousands of chemicals for potential bioactivity 
(Ref. 6).
    As part of EPA's commitment to gather and share its chemical data 
openly and clearly, all ToxCast\TM\ chemical data are publicly 
available through user-friendly web applications called the interactive 
Chemical Safety for Sustainability (iCSS) and EDSP21 dashboards (Refs. 
7 and 8). The EDSP21 and iCSS dashboards provide accessible portals for 
users to search and query the ToxCast\TM\ chemical data. Users can 
review chemicals and data of interest, as well as export the 
information. Making ToxCast\TM\ data available through the dashboards 
creates an environment that encourages external stakeholder 
interactions identifying potential issues, concerns, and suggesting 
improvements.

D. What is meant by the ToxCast\TM\ ER Model for bioactivity?

    The ToxCast\TM\ ER Model for bioactivity (``ER Model'') includes 
data from 18 estrogen receptor (ER) high throughput assays from 
ToxCast\TM\ that detect multiple events in the receptor pathway. The ER 
Model also includes a computational module that integrates the assay 
data to produce a value for ER agonist and antagonist bioactivity for 
each chemical (Ref. 9). An ER agonist binds and activates the receptor, 
and an antagonist binds and blocks activation. These 18 high throughput 
assays measure bioactivity at different sites along the ER pathway 
including receptor binding, receptor dimerization, chromatin binding of 
the mature transcription factor, gene transcription and changes in 
estrogen-receptor growth kinetics. Bioactivity (i.e., response) is 
measured using various detection methods (e.g., fluorescence, etc.) 
across a range of concentrations to examine potential concentration-
response relationships, including no change across concentrations 
indicating no bioactivity. Concentration-response relationships for 
each assay are mathematically integrated in the ``ER Model'' to 
quantify bioactivity from multiple assays. The computational model 
integrates the results of each of the 18 ER assays as an area under the 
curve (AUC) for ER agonist or antagonist bioactivity for each chemical. 
The bioactivity values generally range from 0 to 1 for each chemical, 
with 0 indicating no bioactivity and 1 approximating the positive 
reference chemical (e.g., estradiol for ER agonism).
    In order to validate the ER Model, ToxCast\TM\ data have been 
collected and reviewed on over 1800 chemicals, including ER reference 
agonists and antagonists (Ref. 10). ER agonist and antagonist 
bioactivity scores from the ``ER Model'' compare very well with 
reported bioactivity of reference chemicals across a range of 
structures and potencies. Of the over 1800 chemicals tested, over 1700 
chemicals had very low or no detectable ER bioactivity (Ref. 10). The 
``ER Model'' bioactivity scores were validated by comparing the scores 
to 45 reference chemicals, equivalent to a performance-based approach 
to validation. EPA also compared ``ER Model'' results to a database of 
curated uterotrophic studies published in peer-reviewed literature. ER 
agonist bioactivity scores accurately predicted in vivo ER agonist 
activity for a large set (~150) of chemicals with uterotrophic data 
(Refs. 9 and 11). The validation of the ``ER Model'' as an alternative 
screening method for three current Tier 1 assays (ER binding, ER 
transcriptional activation (ERTA), and uterotrophic) was peer reviewed 
by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 
Scientific Advisory Panel (SAP) in December 2014 (Refs. 9 and 11). The 
FIFRA SAP fully endorsed the use of these alternatives for the ER 
binding and ERTA assays; however, there was not consensus among panel 
members on the use of the ``ER Model'' as an alternative for the 
uterotrophic assay (Ref. 11). In response to the concerns raised by the 
FIFRA SAP, EPA has published a paper clarifying the relationship 
between ``ER Model'' bioactivity and uterotrophic results, and 
illustrating that a uterotrophic assay would provide no added value if 
``ER Model'' data are available (Ref. 12). Based on these findings, EPA 
concludes that ``ER Model'' data are sufficient to satisfy the Tier 1 
ER binding, ERTA and uterotrophic assay requirements. The Agency 
intends to build on the performance-based validation approach presented 
at the December 2014 FIFRA SAP expanding this approach to include

[[Page 35353]]

other key events in the estrogen pathway.

III. Using High Throughput Assays and Computational Models for 
Screening

A. How Will ToxCast\TM\ data be used for screening in the EDSP?

    The ability to screen chemicals rapidly for bioactivity in several 
endocrine pathways, and reducing the use of animals in testing, have 
been EDSP goals since 1998, when the program was first adopted (Ref. 
4). As previously noted, when the first Tier 1 orders (for List 1 
chemicals) were issued in 2009, EPA had not confirmed the reliability 
and relevance of the ToxCast\TM\ results so that they could be cited as 
``other scientifically relevant information'' to satisfy the Tier 1 ER 
binding, ERTA, and uterotrophic assays (Ref. 13). However, since that 
time, EPA has reached a critical juncture, determining that the science 
has progressed such that reevaluation of EPA's earlier position is 
warranted. Based on scientific advances, EPA intends to implement the 
use of high throughput assays and computational models to evaluate, and 
to a significant extent, screen chemicals. The in vitro high throughput 
and computational model alternatives provide an accurate quantitative 
measure of specific endocrine pathway bioactivity and mechanisms. The 
current Tier 1 battery includes animal-based assays that do not clearly 
identify or differentiate pathways and mechanisms. Specifically, the 
current Tier 1 ER binding, ERTA and uterotrophic assays do not provide 
both estrogen agonist and antagonist activity and animals are required 
to conduct the ER binding and uterotrophic assays.
    EPA is planning to adopt in vitro high throughput assays and 
computational models for detecting and measuring ER agonist and 
antagonist bioactivity as an alternative for three current Tier 1 
assays: 1) ER binding in vitro assay (Ref. 14); 2) ER transcriptional 
activation in vitro assay (ERTA) (Ref. 15); and 3) in vivo uterotrophic 
assay (Refs. 16 and 17). EPA is also planning to accept existing 
results for chemicals that have been evaluated using the ToxCast\TM\ 
``ER Model'' for bioactivity. The accompanying database contains the ER 
agonist bioactivity and ER antagonist bioactivity for over 1800 
chemicals and identifies those chemicals that are pesticide active 
ingredients, pesticide inert ingredients, and on EDSP Lists 1 or 2 
(Ref. 10). This is a ``living'' database that will continue to 
incorporate bioactivity results for chemicals as they become available. 
This database is available at http://www.epa.gov/endo and in the docket 
identified for this document in a format that can be easily reviewed 
and manipulated electronically (Ref. 10). It is important, however, not 
to equate a determination of a chemical's bioactivity from the ``ER 
Model'' with a determination that a chemical causes endocrine 
disruption. The World Health Organization (WHO)/International Programme 
on Chemical Safety (IPCS) defines endocrine disruption as being caused 
by ``an exogenous substance or mixture that alters function(s) of the 
endocrine system . . . and . . .consequently causes adverse health 
effects in an intact organism or its progeny, or (sub)populations'' 
(Ref. 18). Bioactivity is an indicator that a chemical has the 
potential to alter endocrine function, but (1) whether the chemical 
actually alters endocrine function and (2) whether that altered 
function produces an adverse outcome in an intact animal cannot be 
determined without further testing (i.e., Tier 2 testing).
    The EDSP has been developed over the past 19 years, and has 
demonstrated that the current screening process may take upwards of 5 
years before a Tier 1 decision is available or Tier 2 test orders are 
issued. In light of recent advances in high throughput assays and 
computational models, and advances likely to come in the next two 
years, it is prudent for the Agency to consider new, rapid screening 
methods. The availability of additional alternative high throughput 
assays and computational models in the near term will allow EPA to 
screen more chemicals in less time, involve fewer animals, and cost 
less for everyone. Furthermore, reconsideration of the EDSP List 2 
chemicals may be appropriate since ``ER Model'' data are available for 
many List 2 and other chemicals (Refs. 10 and 19). Ongoing use of high 
throughput assays and computational models will address thousands of 
chemicals in the future.
    These advancements in the EDSP screening program will not affect 
the overall framework--i.e., the Tier 1 screening battery and Tier 2 
testing approach focused on estrogen, androgen and thyroid pathways in 
humans and wildlife remains unaffected. Instead, as discussed above, 
EPA is planning to adopt sensitive, specific, quantitative, and 
efficient screening methods that will rapidly screen many chemicals and 
substantially decrease costs and animal use and may be used as an 
alternative to some EDSP Tier 1 screening assays. Accordingly, EPA 
intends a future recipient of an EDSP test order to be able to satisfy 
the screening requirement for ER, ERTA, and uterotrophic in one of 
three ways: (1) cite existing ToxCast\TM\ ``ER Model'' for bioactivity 
data as ``other scientifically relevant information'' (where 
available); (2) generate new data relying on the 18 ER high throughput 
assays and the ToxCast\TM\ ``ER Model'' for bioactivity; or (3) 
generate their own data using the current Tier 1 ER binding, ERTA, and 
uterotrophic assays.

B. How Does EPA intend to use high throughput assays and computational 
models for the EDSP in the future?

    EPA believes that ongoing adoption of alternative methods and 
technologies will continue to advance EDSP screening of chemicals for 
bioactivity in the estrogen, androgen, and thyroid pathways. EPA is 
continuing research on the ``ER Model'' to determine if ToxCast\TM\ 
assays can provide comparable information as that of the Female Rat 
Pubertal and the Fish Short Term Reproduction assays. In addition, 
research continues on the ToxCast\TM\ ``AR Model'' for bioactivity 
which, if fully validated, may be considered as an alternative (alone 
or with the ``ER Model'') for the following current Tier 1 assays: AR 
binding, Male Rat Pubertal, Hershberger, and Fish Short Term 
Reproduction. Research is also underway to develop steroidogenesis 
ToxCast\TM\ (STR) and thyroid (THY) bioactivity models. Over time, the 
Agency's goal is to develop a set of ``non-animal'' high throughput 
assays and computational bioactivity models as an alternative to all of 
the assays in the current Tier 1 screening battery. The following table 
is intended to illustrate the evolution of screening in the EDSP:

------------------------------------------------------------------------
                                           Alternative high throughput
 Current EDSP Tier 1 battery of assays    assays and computational model
                                             for EDSP Tier 1 battery
------------------------------------------------------------------------
Estrogen Receptor (ER) Binding.........  ER Model (alternative).
Estrogen Receptor Transactivation        ER Model (alternative).
 (ERTA).
Uterotrophic...........................  ER Model (alternative).
Female Rat Pubertal....................  ER, STR , and thyroid (THY)
                                          Models (Future).

[[Page 35354]]

 
Male Rat Pubertal......................  AR, STR, and THY Models
                                          (Future).
Androgen Receptor (AR) Binding.........  AR Model (Future).
Hershberger............................  AR Model (Future).
Aromatase..............................  STR Model (Future).
Steroidogenesis (STR)..................  STR Model (Future).
Fish Short Term Reproduction...........  ER, AR, and STR Models
                                          (Future).
Amphibian Metamorphosis................  THY Model (Future).
------------------------------------------------------------------------

    The table indicates combinations of various alternative assays and 
models that might overlap for evaluating potential endocrine 
bioactivity of chemicals. The in vitro high throughput and 
computational model alternatives provide a focused evaluation of the 
mechanistic aspects of endocrine pathways, thereby providing specific 
and quantitative measures of bioactivity. Several assays in the Tier 1 
battery rely on intact animals and identify bioactivity in the multiple 
biological pathways present. For this reason, the specificity of the in 
vitro high throughput and computational model alternatives may be more 
informative of specific endocrine pathway bioactivity.
    The annual EDSP Comprehensive Management Plan and future FIFRA SAP 
meetings are opportunities for staying informed on EPA's scientific 
progress on the evolution of Tier 1 screening in the EDSP. For 
information, visit EPA's Web site (http://www.epa.gov/endo) or sign-up 
to receive announcements go to (http://www.epa.gov/endo/pubs/assayvalidation/listserv.htm).

IV. Issues for Comment

    In connection with EPA's stated intention to use the scientific 
tools discussed in this Notice as alternatives to some of the current 
EDSP Tier 1 screening assays, EPA is specifically seeking public 
comment on the following:
    1. The use of the ToxCast\TM\ ``ER Model'' for bioactivity as an 
alternative method for the current ER binding and ERTA Tier 1 screening 
assays.
    2. The use of the ToxCast\TM\ ``ER Model'' for bioactivity as an 
alternative method for the current uterotrophic Tier 1 screening assay.
    3. The use of results from the ToxCast\TM\ ``ER Model'' for 
bioactivity on over 1800 chemicals as partial screening for the 
estrogen receptor pathway.

V. References

    The following is a listing of the documents that are specifically 
referenced in this document. The docket includes these documents and 
other information considered by EPA, including documents that are 
referenced within the documents that are included in the docket, even 
if the referenced document is not physically located in the docket. For 
assistance in locating these other documents, please consult the 
technical person listed under FOR FURTHER INFORMATION CONTACT.

1. U.S. EPA. Endocrine Disruptor Screening Program; Universe of 
Chemicals and General Validation Principles. November 2012. 
Available at http://www.epa.gov/endo/pubs/edsp_chemical_universe_and_general_validations_white_paper_11_12.pdf.

2. U.S. EPA. Endocrine Disruptor Screening Program for the 21st 
Century: (EDSP21 Work Plan); The Incorporation of In Silico Models 
and In Vitro High Throughput Assays in the Endocrine Disruptor 
Screening Program (EDSP) for Prioritization and Screening; Summary 
Overview. A Part of the EDSP Comprehensive Management Plan. 
September 30, 2011. Available at http://www.epa.gov/endo/pubs/edsp21_work_plan_summary%20_overview_final.pdf.
3. U.S. EPA. Endocrine Disruptor Screening and Testing Advisory 
Committee (EDSTAC); Final Report. August 1998. Available at http://www.epa.gov/endo/pubs/edspoverview/finalrpt.htm.
4. U.S. EPA. Endocrine Disruptor Screening Program; Proposed 
Statement of Policy; Notice. Federal Register (63 FR 71542, December 
28, 1998) (FRL-6052-9).
5. U.S. EPA. Endocrine Disruptor Screening Program; Tier 1 Screening 
Order Issuance Announcement; Notice. Federal Register (74 FR 54422, 
October 21, 2009) (FRL-8434-8).
6. U.S. EPA. Office of Research and Development (ORD); Description 
of Computational Toxicology Research Program. Available at http://epa.gov/ncct.
7. U.S. EPA. Interactive Chemical Safety for Sustainability (iCSS) 
Dashboard, Version 0.5. Available at http://actor.epa.gov/dashboard.
8. U.S. EPA. EDSP21 Dashboard. Available at http://actor.epa.gov/edsp21.
9. U.S. EPA. Integrated Bioactivity and Exposure Ranking: A 
Computational Approach for the Prioritization and Screening of 
Chemicals in the Endocrine Disruptor Screening Program. December 
2014. Docket ID No. EPA-HQ-OPP-2014-0614-0003. Available at http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2014-0614-0003.
10. U.S. EPA. Endocrine Disruptor Screening Program (EDSP); Estrogen 
Receptor Bioactivity Based on ToxCa \TM\ ``ER Model.'' June 1, 2015. 
Available at http://www.epa.gov/endo.
11. U.S. EPA. FIFRA SAP Minutes No. 2015-01. FIFRA SAP Meeting on 
the Integrated Bioactivity and Exposure-Based Prioritization and 
Screening, held December 2-4, 2014. Docket ID No. EPA-HQ-OPP-2014-
0614-0029. March 2, 2015. Available at http://www.epa.gov/scipoly/sap/meetings/2014/december/120214minutes.pdf.
12. Browne, P., Judson, R.S., Casey, W., Kleinstreuer, N., Thomas, 
R.S. Screening Chemicals For Estrogen Receptor Bioactivity Using A 
Computational Model. Manuscript accepted for publication. Environ. 
Sci. Technol. June 12, 2015. Available in the docket and 
electronically at http://pubs.acs.org/journal/esthag.
13. U.S. EPA. Endocrine Disruptor Screening Program; Policies and 
Procedures for Initial Screening; Notice. Federal Register (74 FR 
17560, April 15, 2009) (FRL-8399-9). Note: the status and progress 
of all List 1 Tier 1 orders are available at http://www.epa.gov/endo/pubs/toresources/index.htm.
14. U.S. EPA. Endocrine Disruptor Screening Program Test Guidelines; 
OPPTS 890.1250: Estrogen Receptor Binding Assay Using Rat Uterine 
Cytosol (ER-RUC). October 2009. EPA 740-C-09-005. Available at 
http://www.epa.gov/ocspp/pubs/frs/publications/Test_Guidelines/series890.htm.
15.U.S.EPA. Endocrine Disruptor Screening Program Test Guidelines; 
OPPTS 890.1300: Estrogen Receptor Transcriptional Activation (Human 
Cell Line (HeLa-9903)). October 2009. EPA 740-C-09-006. Available at 
http://www.epa.gov/ocspp/pubs/frs/publications/Test_Guidelines/series890.htm.
16.U.S.EPA. Endocrine Disruptor Screening Program Test Guidelines; 
OPPTS 890.1600: Uterotrophic Assay. October 2009. EPA 740-C-09-0010. 
Available at http://www.epa.gov/ocspp/pubs/frs/publications/Test_Guidelines/series890.htm.
17. Organization of Economic Co-operation and Development (OECD). 
Test Guideline No. 440:Uterotrophic Bioassay in Rodents: A short-
term screening test for oestrogenic properties. OECD Guidelines for 
the Testing of Chemicals, Section 4, OECD Publishing, Paris. DOI: 
http://dx.doi.org/10.1787/

[[Page 35355]]

9789264067417-en.
18. World Health Organization (WHO)/International Programme on 
Chemical Safety (IPCS). Global Assessment of the State-of-the-
Science of Endocrine Disruptors. WHO/IPCS/EDC/02.2. 2002. Available 
at http://www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en.
19. U.S. EPA. Endocrine Disruptor Screening Program; Final Second 
List of Chemicals and Substances for Tier 1 Screening; Notice. 
Federal Register (78 FR 35922, June 14, 2013) (FRL-9375-8). 
Available at http://www.gpo.gov/fdsys/pkg/FR-2013-06-14/pdf/2013-14232.pdf.

    Authority:  21 U.S.C. 346a(p).

    Dated: June 11, 2015.
James J. Jones,
Assistant Administrator, Office of Chemical Safety and Pollution 
Prevention.
[FR Doc. 2015-15182 Filed 6-18-15; 8:45 am]
BILLING CODE 6560-50-P