International Society of Regulatory Toxicology and Pharmacology 2009 Endocrine Workshop The Endocrine Disruptor Screening Program: What Can Screening Results Tell Us About Potential Adverse Endocrine Effects? September 9-10, 2009 Lister Hill Auditorium NLM, National Institutes of Health Bethesda, Maryland 1 Quill Law Group LLC

Welcome Terry F. Quill Quill Law Group LLC 1667 K St, NW Washington, DC Quill Law Group LLC

Getting Started Announcements Reception Breaks Membership Opportunities Thank you Sponsors EPA Speakers Goals Some Perspective 3 Quill Law Group LLP

Goals Open an Industry/Agency and Inter-industry Dialogue to: Facilitate EDSP Implementation Better understand procedural steps Address Interpretation of Tier 1 Screening Results Address the issue of “Functional Equivalence” Express lingering industry concerns Open a dialogue with the scientific community and among potential order recipients Tee up future EDSP issues 4 Quill Law Group LLC

Some Perspective Lets look at the EDSP and potential issues in light of the Congressional mandate. Issues related to the endocrine screening provisions of: The Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(p) (FFDCA §408p); the Food Quality Protection Act (FQPA); and The Safe Drinking Water Act, 42 U.S.C. §300j Quill Law Group LLC

Issues Related to FFDCA §408(p) (1) Development Not later than 2 years after August 3, 1996, the Administrator shall in consultation with the Secretary of Health and Human Services 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 endocrine effect as the Administrator may designate. 6 Quill Law Group LLC

Issues “Screening Program” EPA’s program likely exceeds Congressional intent. But more complete screening and testing will help to minimize false positive results that would be seen with minimal screening programs. Screens/tests must be validated. What constitutes validation? Deliberate and methodical validation effort over the last 10+ years. E.g., has the frog metamorphosis assay been “validated”? Human testing only? It may be possible to challenge wildlife testing to the extent it is required pursuant to FQPA order authority. 7 Quill Law Group LLC

Issues Continued “Estrogenic or other endocrine effect” What is an estrogenic or other endocrine effect? How will it be determined that a substance may have such an effect? EPA is addressing estrogen, androgen and thyroid effects. Environmental community and Congress are moving toward other effects such as metabolism and weight regulation. HR 2996 Committee Report Theo Colborn 1996: Association  Causation 2009: Theory  Causation EPA will come under greater pressure to expand the program to new areas, include a greater number of substances, include new media (drinking water), and speed up screening and testing. 8 Quill Law Group LLC

Issues Continued EPA relied on the advice of the EDSTAC to develop the EDSP. EPA, not EDSTAC, must comply with the statutory requirements. Two tiered program. What is the purpose of Tier 1 Screening? Ability to interact with the endocrine system. What does “interact” mean? What about dose? Doesn’t everything interact with the endocrine system in some way at some dose? Trigger Tier 2 Testing. Do we need to know the Tier 2 assays first? What are the Tier 2 assays? 9 Quill Law Group LLC

Issues Continued What can the Tier 1 assays tell us? What can’t they tell us? HR 2996 Committee Report “Develop and publish criteria for evaluating the results of Tier I screening and determining whether a chemical should undergo Tier II analysis within one year of enactment.” ISRTP Workshop, Session 1 What is “other scientifically relevant information”? Functionally equivalent data? EPA Criteria. EPA’s Approach for Considering Other Scientifically Relevant Information (two page document) ISRTP Workshop Session 2 What data are generally available for pesticide chemicals? 10 Quill Law Group LLC

Issues Continued Can screening results be used to conduct cumulative risk assessments? Can risk assessments be conducted with tier 1 data? Can exposures to different chemicals be “added”? Workshop Session Quill Law Group LLC

Issues Continued Where do we go after initial screening? How will EPA use the data? Will new screening assays be developed? Will screening results influence Tier 2 Assay development? Will further validation be necessary? Can we address concerns of animal rights groups? Will Congress and special interest groups change the program? What can be done to improve the screening battery? ISRPT Workshop Session Quill Law Group LLC

(2) Implementation Not later than 3 years after August 3, 1996, after obtaining public comment and review of the screening program described in paragraph (1) by the scientific advisory panel established under section 25(d) of the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 136w(d)) or the science advisory board established by section 4365 of title 42, the Administrator shall implement the program. Implementation was an issue in the Deadline Lawsuits (NRDC, et al. v. Whitman). EPA claimed that it implemented the program with publication of its Policy Statement. 53 Fed. Reg (Dec. 28, 1998). ISRTP Workshop, Session Quill Law Group LLC

(3) Substances In carrying out the screening program described in paragraph (1), the Administrator (A) shall provide for the testing of all pesticide chemicals; and (B) may provide for the testing of any other substance that may have an effect that is cumulative to an effect of a pesticide chemical if the Administrator determines that a substantial population may be exposed to such substance. 14 Quill Law Group LLC

Issues Under FFDCA, “pesticide chemicals” includes inerts. Phase 1 consists of 58 active pesticide ingredients and 9 inerts. Phase 1 based on exposure potential of “pesticide chemicals.” Prevent product deselection. EPA could use FIFRA data call-ins to require testing of pesticide chemicals. What does “cumulative to an effect of a pesticide chemical” mean? What is a “substantial population”? Are mixtures “substances” under the Act? Ironically, pesticide chemicals may be the most data rich chemicals and may generate the least concern for endocrine effects. Yet Congress focused on those substances. DCI provisions obviate need for FQPA testing. Data rich substances may be best to validate EDSP battery. Are we validating screening assays on the backs of the pesticide industry and initial order recipients? 15 Quill Law Group LLC

(4) Exemption Notwithstanding paragraph (3), the Administrator may, by order, exempt from the requirements of this section a biologic substance or other substance if the Administrator determines that the substance is anticipated not to produce any effect in humans similar to an effect produced by a naturally occurring estrogen. Will EPA provide for exemptions? It is not required to provide exemptions. How is it “anticipated” that a substance does not produce an effect? Are those substances with sufficient available data? Does this overlap with the requirement that EPA must minimize duplicative testing? Does this apply only to screening/testing for human effects and only to estrogenic effects? Did Congress intend to allow wildlife testing but allow exemptions only for human effects? 16 Quill Law Group LLC

(5) Collection of information (A) In general The Administrator shall issue an order to a registrant of a substance for which testing is required under this subsection, or to a person who manufactures or imports a substance for which testing is required under this subsection, to conduct testing in accordance with the screening program described in paragraph (1), and submit information obtained from the testing to the Administrator, within a reasonable time period that the Administrator determines is sufficient for the generation of the information. (B) Procedures To the extent practicable the Administrator shall minimize duplicative testing of the same substance for the same endocrine effect, develop, as appropriate, procedures for fair and equitable sharing of test costs, and develop, as necessary, procedures for handling of confidential business information. 17 Quill Law Group LLC

Issues EPA shall issue testing orders to: Registrants Manufacturers Importers What is a testing order; what are the procedures? Will there be due process protections? For example, can a manufacturer challenge a testing order? What is a “reasonable time period”? EPA must (to the extent practicable) : Minimize duplicative testing. Develop procedures for cost sharing. Will EPA recreate the data compensation problems of FIFRA? Develop procedures for developing CBI. 18 Quill Law Group LLC

Noncompliance (C) Failure of registrants to submit information Much like FIFRA procedures. (D) Noncompliance by other persons Any person (other than a registrant) who fails to comply with an order under subparagraph (A) shall be liable for the same penalties and sanctions as are provided under section 16 of the Toxic Substances Control Act (15 U.S.C. 2615) in the case of a violation referred to in that section. Such penalties and sanctions shall be assessed and imposed in the same manner as provided in such section 16. TSCA §16 provides for both civil ($32,500 per day) and criminal (up to 1 year imprisonment and $32.5K/day). TSCA testing rules, unlike testing orders, result from rulemaking prior to requiring testing. This provides sufficient notice and due process (the rule could be challenged). 19 Quill Law Group LLC

(6) Agency action In the case of any substance that is found, as a result of testing and evaluation under this section, to have an endocrine effect on humans, the Administrator shall, as appropriate, take action under such statutory authority as is available to the Administrator, including consideration under other sections of this chapter, as is necessary to ensure the protection of public health. How will it be determined whether a substance has an “endocrine effect on humans”? Can Tier 1 lead to action? Will Tier 2 allow for an evaluation of human effects? Did Congress intend to allow wildlife testing while not allowing EPA to take action on testing results for wildlife? 20 Quill Law Group LLC

Issues and Comments Related to the Safe Drinking Water Act Sec. 300j-17. Estrogenic substances screening program In addition to the substances referred to in section 346a(p)(3)(B) of title 21 the Administrator may provide for testing under the screening program authorized by section 346a(p) of title 21, in accordance with the provisions of section 346a(p) of title 21, of any other substance that may be found in sources of drinking water if the Administrator determines that a substantial population may be exposed to such substance. 21 Quill Law Group LLC

Issues Note that this provision utilizes the procedures of FFDCA § 408p. Therefore, EPA may issue testing orders under the SDWA. The SDWA only adds substances to the provisions of the FFDCA endocrine screening program. It is unclear from the language of the SDWA what additional substances may be added. “may be found in sources of drinking water” What is meant by “may be found” What are “sources of drinking water”? “that a substantial population may be exposed to...” What is a “substantial population”? What is meant by “may be exposed” HR 2996 Will we see these substances added soon? 22 Quill Law Group LLC