ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC

Concerns of the animal protection community (and others) Current scope of the EDSP exceeds original Congressional intent FQPA repeatedly specifies “estrogen”-like effects “in humans” Inflexible “one size fits all” approach to test orders/DCIs Battery vs. toolbox / targeted approach Multiplicity of in vivo screens for the same endpoint “Extravagant” use of animals ~600 animals per Tier 1 battery as currently structured “Phase 1” = a validation exercise for the Tier 1 battery Domestic/OECD validation work to date has failed to determine relative sensitivity, specificity, positive/negative predictivity?! Ongoing development of avian 2-gen despite movement away from routine production of F 2 in mammals

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Q: How can the EDSP be implemented (and/or restructured) in order to fulfill EPA’s statutory obligations and minimize new animal testing / other costs?

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC #1 Begin with the most data-rich substances

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Statutory mandate (FQPA; 21 U.S.C. §346a, et seq.) `(p) ESTROGENIC SUBSTANCES SCREENING PROGRAM– `(1) DEVELOPMENT– Not later than 2 years after the date of enactment of this section, the Administrator shall … 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. `(2) IMPLEMENTATION– Not later than 3 years after the date of enactment of this section … the Administrator shall implement the program. `(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.

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Standard data requirements by pesticide / chemical class Endpoint# animalsConventionalAntimicrobial*Inert/HPV** 2-gen repro.2,600+ ratsRRNNR (TG422) DNT1,300+ ratsCR NNR Prenat. develop. 1,300 rats / 650 rabbits R (2 species) CR (rat) Subchron.120 rats / 32 dogsR (2 species) NNR (TG407) Chronic160 rats (32 dogs) R (rat)CR (rat)NNR Carcino.400 rats / 400 mice R (2 species)R / CRNNR Avian repro.1,500+ birdsR (2 species)CRNNR Fish lifecycle700+ fishCR NNR * Proposed rule ** NNR = not normally required; baseline = SIDS, but full §158 data set may be triggered

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC EDSTAC-proposed 2-gen enhancements* ER/AR-sensitive endpointsThyroid-sensitive endpoints Accessory sex organ functionNeurobehavioral deficits Androgen & estrogen levelsTSH, T4, thyroid weight & histology FSH & LH levelsDevelopmental landmarks: Testis descent  Prewean = pinnea detachment, surface righting reflex, auditory startle, etc.  Postwean = motor activity at PND 21, learning + memory at PND 60, etc.  Brain weight, whole & cerebellum  Brain histology * EDSTAC Final Report: Volume 1, August 1998

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC EDSTAC framework

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Registration review vs. blanket test orders/DCIs Test orders/DCIs likely to follow a “test everything for everything” approach without taking account of existing data Likely to overestimate actual data needs; places onus on industry to file waivers, reformulate, voluntarily cancel, etc. OPP’s registration review process takes account of available information for a substance when determining whether additional data/testing will add value to a risk assessment Additional testing, if any, will be targeted “Tick-box toxicology” “Thoughtful toxicology”

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Summary of Recommendation #1 Begin EDSP implementation with pesticides Most data-rich conventional chemical AIs come first Antimicrobials come second Inerts come third Use existing OPP registration review process vs. blanket “one size fits all” test orders/DCIs Transfer responsibility for EDSP implementation from OSCP to OPP

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC #2 By the time 1,000+ data-rich pesticides have been assessed, will the current EDSTAC paradigm be obsolete?

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC #3 Transition to a “21st century” paradigm in toxicology & risk assessment

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Vision of 21 st century toxicology 2007 NRC report “Toxicity Testing in the 21st Century: A Vision and a Strategy” calls for a fundamental paradigm shift in toxicity testing in order to: Develop a more robust scientific basis for assessing risks of environmental agents (mechanistic data) Provide broader coverage of chemicals, mixtures, outcomes & life stages Reduce testing time & costs Base decisions on human rather than rodent biology & focus on more relevant dose levels “... a not ‐ so ‐ distant future where all routine toxicity testing will be conducted in human cells or cell lines in vitro by evaluating perturbations of cellular responses in a suite of toxicity pathway assays using rapid robotic ‐ assisted methodologies.” (Tox Sci. 2009;107:324-30)

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Application to the EDSP EDSP implementation needs to be flexible & closely aligned with advances in toxicological assessment tools Only hope for expanding to the broader chemical universe ~80,000 existing substances + ~1,500 new substances/year + mixtures TSCA reauthorization / Kid Safe Chemicals Act Some relevant methods already available or in advanced stage of development EPA ORD (P. Schmieder) QSAR screening model for estrogenic activity EPA ToxCast high throughput in vitro assays

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC #4 Reconsider battery approach / composition

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC 4.1. Eliminate (or minimize) redundancies in Tier 1 battery EAT ER bindingAR bindingAmphibian metamorph. UterotrophicHershbergerPubertal female Pubertal male Fish screen (Transactivation?) Is it necessary to have both fish & amphibian data?

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC 4.2. From Tier 2 battery to targeted testing The need for Tier 2 testing should be determined by weight-of- evidence in consideration of Tier 1 results & relevant human / environmental exposure Not an “in for a dime, in for a dollar” approach for all 5 tests Is it necessary to have both fish & amphibian data?

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC 4.3. Discontinue work on avian 2-gen Several large-scale retrospective reviews of mammalian 2-gen studies have questioned the value of routine production of F 2 animals HESI-ACSA proposal for an “extended 1-gen” study design Draft OECD test guideline currently in advanced stage of development If the mammalian side is maneuvering to move away from routine 2- gen studies, is it necessary/appropriate for work to validate 2-gen designs to continue on the eco side? Animal use in validation studies for new endocrine endpoints could be reduced substantially if conventional 1-gen design was used

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Q: How can the EDSP be implemented (and/or restructured) in order to fulfill EPA’s statutory obligations and minimize new animal testing / other costs?

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Regulatory mindset needs to change from “Test everything for everything” to “Only as much testing & assessment as is required to set a substance aside as a non-priority or to inform sound risk management”

ISRTP 2009 Endocrine Workshop | 9-10 September 2009 | Washington, DC Thank You!