Comments on Incorporating Existing Data into the EDSP James C. Lamb, Ph.D. DABT, Fellow, ATS

1. environmental • failure analysis & prevention • health • technology development Comments on Incorporating Existing Data into the EDSPJames C. Lamb, Ph.D.DABT, Fellow, ATS A leading engineering & scientific consulting firm dedicated to helping our clients solve their technical problems.

2. Evolution of the EDC Issue • Diethylstilbestrol • Exposures in the 1950s, effects in the 1970s • Human effects • Mouse model • Environmental effects of various substances • “Wingspread” and other conferences and books on the hypothesis Are we at risk of harm from environmental exposures to EDCs?

3. Long-term View of TestingProgression anticipated and encouraged In vivo testing Tiered in vivo testing In vivo and in vitro In vitro and computational

4. Design of Endocrine Screening and Testing – EPA’s Mandate • “Tier 1 screening … identify substances that have the potential to interact with the estrogen, androgen, or thyroid hormone systems using a battery of assays.” • “Tier 2 testing … identify and establish a dose-response relationship for any adverse effects that might result from the interactions identified through the Tier 1 assays.” Federal Register /Vol. 74, No. 71 /April 15, 2009 http://www.epa.gov/endo/pubs/final_list_frn_041509.pdf

5. EPA Endocrine Screening Program • Tier 1 Screening proposed for 67 chemicals including active ingredients, pesticide inerts and non-pesticide chemicals • 58 pesticide actives, 9 HPV/pesticide inerts • Exposure pathway assessment • “List of chemicals was selected on the basis of exposure potential only, it should neither be construed as a list of known or likely endocrine disruptors nor characterized as such”

6. Screening Process defined by the EPA • “A test order recipient can elect to cite or submit existing data the recipient believes can be used to satisfy part or all of the Tier 1 Order” • Many of these chemicals have been tested in studies equivalent to Tier 1 testing already • EPA will make a “case-by-case determination of whether the information submitted is of high quality and achieves the objective of Tier 1”

7. What is already known? • Many substances on the list have 2-generation reproductive toxicology studies • Some old, some new • Chronic/onco studies • Subchronic toxicity studies • Clinical chemistry, histopathology, relative importance of systemic toxicity and endocrine MOA

8. What is the value of in vitro data for most of these substances? • Mode of Action? • Relate animal to human MOA for risk assessment? • Dose response? • Create lists of potential EDCs? • Regulatory action?

9. How does one assess that available data are functionally equivalent? • Are the data identical to the EDSP? • Is each MOA that is evaluated in the EDSP adequately addressed in alternative studies? • Must address this for each endpoint assessed in the EDSP • Some endpoints are easy, some are nearly impossible to satisfy “functional equivalence” test