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What can EDSP screening tell us that the FIFRA guidelines cannot?

What can EDSP screening tell us that the FIFRA guidelines cannot?. James T. Stevens, PhD, DABT, ATS, ERT Wake Forest University Health Sciences.

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What can EDSP screening tell us that the FIFRA guidelines cannot?

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  1. What can EDSP screening tell us that the FIFRA guidelines cannot? James T. Stevens, PhD, DABT, ATS, ERT Wake Forest University Health Sciences

  2. To briefly review some of the history of crop protection chemical industry’s response to EDSTAC proposal to endocrine screening and testing, and the history of the FIFRA guidelines. To review the FIFRA guideline mammalian toxicology tests in regard to their ability to detect an endocrine - active chemicals (EACs). To give my candid assessment in regard to value –added by the EDSP Tier 1 screens to the crop protection registration process. Objectives 2

  3. Crop Life America’s and the European Crop Protection Association’s early history with EDSP • NACA (CLA’s former name) position in 19971:…“ the FIFRA testing procedures have been demonstrated to identify endocrine modulators of sufficient potency to represent a concern to human health.” • ECPA position in 19982: …“these screening tests do not add value to the current regulatory battery… the regulatory safety paradigm has a low likelihood of missing potential endocrine-active chemicals…” 1Stevens J, Tobia A, Lamb J, Tellone C, and O’neil F.(1997). FIFRA Subdivision F Testing Guidelines: Are These Tests Adequate to Detect Potential Hormonal Activity For Crop Protection Chemicals. J Toxicol Environ Health, 50: 415-31. 2Stevens J, Gfeller W, Machemer L, and Leist KH. (1998). Adequacy of Required Regulatory Hazard Testing for the Detection of Potential Hormonal Activity of Crop Protection Chemicals. J Toxicol Environ Health, Part B, 1: 59-79.

  4. What are the FIFRA Guidelines?History and Scope • The Federal insecticide, Fungicide and Rodenticide Act (FIFRA) was passed by Congress in 1947. • The EPA was granted authority to administer FIFRA in 1970. • FIFRA defines the requirement of the registration of a pesticide under the Code of the Federal Regulations (40 CFR part 150-189). • Some of Part 158 testing requirements: • Subdivision D - Product Chemistry • Subdivision E - Hazard Evaluation: Wildlife & Aquatic Organisms • Subdivision F - Hazard Evaluation: Humans & Domestic Animals • Subdivision G – Product Performance • Other subdivisions cover experiment use permits, nontarget plants and insects, reentry, biorational pesticides, environmental fate, residue chemistry, spray drift, and application exposure monitoring • The Food Quality Protection Act (FQPA) of 1996 amended FIFRA to include, among other things, the development of assays to detected substances that may cause estrogenic effects.

  5. Are the FIFRA guideline Studies Designed to detect EACs? • The EDSTAC and the EPA EDSP have setthe FIFRA OPPTS two generation reproduction study in the ratas the definitive EDSP mammalian Tier II test. • But how about, the other FIFRA subdivision F studies that may detect EACs? • Acute testing (oral, dermal, inhalation, irritation, sensitization) are designed to determine single exposure hazard estimates and used for product labeling purposes. • Subchronic studies [90-day neurotoxicity(neuroendocrine); 90-day Feeding studies-rodent and non-rodent (organ toxicity); 21-day Dermal /90-day Dermal (organ toxicity); and 90-day Inhalation (organ toxicity) by design can and have yielded information on EACs. 5

  6. The Design of a FIFRA Subchronic Study Affords the Potential to Identify EACs. Typical Experimental Design 1100x the anticipated crop residue; 2100x anticipated worker exposure

  7. Are the FIFRA Guideline Studies Designed to Detect EACs?Developmental Toxicity studies – Rat and Rabbit • At minimum, the test substance (minimum of 3 doses + control) is administered daily from implantation to the day 20 (prior to the expected day of parturition) to 20 pregnant females/test group. Litters are harvested by caesarian. • Pregnancy status, gravid uterus (with cervix) weighed and uterine contents should be examined for embryonic or fetal deaths and the number of viable fetuses. • For each fetus, the gender, body weight, and malformations as well as skeletal and soft tissue anomalies are determined.

  8. OPPTS 870.3550(OECD 421)Reproduction/developmental toxicity screening test. OPPTS 870.3650(OECD 422)Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. The OECD 422 study was designated as an acceptable screen by the EPA to use of evaluating the potential reproductive and/or developmental toxicity for over 100 inerts used in pesticide formulations(Joint Inerts Task Force/Exponet). OPPTS 870.5450 Rodent dominant lethal assay (Optional Genotoxicity Tests) Additional reproduction / developmental and genotoxicity tests that are on the FIFRA books

  9. Are the FIFRA guideline Studies Designed to detect Potential EACs?Combined chronic toxicity/carcinogenicity in the rat • The combined chronic toxicity/carcinogenicity study was designed to determine the potential chronic toxicity and/or tumorigenicity of a chemical administered over the lifetime of a rat. • Endpoints included in this study are designed to measure the potential to produce neurological, physiological, endocrinologic, biochemical, hematological, and pathological change. • Tumors of the of the endocrine tissues , i.e., testes, ovary, uterus, and mammary gland may yield the key to detecting weak hormonally mediated effects.

  10. Endpoints in FIFRA Subdivision F Tests Methods for the Detection of Hormonally Mediated Responses in Adult Animals 10

  11. Endpoints in FIFRA Subdivision F Tests Methods for the Detection of Hormonally Mediated Responses in Adult Animals (cont’d) 11

  12. Endpoints in FIFRA Subdivision F Tests Methods for the Detection of Hormonally Mediated Responses in Offspring 12

  13. Examples of EACs responses detected in the FIFRA Guideline Tests

  14. A Nonylphenol 3-Generatiion Study with 17-β Estradiol as a Positive Control (Tyl et al., 2006) • Twenty-five rats/sex/group were administered concentrations of 0, 20, 200, 650 and 2000 ppm of nonylphenol in Purina 5002 diet and 0 and 650 ppm of nonylphenol in NIH-07 diet. 17-β Estradiol was used as a positive control at 2.5 ppm in Purina 5002 diet over 3 generations. • No effects were seen on any reproductive parameter with nonylphenol over three generations. Ovarian weights were reduced at 2000 ppm and kidney toxicity at 650 and 2000 ppm in males. • An 800-fold lower dose of 17-β Estradiol produced renal, reproductive, and developmental (lactational and peripubertal effects) toxicity in all three generations.

  15. Did the FIFRA Mammalian Toxicology Test Identify Possible EACs in the Process of Registration and Re-registration of Crop Protection Chemicals? 1 The majority of crop protection chemicals registered for use in the US were reviewed (Breckenridge and Stevens (2007) Chapter 16, Principles and Methods of Toxicology. 5th Ed. AW Hayes, Ed. Pp.727-839. 2 Some of the developmental effects may be associated with maternal toxicity. 3 Identified by an increased incidence of ovarian, mammary, testicular or thyroid tumors; however, some of these may be due to overdosing.

  16. What Value Does the EDSP Tier 1 Screening Battery Add to the Crop Protection Crop Registration and Registration Process? • To the registrant who already conducted the FIFRA definitive guideline tests in order to register a product, the EDSP Tier 1 screens brings little to no value to the process. • Yet 58 crop protection chemicals, each of which have already been using the Tier II FIFRA 2- generation reproduction study as well as the other FIFRA tests previously considered, are scheduled to be evaluated in the EDSP Tier 1 screening battery. • Wissenschaftlich und logisch? Nein! 1This is my personal opinion which does reflect my more than a decade of service on EDSP advisory subcommittees/committees, but does not reflect the opinion of Wake Forest University or my former employers!

  17. Release in 1st Qtr of 2010 Pre-lease sales on Informahealthcare, Amazon, Target, Flipkart, Keenzo and Chaos.

  18. J. Charles Eldridge, James T. Stevens (WFUHS) – Preface James C. Lamb, Karin L. Hantz (Exponent, Alexandria, VA) - Chapter 1: Impact of Endocrine Disruptor Policies and Regulations J. Charles Eldridge (WFUHS), Susan C. Laws (NHEERL, ORD, US EPA) - Chapter 2: The US EPA'S Tier 1 Screening Battery for Endocrine Disruptor Compounds Derek V. Henley, Kenneth S. Korach (LRDT, NIEHS) - Chapter 3: Modulation of Estrogen Receptor Signaling by Endocrine-Disrupting Chemicals Terry R. Brown (Johns Hopkins University) - Chapter 4: Androgen Receptor Binding and Transactivation Assays Identify Environmental Chemicals as Endocrine Disruptors James Devillers (Centre de Traitement de l'Information Scientifique, France) Chapter 5: Structure-Activity Modeling of Endocrine Disruptors Stephen Safe, Gayathri Chadalapaka, Indira Jutooru (Texas A&M University) - Chapter 6: Aryl Hydrocarbon Receptor Ligands: Toxic, Biochemical and Therapeutic Effects Table of Contents

  19. Table of Contents (continued) • Tammy E. Stoker, Leah M. Zorrilla (NHEERL, ORD, US EPA) - Chapter 7: The Effects of Endocrine Disrupting Chemicals on Pubertal Development in the Rat: Use of the EDSP Pubertal Assays as a Screen • Tomoya Yamada (Sumitomo Chemical Co., Japan) - Chapter 8: Male Reproductive Endpoints and the Rodent Hershberger Assay • Jerome C. Goldman, Ralph L. Cooper (NHEERL, ORD, US EPA) – Chapter 9: The Impact of Centrally-Acting Pesticidal/Environmental Toxicants on the Neuroendocrine Regulation of Reproductive Function in the Female Rodent: Relevance to Human Reproductive Risk Assessment? • E. Keith Inskeep (West Virginia University) – Chapter 10: Time Dependent Embryotoxicity of the Endogenous Luteolysin, Prostaglandin F2alpha, in Ruminants • Michael C. Henson, Martina Piasek, P. Jorge Chedrese (Purdue University Calumet), V. Daniel Castracane (Texas Tech University)- Chapter 11: Metal Toxicity in Mammalian Reproduction • Gerald A. LeBlanc (North Carolina State University) – Chapter 12: Overview of Endocrine Disruptor Ecotoxicity in Wildlife 19

  20. Table of Contents (continued) • Leslie W. Touart (OPPTS, OSCP, US EPA), Mary Ann Ottinger (University of Maryland) – Chapter 13: Avian Endocrine Toxicology • Stephen J. Jordan, Christy M. Foran, Erin R. Bennett, Erin M. Snyder, William H. Benson. (Gulf Ecology Division, ORD, US EPA) – Chapter 14: Endocrine-Disrupting Compounds in Aquatic Ecosystems • Gerald T. Ankley, Geraldine Cripe, Sigmund J. Degitz, Mary L. Haasch, Kathleen M. Jensen, Rodney D. Johnson, Allen W. Olmstead, Joseph E. Tietge (Mid-Continent Ecology Division, US EPA) - Chapter 15: Overview of US EPA Tests with Aquatic Vertebrates for Detecting and Assessing Endocrine Disrupting Chemicals • Werner Kloas (Humboldt University, Germany) and Ilka Lutz (Leibniz Institute, Germany) - Chapter 16: The Hypothalamic-Pituitary-Gonadal Axis in Anuran Amphibians • Benjamin D. Stanford, Mark J. Benotti, Shane A. Snyder (Southern Nevada Water Authority) – Chapter 17: Impact of Endocrine Disruptors to the Water Industry 20

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