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Final Detailed Review Paper on In FINAL DETAILED REVIEW PAPER ON IN UTERO/LACTATIONAL PROTOCOL EPA Contract Number 68-W-01-023 Work Assignments 1-8 and 2-8 July 14, 2005 Prepared For: Gary E. Timm Work Assignment Manager U.S. Environmental Protection Agency Endocrine Disruptor Screening Program Washington, DC By: Battelle 505 King Avenue Columbus, OH 43201 AUTHORS Rochelle W. Tyl, Ph.D., DABT Julia D. George, Ph.D. Research Triangle Institute Research Triangle Park, North Carolina TABLE OF CONTENTS Page List of Abbreviations .................................................................. iv 1.0 EXECUTIVE SUMMARY ........................................................ 1 2.0 INTRODUCTION .............................................................. 2 2.1 Developing and Implementing the Endocrine Disruptor Screening Program ......... 2 2.2 The Validation Process .................................................. 3 2.3 Purpose of the DRP ..................................................... 5 2.4 Objective of the in Utero/lactational Protocol Within the EDSP .................... 5 2.5 Methodology Used in this Analysis .......................................... 6 2.6 Definitions ............................................................. 7 3.0 SCIRNTIFIC BASIS OF THE IN UTERO/LACTATIONAL PROTOCOL .................... 8 3.1 Background ........................................................... 8 3.2 Sexual Developm ent in Mam mals ......................................... 11 3.2.1 Both Sexes .................................................... 13 3.2.2 Males ......................................................... 13 3.2.3 Females ...................................................... 15 3.3 Sex-Specific Behaviors ................................................. 16 3.4 Appropriateness of Endpoints for Measuring the Endocrine Disruption after in Utero/lactational Exposure ......................................... 18 3.5 Selected Studies ...................................................... 26 3.5.1 GnRH Modulators ............................................... 26 3.5.2 Estrogen Modulators ............................................. 32 3.5.3 Androgen Modulators ............................................ 40 3.5.4 Metabolic Inhibitors .............................................. 50 3.5.5 Other ......................................................... 52 4.0 CANDIDATE PROTOCOLS .................................................... 53 4.1 Candidate Assay A - ICH Guideline Perinatal/Postnatal Study ................... 53 4.1.1 System Model - in Vivo Pre- and Postnatal Exposure in Rodents .......... 53 4.1.2 Flow Diagram of the ICH Guideline Perinatal/Postnatal Study (Protocol A) .................................................... 53 4.1.3 Description of the ICH Guideline Prenatal/Postnatal Study (Protocol A) .................................................... 54 4.1.4 Strengths of the ICH Guideline Perinatal/Postnatal Study ................ 58 4.1.5 Weaknesses of the ICH Guideline Perinatal/Postnatal Study .............. 59 4.1.6 Test Method Performance - Statistical Power of Approach ............... 59 4.1.7 Test Method Relaiability - Assistance of in Vivo Biological Test Vigor, Sensitivity, and Reproducibility ................................ 59 4.2 Candidate Assay B - Protocol for a Possible in Utero/lactational Exposure Assay ....................................................... 59 4.2.1 System Model - in Vivo in Utero/lactational Exposure in Rodents .......... 59 4.2.2 Flow Diagram of the Possible in Utero Developmental Screening Assay (Protocol B) ...................................... 60 4.2.3 Description of Protocol B .......................................... 60 4.2.4 Strengths of the Protocol B Study Design ............................. 63 Battelle Final i July 2005 Table of Contents (cont’d) Page 4.2.5 Weaknesses of the Protocol B Assay ................................ 63 4.2.6 Test Method Performance - Statistical Power of Approach ............... 64 4.2.7 Test Method Reliability - Assurance of in Vivo Biological Test Vigor, Sensitivity, and Reproducibility ................................ 64 4.3 Candidate Protocol C - Developmental Toxicity Protocol for Evaluation of Endocrine Disruption ................................................. 64 4.3.1 System Model in Vivo in Utero/lactational Exposure in Rodents ............ 64 4.3.2 Flow Diagram of the in Utero/lactational Screening Assay (Protocol C) .................................................... 65 4.3.3 Description of the in Utero/lactational Screening Assay (Protocol C) ........ 65 4.3.4 Strengths of the Protocol C Study Design ............................. 68 4.3.5 Weaknesses of the Protocol C Assay ................................ 68 4.3.6 Test Method Performance - Statistical Power of Approach ............... 69 4.3.7 Test Method Reliability - Assurance of in Vivo Biological Test Vigor, Sensitivity, and Reproducibility ..................................... 69 4.4 Related Study Design ................................................... 69 4.4.1 Description of Lactational Exposure Studies ........................... 69 4.4.2 Description of Multigenerational Exposure Studies ...................... 69 4.4.3 Description of Studies Using Direct Exposure to Pups ................... 70 4.4.4 Discussion of Related Study Designs ................................ 70 5.0 RECOMMENDED STUDY DESIGN .............................................. 73 5.1 Flow Diagram of the in Utero/lactational Screening Assay (Protocol D) ............ 73 5.2 Studies .............................................................. 74 5.3 Test Chemicals Applicable to Assay ....................................... 75 5.4 Route and Duration of Exposure .......................................... 75 5.5 Test Conditions ....................................................... 76 5.6 Endpoints ............................................................ 76 5.7 Data Collected ........................................................ 77 5.8 Relevance of Data Collected and Associated Endopoints ....................... 78 5.9 Data Analysis ......................................................... 78 5.9.1 Independent Continuous Data ...................................... 78 5.9.2 Independent Binary Data .......................................... 79 5.9.3 Cluster-Correlated Data .......................................... 79 6.0 IMPLEMENTATION CONSIDERATIONS .......................................... 81 6.1 Establishment of Assay ................................................. 81 6.1.1 Ease of Setup and Execution ...................................... 81 6.1.2 Information on Facilities and Major Fixed Equipment Needed to Conduct the Test ................................................ 82 6.1.3 General Availability of Other Necessary Equipment and Supplies .......... 82 6.1.4 Implementation Considerations ..................................... 82 6.2 Cost/Time Required .................................................... 82 6.3 Animal Welfare Considerations ........................................... 82 6.3.1 Advantages/Disadvantages of the Endocrine Disruptor Assays Related to Animal Use ............................................ 82 6.3.2 Rationale for the Need to Use Animals ............................... 82 Battelle Final ii July 2005 Table of Contents (cont’d) Page 6.3.3 Type of Animals Required and Rationale ............................. 83 6.3.4 Num ber of Animals Required and Rationale ........................... 83 6.3.5 Relative Paint or Distress for Animals ................................ 83 6.4 Assurance of Biological Test Vigor, Sensitivity, and Reproducibility ............... 84 7.0 DEVELOPMENTAL STATUS OF THE ASSAY 7.1 Current Status ........................................................ 84 7.2 Uncertainties and Data Needs ............................................ 84 7.3 Recommendation for Further Research and Development ...................... 84 7.4 Recommendation for Prevalidation Studies .................................. 84 7.5 Recommendation for Validation Studies .................................... 84 8.0 REFERENCES .............................................................. 85 LIST OF TABLES Table 1. Terms Used in the DRP .................................................. 7 Table 2. Anticipated Effects of Various Endocrine-Active Chemicals with Various Mechanisms on Maternal and Offspring Endpoints in the in Utero/lactational Screening Protocol ..................................................... 27 Table 3. Selected Studies of GnRH Modulators ..................................... 103 Table 4. Selected Studies of Estrogen Modulators .................................. 105 Table 5. Selected Studies of Androgen Modulators .................................. 119 Table 6. Selected Studies of Other Endocrine Active Compound Modulators .............. 139 Table 7. Comparison of the Parameters Included in Protocols A, B, C, and D ............. 140 LIST OF FIGURES Figure 1. ICCVAM Test Method Validation Process .................................... 4 Figure 2. Sim plified Overview of the Hormonal Feedback Systems in a Generic Mammalian Male System ................................................ 11 Figure 3. Primary Sex Determination in Mammalian Gonads ............................ 12 Figure 4. Results of the Multigeneration Study of PBA ................................. 37 Battelle Final iii July 2005 List of Abbreviations The following list of abbreviations are used in this Detailed Review Paper (DRP):
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