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A Literature Review of the State of the Science Regarding Species

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A Literature Review of the State of the Science Regarding Species A LITERATURE REVIEW OF THE CURRENT STATE OF THE SCIENCE REGARDING SPECIES DIFFERENCES IN THE CONTROL OF, AND RESPONSE TO, THYROID HORMONE PERTURBATIONS. PART 1: A HUMAN HEALTH PERSPECTIVE Report No: RSA/ECPA001_THYROID Report prepared for Sponsor: European Crop Protection Association Prepared by: Regulatory Science Associates Regulatory Science Ltd1 Kip Marina Inverkip Renfrewshire PA16 0AS APRIL 2018 1 Regulatory Science Ltd is a registered company in England and Wales. Registered office address: c/o Dafferns LLP, One Eastwood, Harry Weston Road, Binley Business Park, Coventry CV3 2UB Company Registration No. 6233406 VAT No. 907 7657 89 A LITERATURE REVIEW OF THE CURRENT STATE OF THE SCIENCE REGARDING SPECIES DIFFERENCES IN THE CONTROL OF, AND RESPONSE TO, THYROID HORMONE PERTURBATIONS. PART 1: A HUMAN HEALTH PERSPECTIVE STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS No claim of confidentiality, on any basis whatsoever, is made for any information contained in this document. I acknowledge that information not designated as within the scope of FIFRA §10(d)(1)(A), (B), or (C) and which pertains to a registered or previously registered pesticide is not entitled to confidential treatment and may be released to the public, subject to the provisions regarding disclosure to multinational entities under FIFRA 10(g). Sponsor: Submitter: ________________________________ Date: ________________________ Typed name of signer: _______________________ Typed name of company: _____________________________ Regulatory Science Ltd: Nov 2017 Report: RSA/ECPA001-THYROID Prepared for: ECPA Page 2 of 85 A LITERATURE REVIEW OF THE CURRENT STATE OF THE SCIENCE REGARDING SPECIES DIFFERENCES IN THE CONTROL OF, AND RESPONSE TO, THYROID HORMONE PERTURBATIONS. PART 1: A HUMAN HEALTH PERSPECTIVE STATEMENT OF COMPLIANCE WITH GOOD LABORATORY PRACTICE STANDARDS This report is a review of existing data. Good Laboratory Practice Standards, 40 CFR Part 160, are not applicable to this submission. SPONSOR & SUBMITTER: SUBMITTER: ____________________________ DATE: ___________________ Typed name of signer: _______________________ Typed name of company: ______________________________ Regulatory Science Ltd: Nov 2017 Report: RSA/ECPA001-THYROID Prepared for: ECPA Page 3 of 85 A LITERATURE REVIEW OF THE CURRENT STATE OF THE SCIENCE REGARDING SPECIES DIFFERENCES IN THE CONTROL OF, AND RESPONSE TO, THYROID HORMONE PERTURBATIONS. PART 1: A HUMAN HEALTH PERSPECTIVE STUDY APPROVAL THIS REPORT IS APPROVED AND ISSUED BY: AUTHOR: _____________________________________ DATE: ____________________ Prof John R Foster BSc, PhD, DipRCPath, FRCPath, FIATP REVIEWER: _____________________________________ DATE: _________________ Dr M Provan BSc PhD SPONSOR REPRESENTATIVE: ______________________ DATE:_________________ Regulatory Science Ltd: Nov 2017 Report: RSA/ECPA001-THYROID Prepared for: ECPA Page 4 of 85 A LITERATURE REVIEW OF THE CURRENT STATE OF THE SCIENCE REGARDING SPECIES DIFFERENCES IN THE CONTROL OF, AND RESPONSE TO, THYROID HORMONE PERTURBATIONS. PART 1: A HUMAN HEALTH PERSPECTIVE Table of Contents 1. Executive Summary ...................................................................................................................... 7 2. Introduction ................................................................................................................................... 8 3. Thyroid hormone function – the established understanding ......................................................... 9 4. ECPA Question: Consider the references in the draft guidance document – is this the state of the science? If not, what is? ...................................................................................................... 16 5. ECPA Question: Is the way in which the references are used in the GD appropriate? ............. 18 6. ECPA Question: Comparison between human and key laboratory animal species (rodent, dog, monkey) ...................................................................................................................................... 18 6.1. Species comparison of the functional morphology of the thyroid gland ..................................... 18 6.2. Species comparison of thyroid hormone binding proteins in the plasma ................................... 19 6.3. The role of transthyretin (TTR) .................................................................................................. 21 6.4. Species differences in thyroid hormone metabolism .................................................................. 22 6.5. Hepatic metabolism of thyroid hormones (Fig. 5). ..................................................................... 23 6.6. The importance of thyroid hormone sulphation .......................................................................... 24 6.7. Species comparison of thyroid hormone and TSH half-life ........................................................ 24 6.8. Comparison of thyroid modifying chemicals in human and animal species ............................... 25 6.8.1. Thyroid modifying chemicals in humans....................................................................... 25 6.8.2. Thyroid modifying chemicals in rodents ....................................................................... 26 6.9. Comparison of thyroid hormone involvement in neurodevelopment in humans and rodents .... 30 6.9.1. Thyroid hormone and neurodevelopment in humans ................................................. 30 6.9.2. Comparison of the stages of thyroid hormone dependency in the rat and human foetus 31 6.10. Comparison of thyroid cancer in human and animal species ............................................... 32 6.10.1 The association between iodide deficiency, goitre and thyroid cancer in the human population ..................................................................................................................................... 33 6.10.2 Comparative cancer studies in laboratory animals and humans for goitrogenic chemicals ...................................................................................................................................................... 34 6.10.3. Thyroid hormone perturbation and thyroid cancer in rodents ........................................ 35 6.10.4. Is chemically-induced rodent thyroid cancer relevant to man? ....................................... 36 6.11. Cross-species extrapolation for thyroid effects ..................................................................... 37 7. ECPA Question: Is there evidence for a threshold/correlation for adversity linked to serum thyroid hormone levels (T3, T4, TSH and sulphated thyroid hormone), between species ................ 38 7.1. Thyroid hormone changes in the absence of histological changes ........................................... 39 Regulatory Science Ltd: Nov 2017 Report: RSA/ECPA001-THYROID Prepared for: ECPA Page 5 of 85 A LITERATURE REVIEW OF THE CURRENT STATE OF THE SCIENCE REGARDING SPECIES DIFFERENCES IN THE CONTROL OF, AND RESPONSE TO, THYROID HORMONE PERTURBATIONS. PART 1: A HUMAN HEALTH PERSPECTIVE 7.2. Evidence for dose response/threshold relationships for thyroid hormone effects ..................... 41 7.2.1. Evidence in animal studies ............................................................................................ 41 7.2.2. Evidence in human studies ........................................................................................... 42 7.3. Evidence for dose responses/thresholds for neurodevelopmental disorders of thyroid homeostasis ................................................................................................................................ 43 7.4. Is there evidence for a threshold for chemicals inducing thyroid cancer through thyroid hormone disruption? .................................................................................................................................. 46 8. ECPA Question: Are there non-endocrine causes of the same adverse effects e.g. stress, starvation, environmental factors such as temperature? .................................................................. 47 8.1. Thyroid hormone changes in disease states .............................................................................. 48 8.2. Specific thyroid hormone changes in liver disease ..................................................................... 48 8.3. Effects of temperature on thyroid hormones .............................................................................. 48 8.3.1. Effects in humans .......................................................................................................... 48 8.3.2. Effects in laboratory animals ........................................................................................ 49 8.4. The relationship of fasting and obesity to thyroid hormones ...................................................... 49 9. ECPA Question: What are the non-thyroid hormone activities of the thyroid hormone transport proteins? Are there quantitative and/or qualitative species differences? ....................................... 50 9.1. Thyroid hormone binding proteins as acute phase proteins ....................................................... 50 10. ECPA Question: What are the remaining uncertainties? How may they be addressed? ............. 50 10.1. The current assays and their assessment of thyroid effects ................................................. 51 10.2. The need for additional screens for chemicals that might disrupt the
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