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Overview of OECD Test Guidelines for Thyroid Effects

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OECD Test Guidelines Programme - Activities on Endocrine Disrupters Testing and Assessment

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Overview of OECD Test Guidelines for Thyroid Effects

  1. 1. OVERVIEW OF OECD TEST GUIDELINES FOR THYROID EFFECTS OECD Test Guidelines Programme Activities on Endocrine Disrupters Testing and Assessment
  2. 2. • Five levels – Level 1: existing information – Level 2: in vitro assays that provide mechanic data – Level 3: in vivo assays that provide data on single endocrine modes of action – Level 4: in vivo assays that provide data on multiple models of action – Level 5: in vivo assays that provide data on adverse effects • Levels 3-5 are divided into Mammalian and Non- mammalian categories – Recognition that mammalian/non-mammalian may be mutually informative OECD (2012) Conceptual Framework Underlying Endocrine Testing
  3. 3. Mammalian and non mammalian Toxicology Level 1 Existing Data and Non-Test Information  Physical & chemical properties (MW reactivity, volatility, biodegradation)  Production, use, transport  All available (eco)toxicological data from standardized and non- standardized tests.  Read across, chemical categories, QSARs and other in silico predictions, and ADME model predictions Level 2 In vitro assays for selected endocrine mechanism(s) / pathways(s)  Estrogen or androgen receptor binding affinity (OECD TG 493)  Estrogen receptor transactivation (OECD TG 455)  Androgen receptor transactivation (OECD TG 458)  Steroidogenesis in vitro (OECD TG 456) EDTA Conceptual Framework: Levels 1 & 2
  4. 4. Mammalian and non mammalian Toxicology Level 1 Existing Data and Non-Test Information  Physical & chemical properties (MW reactivity, volatility, biodegradation)  Production, use, transport  All available (eco)toxicological data from standardized and non- standardized tests.  Read across, chemical categories, QSARs and other in silico predictions, and ADME model predictions Level 2 In vitro assays for selected endocrine mechanism(s) / pathways(s)  Estrogen or androgen receptor binding affinity (OECD TG 493)  Estrogen receptor transactivation (OECD TG 455)  Androgen receptor transactivation (OECD TG 458)  Steroidogenesis in vitro (OECD TG 456)  NO TG FOR IN VITRO THYROID MECHANISMS EDTA Conceptual Framework: Levels 1 & 2
  5. 5. Mammalian Toxicology Non-mammalian Toxicology Level 3 In vivo assays for selected endocrine mechanism(s) / pathway(s)1  Uterotrophic assay (OECD TG 440)  Hershberger assay (OECD TG 441)  Fish Short-term Reproduction Assay (OECD TG 229)  21-day Fish Screening Assay (OECD TG 230)  Amphibian metamorphosis assay (OECD TG 231)  Xenopus embryo thyroid signalling assay (draft TG) EDTA Conceptual Framework: Level 3
  6. 6. Mammalian Toxicology Non-mammalian Toxicology Level 3 In vivo assays for selected endocrine mechanism(s) / pathway(s)1  Uterotrophic assay (OECD TG 440)  Hershberger assay (OECD TG 441)  Fish Short-term Reproduction Assay (OECD TG 229)  21-day Fish Screening Assay (OECD TG 230)  Amphibian metamorphosis assay (OECD TG 231)  Xenopus embryo thyroid signalling assay (draft TG) EDTA Conceptual Framework: Level 3 3-week exposure, contains T-related endpoints: • Hind-limb length • Whole body length • Development stage • Thyroid histology
  7. 7. Mammalian Toxicology Non-mammalian Toxicology Level 3 In vivo assays for selected endocrine mechanism(s) / pathway(s)1  Uterotrophic assay (OECD TG 440)  Hershberger assay (OECD TG 441)  Fish Short-term Reproduction Assay (OECD TG 229)  21-day Fish Screening Assay (OECD TG 230)  Amphibian metamorphosis assay (OECD TG 231)  Xenopus embryo thyroid signalling assay (draft TG) EDTA Conceptual Framework: Level 3 3-week exposure, contains T-related endpoints: • Hind-limb length • Whole body length • Development stage • Thyroid histology 4-day exposure, will also contain T-related endpoints: • Fluorescence as indication of thyroid activity
  8. 8. Mammalian Toxicology Non-mammalian Toxicology Level 3 In vivo assays for selected endocrine mechanism(s) / pathway(s)1  Uterotrophic assay (OECD TG 440)  Hershberger assay (OECD TG 441)  Fish Short-term Reproduction Assay (OECD TG 229)  21-day Fish Screening Assay (OECD TG 230)  Amphibian metamorphosis assay (OECD TG 231)  Xenopus embryo thyroid signalling assay (draft TG) EDTA Conceptual Framework: Level 3 3-week exposure, contains T-related endpoints: • Hind-limb length • Whole body length • Development stage • Thyroid histology 4-day exposure, will also contain T-related endpoints: • Fluorescence as indication of thyroid activity Non T specific, but contains relevant T endpoints: • T3 and T4 hormone measurement are optional
  9. 9. Mammalian Toxicology Non-mammalian Toxicology Level 3 In vivo assays for selected endocrine mechanism(s) / pathway(s)1  Uterotrophic assay (OECD TG 440)  Hershberger assay (OECD TG 441)  Fish Short-term Reproduction Assay (OECD TG 229)  21-day Fish Screening Assay (OECD TG 230)  Amphibian metamorphosis assay (OECD TG 231)  Xenopus embryo thyroid signalling assay (draft TG) EDTA Conceptual Framework: Level 3 Could contain T- related endpoints
  10. 10. Mammalian Toxicology Non-mammalian Toxicology Level 4 In vivo assays providing data on adverse effects on endocrine relevant endpoints 2  Repeated dose 28-day study (OECD TG 407)  Repeated dose 90-day study (OECD TG 408)  Prenatal developmental toxicity study (OECD TG 414)  1-generation reproduction toxicity study (OECD TG 415)  Combined 28-day/reproductive screening assay (OECD TG 421/422)  Developmental neurotoxicity (OECD TG 426)  Chronic toxicity/carcinogenicity studies (OECD TG 451-3)  Avian Reproduction Assay (OECD TG 206)  Fish Early Life Stage Toxicity Test (OECD 210)  Fish sexual development test (OECD TG 234)  Larval Amphibian Growth & Development Assay (OECD TG 241) EDTA Conceptual Framework: Level 4
  11. 11. Mammalian Toxicology Non-mammalian Toxicology Level 4 In vivo assays providing data on adverse effects on endocrine relevant endpoints 2  Repeated dose 28-day study (OECD TG 407)  Repeated dose 90-day study (OECD TG 408)  Prenatal developmental toxicity study (OECD TG 414)  1-generation reproduction toxicity study (OECD TG 415)  Combined 28-day/reproductive screening assay (OECD TG 421/422)  Developmental neurotoxicity (OECD TG 426)  Chronic toxicity/carcinogenicity studies (OECD TG 451-3)  Avian Reproduction Assay (OECD TG 206)  Fish Early Life Stage Toxicity Test (OECD 210)  Fish sexual development test (OECD TG 234)  Larval Amphibian Growth & Development Assay (OECD TG 241) EDTA Conceptual Framework: Level 4 10-week aquatic exposure, contains several T-related endpoints Contains T hormone measurements Contains optional T hormone measurements Contains development al endpoints, not T- specific
  12. 12. Mammalian Toxicology Non-mammalian Toxicology Level 4 In vivo assays providing data on adverse effects on endocrine relevant endpoints 2  Repeated dose 28-day study (OECD TG 407)  Repeated dose 90-day study (OECD TG 408)  Prenatal developmental toxicity study (OECD TG 414)  1-generation reproduction toxicity study (OECD TG 415)  Combined 28-day/reproductive screening assay (OECD TG 421/422)  Developmental neurotoxicity (OECD TG 426)  Chronic toxicity/carcinogenicity studies (OECD TG 451-3)  Avian Reproduction Assay (OECD TG 206)  Fish Early Life Stage Toxicity Test (OECD 210)  Fish sexual development test (OECD TG 234)  Larval Amphibian Growth & Development Assay (OECD TG 241) EDTA Conceptual Framework: Level 4 Could be updated to include T-related endpoints
  13. 13. Mammalian Toxicology Non-mammalian Toxicology Level 5 In vivo assays providing data on adverse effects on endocrine relevant endpoints over more extensive parts of the life cycle  Extended one-generation reproductive toxicity study (OECD TG 443)  2-Generation reproduction toxicity study (OECD TG 416)  Medaka Extended One Generation Reproduction Test (OECD TG 240)  Zebrafish Extended One Generation Reproduction Test (draft TG) EDTA Conceptual Framework: Level 5
  14. 14. Mammalian Toxicology Non-mammalian Toxicology Level 5 In vivo assays providing data on adverse effects on endocrine relevant endpoints over more extensive parts of the life cycle  Extended one-generation reproductive toxicity study (OECD TG 443)  2-Generation reproduction toxicity study (OECD TG 416)  Medaka Extended One Generation Reproduction Test (OECD TG 240)  Zebrafish Extended One Generation Reproduction Test (draft TG) EDTA Conceptual Framework: Level 5 Comprehensive tests, contain several T-related endpoints (hormone dosage, organ weight and histopathology, …)
  15. 15. Mammalian Toxicology Non-mammalian Toxicology Level 5 In vivo assays providing data on adverse effects on endocrine relevant endpoints over more extensive parts of the life cycle  Extended one-generation reproductive toxicity study (OECD TG 443)  2-Generation reproduction toxicity study (OECD TG 416)  Medaka Extended One Generation Reproduction Test (OECD TG 240)  Zebrafish Extended One Generation Reproduction Test (draft TG) EDTA Conceptual Framework: Level 5 Could be updated to include some T-specific endpoints
  16. 16. Duration Age at start Age at termination Thyroid Endpoints AMA TG 231 21 days Sampling at: 7 days 21 days NF stage 51 (~17 days) ~38 days NF stage Asynchronous development Hind limb length SVL/wt Thyroid histo(patho)logy (termination) LAGDA TG 241 ~112 days NF stage 62 + 10 wks Sampling at: NF 62 (~49 d) Termination (NF 62 + 10 wks) NF stage 8-10 (about 5h embryo) ~112 days NF 62: Time stage 62 SVL/wt Morphological abnormalities Thyroid histo(patho)logy Termination: SVL/wt Genotypic/phenotypic sex ratios Histology (liver, gonads, repro ducts, kidneys) Summary of amphibian assays (Level 3 & 4 of the Conceptual Framework)
  17. 17. Amphibian protocols NF stage 51 Day 0 7 21 NF stage Synchronous dev HLL SVL weight NF stage Synchronous dev HLL SVL Weight Thyroid histology Day 8 0 NF stage ~112~41 62 70 66 Cull Time to stage 62 SVL/wt Morphological abnormalities Thyroid histology SVL/wt Geno/pheno sex ratios LSI Histology (liver, gonads + repro ducts, kidneys) TG 231 AMA TG 241 LAGDA
  18. 18. Summary of mammalian assays (Level 3 & 4 of the Conceptual Framework) Duration Age at start Age at termination Thyroid Endpoints Hershberger TG 441 10 d PND 49-60 peripubertal PND 59-70 T3/T4 (optional) Repeated dose 28d oral tox TG 407 28 d ~4-9 wk (young mature; F nulliparous) ~8-12 wks optional control/high dose groups held 14 d > final dose Thyroid histology Other organ histology T3/T4/TSH (optional) Thyroid wt (optional) Repeat 90d oral tox TG 408 90 d ~4-9 wks (young mature; F nulliparous) ~16.5-19 wks Thyroid histology Other organ histology Repro/dev tox; Combined 28d Repro/dev tox TG 421/422 M 28 d (2 wk<mating, 2 wk > mating) F ~63 d (2 wk<mating, 2 wk > mating, 22 d gestation, 13 d lactation) ~10-12 wks (healthy unmated, mature) F0 ~14 wks (M) ~19 wks (F) F1 PND4/PND13 F0 M: T4 (termination) Thyroid histology, wt (optional) F0 F: wt gestation/lactation/termination T4 (if relevant*) TSH (optional) Thyroid histology, wt (optional) F1: PND0: wt PND4: wt, T4 (optional) PND13: wt, T4 + thyroid histology Chronic tox Carcinogen TG 451-3 12 mo 18-24 mo ~4 wks ~56-116 wks Wt Thyroid CNS +PNS
  19. 19. Duration Age at start Age at termination Thyroid Endpoints DNT TG 426 F0: ~37 d (usually post implantation though weaning) F1: (in utero) + 10 wks F0: ~10-12 wks (nulliparous females) F1: GD6 to PND 21 + 7 wks post-wean F0: ~15 wks F1: ~10 wks F0: Wt (weekly) F1: • Wt (1/wk to wean; 1/ 2wk to termination) • Brain wt (PND 22; PND70) • Brain histology and morphometrics (<PND 22; PND 70) • CNS+PNS histology and morphometrics (PND70) • behavior (<PND 22) • Motor activity (throughout) • Motor + sensory function (PND25; PND 70) • Learning + memory (PND25; PND 70) Neurobehavior/chemistry/pathology can be added EOGRT TG 443 F0: >10 wk (2 wk<mating, to F1 wean) F1: in utero + 3/11 wk F2: weaning+ FEXIBLE F0: ~10-12 wk F1: (in utero + lactation) PND 21 F0:~20 wk F1: varies by cohort; 1A 2A: ~11wks 2B: PND 22 3: 8 wks F2 (if triggered from 1A) wean Fo: (termination) • Wt • T4/TSH • Thyroid wt F1: wt PND 0, 4, weekly PND 4: T4 as available PND 22: T4/TSH (if not selected for cohort) • 1A ~13wk: T4/TSH, thyroid wt, thyroid histology, PNS histology • 2B ~PND 21 neuropath; brain wt • 2A PND 24 startle test; motor activity neuropath • 2A ~10wk: neurobehavior, brain wt/perfusion/ histology • 3 immunotox Summary of mammalian assays (Level 5 of the Conceptual Framework)
  20. 20. Mammalian protocols TG 441: Peri-pubertal ♂: T4/TSH TG 407: thyroid wt, histology, T4/TSH TG 408: histology TG 421/422: thyroid wt, histology, T4/TSH F1 F0 F0 F1 TG 426: CNS + PNS histology and morphometrics; behavior F0 F1 TG 443: CNS + PNS histology and morphometrics; behavior Gestation Lactation Growth and Development 14 d 21 d 19 wk Mating 22 d TG 451-453
  21. 21. Mammals Amphibians KEY EVENT (Lighter shade indicates optional endpoint) Level 3 Level 4 Level 5 Level 4 Level 5 441 407 408 421/ 422 426 451-3 443 231 241 MIE Early key event Altered TSH/T4/T3 Early key event Altered thyroid wt/histology Late key event Altered metamorphosis; CNS/PNS morphology, histology AO/Phenotype Altered learning/memory/ motor/sensory function OECD TGs by key events on the thyroid-related pathways
  22. 22. OECD TGs by life stage LIFE STAGE Mammals Amphibians 441 407 408 421/ 422 426 451- 3 443 231 241 In utero/early embryo development F1 F1 F1 Early postnatal development (lactation/early metamorphosis F1 F1 F1 Adolescence/puberty/late metamorphosis F1 F1* Adult F0 F0 F1 F0 F1* Reproduction FO FO FO F1* Chronic (> 12 months) Multigeneration
  23. 23. • 2017: Update to Guidance Document No. 150 to include additional validated assays and revisions to existing assays: – More user friendly – Lessons learned from recent regulatory activities – Improve opportunities for cross-species extrapolation to reduce unnecessary testing – Make better use of the AOP concept to develop integrated approaches to testing and assessment – Draft includes recognition of endpoints that are potentially sensitive to by not diagnostic of EATS and other endocrine modalities Ongoing work at OECD to develop further guidance and Test Guidelines
  24. 24. • Validation of XETA test method and develop draft TG (France) • Analysis of other in vivo TG that may provide thyroid-related data: – TG 408 (Netherlands) and TG 414 (Denmark) – Research to determine potential utility of including thyroid histology in fish assays (US and Denmark) • No in vitro method yet ready for the thyroid pathway – 2012 DRP for novel in vitro and in vivo methods for evaluating endocrine disruptors No. 178 – 2014 Thyroid scoping document N0. 207 – Call for proposals to validate in vitro thyroid assays (NO RESPONSES) • Expectations that the development of Adverse Outcome Pathways will help justify further in vitro test methods development and validation Ongoing work at OECD in 2017

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