Tiered Evaluation Strategies: An Animal Protection Perspective. Martin Stephens, Ph.D. The Humane Society of the United States

Transcription

1 Tiered Evaluation Strategies: An Animal Protection Perspective Martin Stephens, Ph.D. The Humane Society of the United States

2 2 ISRTP Workshop, Baltimore, Nov , 2005

3 3 ISRTP Workshop, Baltimore, Nov , 2005

4 The Humane Society of the United States (HSUS) A non-governmental organization (NGO) Not affiliated with local humane societies Funded by private donations $89M budget for 2005 ~ 10 million members and constituents ~ 280 employees Addresses full array of issues concerning companion, wild, farm, & lab animals Motto: Promoting the Protection of All Animals 4 ISRTP Workshop, Baltimore, Nov , 2005

5 HSUS Perspective on Animal Use & 3Rs We want to see the day when no animal is used in harmful testing We realize that day is a long way away Progress towards that goal can be hastened, and current animal suffering lessened, through 3Rs 3Rs framework is a win/win approach, yielding... advances in science + incremental gains in animal welfare Animal protection organizations have an important role to play in advancing the 3Rs 5 ISRTP Workshop, Baltimore, Nov , 2005

6 Tiered Evaluation Strategies APICAL TESTS triggers e.g. reprotox Animal Use OUTCOMES TESTS SCREENS triggers triggers e.g. MTS e.g. HTPS PRE-SCREENS existing information triggers e.g. comp. tox prioritization 6 ISRTP Workshop, Baltimore, Nov , 2005

7 Tiered Evaluation Strategies as Reduction Approaches individual test methods or procedures Up & Down Method vs. LD50 Test Reduction testing strategies or programs Tiered Evaluation + other ITS 7 ISRTP Workshop, Baltimore, Nov , 2005

8 TES: Advancing the 3Rs Short-term Medium-term Long-term animal use limited to middle & higher tiers animal use limited to top tier only (as confirmation) no animals used ( zero option ) 8 ISRTP Workshop, Baltimore, Nov , 2005

9 TES in the Larger Context of Intelligent Testing Strategies risk management context physico-chemical properties QSAR, comp tox in vitro tests invertebrate-based tests refined in vivo methods read-across tiered evaluation thresholds of toxicological concern exposure assessment weight of evidence assessment versus one-size-fits-all, check-box approach 9 ISRTP Workshop, Baltimore, Nov , 2005

10 TES/ITS Help in Addressing Inevitable Compromises DEPTH in-depth testing on a few chemicals e.g. pesticides/ilsi vs. SCOPE limited testing on 1000s of chemicals e.g. HPV, REACH Practical considerations e.g. cost, time Welfare considerations e.g., numbers, suffering TES/ITS Existing Methods Output 10 ISRTP Workshop, Baltimore, Nov , 2005

11 TES: Animal Welfare Principles Multi-stakeholder involvement Transparency Data sharing on existing chemicals International collaboration Fullest application of ITS Precautionary principle Outcome: limited animal testing little or no animal testing in early Ts Ts & triggers screen out chemicals making negatives definitive risk management context physico-chemical properties QSAR, comp tox in vitro tests invertebrate-based tests refined in vivo methods read-across tiered evaluation thresholds of tox concern exposure assessment weight of evidence assessment 11 ISRTP Workshop, Baltimore, Nov , 2005

12 HPV Chemical Testing Program (hazard ID) Fill SIDs gaps w/ existing & new data Devised originally as a battery, not a TES Exposure only indirectly involved (HPV status) AP-ists excluded from program formulation Subsequent multistakeholder workshops showed potential of TES/ITS Animal advocacy helped convince govt. to make changes 12 ISRTP Workshop, Baltimore, Nov , 2005

13 HPV Meets ITS: Key Animal Welfare Principles Use in vitro versus in vivo genotoxicity No repeat dose/repro testing for closed system intermediates Maximize use of existing data Partial amnesty for companies to reveal data previously withheld Use weight-of-evidence avoiding checklist toxicology (Wayland, 1999) 13 ISRTP Workshop, Baltimore, Nov , 2005 No terrestrial testing No new dermal testing (generally) Maximize use of categories of related chemicals, testing representative chemicals 2-year delay in testing chemicals not in categories, so pending alt. tests might be incorporated into program $4.5 million commitment from NIEHS, NTP, and EPA for nonanimal methods

14 HPV Program: Problems in Compliance Compliance voluntary, not enforced AP consortium, lead by PCRM & PeTA, devoted enormous effort to critique test plans Non-compliance widespread 75% of test plans contravened AW measures. made little use of existing info, calling instead for checklist battery of animal tests failed to show relevance (e.g., fish tests on insoluble materials??) Other regulatory reqts. often used as justification for animal testing (e.g., in anticipation of REACH) Some responsiveness to criticism 14 ISRTP Workshop, Baltimore, Nov , 2005

15 Example of ITS Approaches to HPV Test Plans: RAPID HYDROLYSIS Triisopropyl borate Rapidly hydrolyzes to boric acid and isopropanol in aqueous environment EPA agreed to accept bench hydrolysis study at stomach acid ph = 1.2 Rapid hydrolysis to well studied products could be used to meet SIDS No additional animal testing required 15 ISRTP Workshop, Baltimore, Nov , 2005

16 REACH ~3.9M animals?! Proposed TES/ITS elements weight of evidence chemical grouping consortia of companies data sharing exposure consideration/tonnage triggers substances produced or imported b/w 1-10 ton/yr & per manufacturer or importer, testing should generally be limited to in vitro methods thoughtful assessment of existing information data from epidemiological studies, computer calculations & international sources will be taken into account before deciding whether additional testing is necessary Recently announced ECVAM partnership 16 ISRTP Workshop, Baltimore, Nov , 2005

17 17 ISRTP Workshop, Baltimore, Nov , 2005

18 ECEAE 18 ISRTP Workshop, Baltimore, Nov , 2005

19 Endocrine Disruption: US EPA Conceptual Framework Proposed Tier 1 screens: ER/AR binding Steroidogenesis Aromatase Uterotrophic Hershberger Pubertal female/male Amphibian metamorphosis Fish reproduction screen Proposed Tier 2 tests: Mammalian 2-gen Avian 2-gen Fish 2-gen Amphibian 2-gen Invertebrate chronic 19 ISRTP Workshop, Baltimore, Nov , 2005

20 20 ISRTP Workshop, Baltimore, Nov , 2005 (from the British Union for the Abolition of Vivisection)

21 ILSI/HESI

22 Barriers & Challenges Over-confidence in animal methods Variability in animal data Black-box nature of animal tests Under-confidence in non-animal methods Institutional inertia Low empathy factor for rodents Limited AP stakeholder access & influence Limited exposure data Limited data sharing Limited human data Statutory, regulatory, or public pressure to move forward 22 ISRTP Workshop, Baltimore, Nov , 2005 Lack of data on mechanism & systems biology Translating latest biological techniques into test methods Limited funding for translational research on methods Translating industry s in-house methods into regulatory tox. Perceived hassle of validation Risk managers reliance on built-in redundancy of tests

23 Acknowledgements PeTA PCRM BUAV Eurogroup for Animal Welfare European Coalition to End Animal Experiments 23 ISRTP Workshop, Baltimore, Nov , 2005