WHAT S NEW IN ALTERNATIVES?

Transcription

1 WHAT S NEW IN ALTERNATIVES? Joanne Zurlo, PhD Center for Alternatives to Animal Testing (CAAT) Johns Hopkins Bloomberg School of Public Health Baltimore, MD

2 What are alternatives? Alternative are sometimes equated with the Three Rs: Reduction - methods that allow comparable amounts of data to be obtained from the use of fewer animals, or that allow more information to be obtained from a given number of animals, so that in the long run, fewer animals are needed to perform a given experiment or test Refinement methods that alleviate or minimize potential pain and distress and that enhance animal well-being Replacement methods that are performed without the use of animals

3 The Required Search for Alternatives

4 ALTWEB

5 Altweb Project Team Members Alternatives Research & Development Foundation APHIS- USDA Animal Welfare Information Center Canadian Council on Animal Care Center for Animal Welfare (MSPCA) Environmental Protection Agency ECVAM (EU) ecopa (Europe) eurca (Europe) Food & Drug Administration FRAME (UK) Humane Society of the US Inst. for Laboratory Animal Research Interagency Coordinating Committee for the Validation of Alternative Methods I-CARE (International) Johns Hopkins CAAT Norwegian School of Veterinary Science NC3Rs (UK) National Library of Medicine (NIH) Procter & Gamble RSPCA (UK) Scientists Center for Animal Welfare UC Center for Animal Alternatives Utrecht University NCA (Netherlands) Veterans Administration Zebet (Germany)

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12 Animal Welfare and Refinement

13 What is animal welfare? Maintenance of good health Minimization of negative states, e.g., pain and distress and enhancement of positive states Freedom to exhibit species-specific behaviors (Fraser, 2009)

14 Refinement Considerations Pain - Recognition and alleviation Distress - Minimization (prevention), recognition and alleviation Humane Endpoints Environmental enrichment

15 Specific Issues for Laboratory Animals Confinement in cages little freedom of movement Few guidelines for enrichment are laboratory animals normal? Caregivers not proficient in animal behavior of laboratory animals

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17 Refinement Information

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20 Alternatives and Toxicity Testing

21 Why test? As of 2005, there were 82,000 chemicals in commerce with approximately 700 new chemicals being introduced per year. There is little publically available safety data for most of these chemicals and many of them are produced in quantities of a million pounds per year or more. Drug testing for efficacy and safety is required by the Food and Drug Administration Pesticides must also be tested because their residues are found in food.

22 Current Toxicity Testing Paradigm for Chemicals Relies on administering high doses of chemicals and drugs to animals, then results are extrapolated for low dose exposures Animals are typically inbred strains, and the results are extrapolated to heterogeneous human populations Results from animal studies do not always reflect results in humans

23 Toxicity Testing in the 21 st Century A Vision and a Strategy A 2007 report by the National Research Council of the National Academies requested by the EPA

24 Vision of the Committee To effect a paradigm shift in the approach to toxicity testing that would: Provide broad coverage of chemicals, chemical mixtures, outcomes and life stages Reduce the cost and time of testing Use fewer animals and cause minimal suffering in the animals used Develop a more robust scientific basis for assessing health effects of environmental agents

25 A New Paradigm: Activation of Toxicity Pathways Exposure Tissue Dose Biologic Interaction Low Dose Higher Dose Higher yet Perturbation Biologic Inputs Normal Biologic Function Adaptive Stress Responses (Courtesy of Mel Andersen) Early Cellular Changes Cell Injury Morbidity and Mortality

26 Toxicity Pathways Toxicity Pathway: A cellular response pathway that, when sufficiently perturbed, is expected to result in an adverse health effect.

27 Tools and Technologies Mapping toxicity pathways: In vitro tests High-throughput methods Microarrays Computational biology Limited in vivo tests

28 Tools and Technologies Dose-response and extrapolation modeling: Physiologically based pharmacokinetic models Dose response models of toxicity pathways

29 29 ToxCast Program (EPA) Over 650 high throughput screening assays testing 1,000 chemicals for in vitro bioactivity. Phase-I: 309 data-rich chemicals (primarily pesticides) having over 30 years of traditional animal studies valued at $2B; in vitro signatures defined by how well they predict outcomes in the mammalian studies. Phase-II: currently screening 1,000 chemicals from a broad range of sources (eg, industrial and consumer products, food additives, failed drugs) to validate, expand, and apply predictive models of toxicity.

30 Thank you! Questions?