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(How) Can In silico and/or In vitro Testing be used for Toxicity Assessment instead of in vivo Approaches? PowerPoint Presentation
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(How) Can In silico and/or In vitro Testing be used for Toxicity Assessment instead of in vivo Approaches?

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(How) Can In silico and/or In vitro Testing be used for Toxicity Assessment instead of in vivo Approaches?

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  1. (How) Can In silico and/or In vitro Testing be used for Toxicity Assessment instead of in vivo Approaches? Timothy J. Shafer 2012 SOT In vitro Lunch Disclaimer: The views expressed in this presentation are solely those of the Author. They do not represent Agency Policy.

  2. What is the Current Toxicity Testing Paradigm? Batteries of in vivo tests in various mammalian species- when agencies have regulatory authority to require testing 27 Different Studies- Does not include Eco http://www.epa.gov/pesticides/regulating/data_requirements.htm

  3. Are there any success stories? • Draize eye test (Ocular Toxicity) • Use validated alternatives • Consideration of chemical properties • Alternative tests for corrosive compounds (acids/bases) • Alternative in vitro tests (hens egg chorioallantoic membrane (HET-CAM) assay; human corneal cells in culture • In vitro tests prior to in vivo • Genetic Tox assays: Ames Test (Mutagenicity/Carcinogenicity) • Tests mutagenicity using bacteria • Is 70% predictive of carcinogens for general classes • Nearly 100% prediction for PAH, Aromatic and heterocyclic amines, nitro aromatics • Poorly predictive for chlorinated organic (chlorophenols chlorinated hydrocarbons) • Rat and mouse are 70% predictive of humans; and 70% predictive of each other

  4. Why do we need a new testing paradigm? • Large number of chemicals for which we do not have complete toxicity information • Need to assess mixtures • Need to assess all endpoints and life stages • Efficiency • Costs associated with in vivo testing • $15-20 M to register 1 food use pesticide • $1M and 1.5yr for a Developmental Neurotoxicity (DNT) guideline study • Humane reasons- use fewer animals and minimize distress Developmental Neurotoxicity < 1%

  5. Who says we need a new testing paradigm? • REACH legislation • Registration, Evaluation, Authorisation and Restriction of Chemical substances • “Under REACH, animal testing is to be avoided in favour of alternative methods and registrants can only carry out tests involving the use of animals as a last resort. “ (http://ec.europa.eu/environment/chemicals/reach/reach_intro.htm). • NAS Toxicity in the 21st Century report • Limitations of current paradigm are high to low dose extrapolations and animal to human extrapolations = limited ability to predict what happens in humans exposed to low doses. • Stakeholders • Public wants safe use of chemicals • Industry wants reduced costs • Animal welfare groups want reduced use of animals

  6. What kinds of decisions do regulators have to make? • Allow a new compound to be produced. • Risk/Benefit (e.g. new drug) vs safety (food additive) • Replace or choose between compounds (Risk/Risk). • Regulate levels released into the environment or use conditions for a compound (e.g. pesticide labels). • Extent of clean up at a hazardous waste site. • Setting exposure levels (RfD, RfC, etc), ambient air quality standards, allowable levels of contamination (e.g. in drinking water).

  7. What kind of information do regulators need to make these decisions? • Who is exposed and to how much? • What is the hazard? • Organ system • Lifestage • Ecological • What are the properties of the chemical? • Will it move in the environment? • Will it bioaccumulate? • Is it reactive? • What is the chemical used for and are there alternatives?

  8. How do we improve the current paradigm? Source: Figure 2-3, NAS, 2007

  9. Exposure ADME Altered Na Channel Function Na Channel Function ?? Altered Neuronal Pathways Neuronal Pathways What is a Toxicity Pathway anyhow? Neuronal Excitability Network Firing Patterns Normal Function Acute Neurotoxicity of Pyrethroid Insecticides Tissue Level Organ Level Key Event Cell Level Altered Neuronal Excitability Altered Network Patterns Adverse Clinical Outcome Developmental Neurotoxicity of Pyrethroid Insecticides ?? ?? Adverse Clinical Outcome ?

  10. Developing Predictive Models for Toxicity Existing Chemicals Hepatotoxicity Chemical Characteristics HTS Assays for Toxicity Pathways Cardiotoxicity Neurotoxicity QSAR Developmental toxicity Quantitative Structure-Activity Relationships (QSAR) Renal toxicity Carcinogenic Immunotoxicity New Chemical

  11. Questions 1. Is it a realistic goal to replace all animal testing? (In what timeframe?) 2. What criteria must be fulfilled for an in vitro approach to replace an in vivo approach? 3. Does the context of the decision to be made, or the level of information required matter? 4. What are the challenges to human risk? How can these be addressed? 5. (How) Can an in vitro approach be useful if the toxicity pathway is not completely understood? 6. If we replace, what are the scientific questions (uncertainties) that we need to be concerned about? 7 Would the public accept and be comfortable with decisions made using in vitro data? What if the decision was made entirely on the basis of in vitro data?