Tox21: Opportunities& Challenges Richard A. Becker Ph.D., DABT American Chemistry Council October 21, 2010
Opportunities and Challenges The manifest challenge is to develop in vitro and in silico approaches that adequately address the range and complexity of biological processes and can predict toxicity responses How can these new technologies be used with requisite degree of scientific confidence in regulatory & product stewardship chemical management programs? 2
Prioritization Opportunities: Prioritization Biological profiling to develop information on activity of chemicals in pathways related to toxicity responses Link with indicators of exposure Risk based priority setting 3
Opportunities: Grouping Chemicals in Categories Category = a group of chemicals whose physicochemical and toxicological properties are likely to be similar. Permits interpolation of responses from one member to another HTS (and other similar approaches) could be used to develop &/or justify a category based on the pattern of activity of chemicals in pathways related to toxicity responses Within structurally related compounds, ID subcategory based on biological responses: C1R C2R and C7R C12R exhibit different profile from C4R C6R 4
Opportunities: Guide Tox Study Design What does the biological profile indicate re: activity of a chemical in pathways related to toxicity responses? Can one deduce potential mode(s) of action based on HTS and other molecular profiling studies? Based on what is known about that mode of action, how should a tox study be designed? Dose levels Animal model most relevant Endpoints to measure Satellite groups specialized studies Test the hypothesis of particular mode of action 5
Opportunities: Screening Level Risk Appraisal As a key element of an Integrated Testing and Assessment Framework A framework that utilizes relevant information from multiple sources including predictive computer models, chemical categories, and in vitro assays with information/results from traditional tox studies to evaluate potential hazards Initial hazard characterization) and derive a tox point of departure (NOAEL/BMD/BMDL) Look at use and exposure scenarios and develop quantitative metrics of exposure Then combine hazard with exposure to yield screening level risk characterization (Margin of Exposure) 6
Challenges To predict toxicity will require extensive collaborative research to forge the solid scientific foundation for developing prediction models using QSAR, genomics profiling and High Throughput Screening methods All need to have confidence in the models regulators, industry and the public If the models are to be used in place of traditional tox testing can we have confidence they ll provide results that will be valid? Health protective?
Challenges Recurrent theme need to understand what the biological profiles indicate re: activity of a chemical in pathways related to toxicity responses Necessary to evaluate relevance, reliability, sensitivity and specificity of advanced high throughput molecular screening and computational profiling methods prior to regulatory acceptance so that regulatory agencies, the regulated community and the public have sufficient confidence in the decisions based on such methods. Toxicity Testing in the 21 st Century: A View from the Chemical Industry Bus and Becker, (2009) TOXICOLOGICAL SCIENCES 112(2), 297 302 (2009 8
Toxicological Sciences Bringing the Vision to Life Andersen and Krewski Toxicol. Sci..2009:107:324 330 Pragmatic Challenges for the Vision of Toxicity Testing in the 21 st Century in a Regulatory Context: Another Ames Test?...or a New Edition of "the Red Book"? Meek and Doull Toxicol. Sci..2009: 108:19 21 Mapping the Road Ahead Hartung Toxicol. Sci..2009: 109: 18 23 View from the Pharmaceutical Industry MacDonald and Robertson Toxicol. Sci..2009: 110: 40 46 View from the Chemical Industry Bus and Becker Toxicol. Sci.2009: 112, 297 302 Biologically relevant exposure science for the 21st century Hubal, Toxicol. Sci. 2009: 111, 226 232. Endless possibilities: stem cells and the vision for toxicity testing in the 21st century Chapin and Stedman, Toxicol. Sci. 2009: 112, 17 22 Toxicity testing in the 21st century: using the new toxicity testing paradigm to create a taxonomy of adverse effects Boekelheide and Campion, Toxicol. Sci.2010 114: 20 24 The Vision of Toxicity Testing in the 21st Century: Moving from Discussion to Action Andersen and Krewski Toxicol. Sci.2010 9 117: 17 24
Challenges A shotgun approach generating large quantities of data and applying informatics to develop correlations will not be very fruitful in developing the models we need Need a thoughtful approach to develop models that are relevant to extrapolating to humans We need to be careful that such approaches as ToxCast don t just lead us to re discover what we already know about toxicity: metabolism is critical, dose is critical, effects at doses which have saturated detoxification systems are not very relevant for extrapolating to low, environmentally relevant levels of exposures to humans
Agent Release Transport/ Transformation Exposure Monitoring Indicators Exposure/Effect Discontinuum Exposure/ Contact Entry & Distribution in Body = Dose No Health Effects Dose Below Threshold or Homeostatic Response Effect Altered Structure/ Function Biomon itoring Indicators Health Outcome Indicators Adverse Health Outcomes Mortality Morbidity
Toxicity Pathway Exposure Effect Discontinuum Response is Dependent on Dose: Not All Exposures Will Produce Adverse Effects Higher Dose Leads to Altered Organ Structure / Function Adverse Health Outcome Response Adaptive Responses Higher Dose Leads to Altered Organ Structure / Function No Adverse Outcomes Higher Dose Leads to Altered Physiology: Adaptive Response No Adverse Outcomes Homeostasis Increasing Dose Higher Dose Elicits Homeostatic Response No Adverse Outcome Chemical Properties Protein binding DNA Binding Receptor Binding Gene Expression Protein Production Altered Signaling Dose Below Threshold No Adverse Outcomes Toxicant Toxicity Pathway Interaction with macromolecules Cellular Responses Effects Organism Responses
Exposure Effect Discontinuum: Illustrated in Graphic from NRC Toxicity Testing in the 21 st Century 2007
Challenge and Opportunity Develop Predictive Models from HTS and Genomic Data That are Fully Transparent Shared Responsibility: Use knowledge of biological pathways and dose response. Predictive models must have: 1)Mechanistic interpretation: MOA, Bio.Pathway, DR 2)Defined endpoint 3)Unambiguous algorithm 4)Defined domain of applicability 5)Appropriate measures of goodness of fit, robustness and predictivity