Outline • Assessment of Mode of ActionHuman Relevance in Risk Assessment • Where does this fit? • What data are relevant? – Mechanistic » Such as?? • How is it done? • A Relevant Framework • An Example • Review of Important Aspects • Reading • Introduction of Case Study Exercise Hazard Identification (Is This Toxic?) • Hazard identification is consideration of the intrinsic property of a substance to cause harm – Toxicological, epidemiological study – “Strength” of evidence – Judgment on the reliability of a given data set supporting a toxicological effect • Quality of the studies and methodology
Considering Mechanistic Data to Assess Mode of Action/Human Relevance M.E. (Bette) Meek McLaughlin Centre University of Ottawa, Ottawa, Canada Email:bmeek@uottawa.ca McLaughlin Centre University of Ottawa 2 Outline • Assessment of Mode of Action/Human Relevance in Risk Assessment • Where does this fit? • What data are relevant? – Mechanistic » Such as?? • How is it done? • A Relevant Framework • An Example • Review of Important Aspects • Reading • Introduction of Case Study Exercise Risk Assessment/Management • Hazard Identification: IS THIS TOXIC? • Hazard Characterization: IS THIS TOXIC TO HUMANS? WHICH ONES? WHICH CONDITIONS? • Dose-Response Assessment: HOW TOXIC IS IT? • Exposure Assessment: WHO IS EXPOSED, HOW MUCH, HOW OFTEN, AND FOR HOW LONG EACH TIME? • Risk Characterization: SO WHAT? • Risk Management: SO WHAT WILL BE DONE ABOUT IT? 3 McLaughlin Centre University of Ottawa 4 Hazard Identification (Is This Toxic?) • Hazard identification is consideration of the intrinsic property of a substance to cause harm – Toxicological, epidemiological study – “Strength” of evidence – Judgment on the reliability of a given data set supporting a toxicological effect • Quality of the studies and methodology McLaughlin Centre University of Ottawa 5 Hazard Identification (Is this Toxic?) Epidemiological Studies Ask the right question • Examine the right species at the right doses Answer it badly • Many factors which complicate interpretation (confounders); not very sensitive Toxicological Studies Ask the wrong question • Examine the wrong species at high doses, Answer it well • Control of Variables Hazard Characterization (Is This Toxic to Humans, Which Humans, Under What Conditions?) • Hazard characterization is the (qualitative) likelihood of causing adverse effects in particular subgroups of humans, based on consideration of results of toxicological/epidemiological studies and mechanistic data (mode of action) • Weight of evidence (WOE) (early, systematic assimilation) – Comprehensive, integrated judgment of all relevant information supporting conclusions regarding a toxicological effect, including human relevance • Consistency, specificity, biological plausibility • Which critical effects for dose-response? McLaughlin Centre University of Ottawa 6 Implications of Mode of Action for Dose Response Analysis (How Toxic is it?) • In dose-response analysis, the likelihood of causing adverse effects in particular subgroups of humans is quantitatively estimated. • Mechanistic data/Mode of Action (MOA) are important in selection of approach – Linear extrapolation or “safe” levels • reference/tolerable/acceptable intakes • Also tells us about magnitude of differences between animals and humans and within humans McLaughlin Centre University of Ottawa 7 MOA Implications for Dose Response PoD = Point of Departure RfD = Reference Dose MoE = Margin of Exposure NOAEL Dose MoE Response x x x Human Exposure x Point of Departure Method of Extrapolation Consideration of “Key Events” to protect human health RfD = PoD/UFs 8 McLaughlin Centre University of Ottawa 9 Non-Linear (Reference or Tolerable Doses) • Reference/Acceptable/Tolerable Intakes = N/LO(A)EL or BMC/D UF N/LOAEL – no evidence of adverse effect BMC/D - Benchmark dose – modelled estimate of specified increase in effect Uncertainty Factor • Interspecies Differences (x10) (between species) • Human Variability (x10) (differences within humans) – interindividual or intraspecies variation • Other – Adequacy of database (x1-100) McLaughlin Centre University of Ottawa 10 Risk Assessment – Qualitative/Quantitative • Hazard Identification – Effects seen in animals and/or humans • Hazard Characterization (qualitative – toxic?) – Mode of Action/Qualitative Relevance to Humans • Dose Response Analyses (quantitative – how toxic?) – Shape of the dose response curve – Quantitative relevance to humans and in various subgroups • Differences between experimental species & humans • Differences within humans • Exposure Estimation • Risk Characterization [...]... the basis of quantitative differences in either kinetic or dynamic factors between animals and humans? NO Implications of kinetic and dynamic data for dose –response 26 1.Weight of Evidence for the Mode of Action in Animals • Introduction, Postulated Mode( s) of Action (MOAs), Key Events • Dose-Response/Temporal (Time) Relationships between Key and End Events • Consistency, Specificity – Do all of the... necessary element of the mode of action, or is a marker for such an element • Examples – Specific metabolic transformation – Chemically induced direct and indirect reaction with genetic material (DNA) – Cytotoxicity (cell death) – Hormonal changes – Increased cell growth and organ weight Examples of MOAs A chain of key events leading to adverse outcome • Metabolic activation, Cell Death (Cytotoxicity) and... Relevance Framework Is the weight of evidence sufficient to establish a mode of action (MOA) in animals? NO Implications of kinetic and dynamic data for dose –response YES MOA not Relevant YES Can human relevance of the MOA be reasonably excluded on the basis of fundamental, qualitative differences in key events between animals and humans? NO MOA not Relevant YES Can human relevance of the MOA be reasonably... metabolism – nature of interaction with biological receptors • E.g., direct or indirect interaction with genetic material, proteins – nature of early effects leading to toxicity • E.g., effects on hormones leading to secondary outcome • Toxicity leading to cell death and repair • Physical irritation of chemical precipitates McLaughlin Centre University of Ottawa 14 How Do Mechanistic Data Help? They address:... Ottawa 23 MOA/HR Framework –How Does it Help? • designed to organize information – Guides assessors in considering the extent of evidence as a basis for decision making and identifying important data gaps • i.e., weight of evidence – Uses established criteria • • • consistency of documentation greater similarity of outcome? developing appropriate data McLaughlin Centre University of Ottawa 24 IPCS/ILSI... different from mechanism of action? – All Events at Molecular Level McLaughlin Centre University of Ottawa 16 Exposure Key event Mode of action (identification of key & necessary steps) Key event versus “Mechanism of action (more detailed understanding at biochemical & molecular level) Key event McLaughlin Centre University of Ottawa Toxicity 17 Mode vs Mechanism (Toxicokinetics/Toxicodynamics) Plausible... hypothesized mode of action make sense based on broader knowledge • E.g biology • Established MOA? 1.Is the Weight of Evidence – for the Mode of Action in Animals Sufficient? (Cont’d) • • • • Introduction, Proposed Mode( s) of Action, Key Events Dose-Response & Temporal Relationship Strength, Consistency, Specificity Biological Plausibility • Assessment, Uncertainties – Weight of evidence is determined (weak to. .. relevant to humans? • Are there subgroups of the human population at special risk? • E.g., children, • the elderly? • What is the risk at the much lower doses to which humans are exposed? – High to low dose extrapolations 15 Mode vs Mechanism (Toxicokinetics/Toxicodynamics) • What is Mode of Action (MOA)? – “Key Events” – Key events are not every step in the process, but rather what is likely to “drive”... (Cytotoxicity) and Repair (Proliferation) • Hormonal perturbation – E.g Interference with the testosterone pathway, leading to male reproductive malformations • Formation of precipitates (stones) in urine, cell death and repair • Protein binding, cell death and repair • Interaction with DNA, mutation, cell death and repair What Helps in Considering Mode of Action and Human Relevance? • International Life Sciences... chemical do to the body? McLaughlin Centre University of Ottawa 11 Exposure-Response Continuum Mode of Action involves identification of several key events between exposure and effect Exposure Tissue Dose Biologically Effective Dose Physiologically Based Pharmacokinetic Models Early Responses Tissue Dose Metric Late Responses Pathology Mode of Action Toxicokinetics Toxicodynamics Toxicokinetics/Toxicodynamics . likelihood of causing adverse effects in particular subgroups of humans, based on consideration of results of toxicological/epidemiological studies and mechanistic data (mode of action) • Weight of. (qualitative – toxic?) – Mode of Action/ Qualitative Relevance to Humans • Dose Response Analyses (quantitative – how toxic?) – Shape of the dose response curve – Quantitative relevance to humans and. Considering Mechanistic Data to Assess Mode of Action/ Human Relevance M.E. (Bette) Meek McLaughlin Centre University of Ottawa, Ottawa, Canada Email:bmeek@uottawa.ca McLaughlin