Perspective on next steps for application in practice Alan R Boobis Imperial College London a.boobis@imperial.ac.uk NC3Rs: Pathway-based approaches across the biosciences London 28 th April, 2016
AOPs An AOP is a sequence of events from the exposure of an individual or population to a chemical substance through a final adverse (toxic) effect at the individual level (for human health) or population level (for ecotoxicological endpoints). The key events in an AOP should be definable and make sense from a physiological and biochemical perspective. AOPs incorporate the toxicity pathway and mode of action for an adverse effect.
AOP/MOA Exposure Molecular Initiating Event Organ Effects Population Cellular Effects Individual (Adverse Outcome) ADME/TK Adverse Outcome Pathway Mode of Action Key events (based on Bradford Hill considerations) Level of confidence
Problem formulation Qualitative Quantitative Product development Screening to de-risk compounds for further development Prioritisation for risk management action Ranking by potency Grouping, for cumulative risk assessment Classification and labelling Indication of worst case effects for emergencies, etc, e.g. during transport Read across Safety assessment e.g. Health-based guidance values As part of risk assessment of compounds to which people will be exposed, e.g. occupationally Cost of false positive
Assessment of key events Hazard ID Hazard characterisation Response POD Dose MOE = POD/Exposure
Establishing fitness-for-purpose of an AOP Method performance characterization Are methods for individual key events adequate Model predictive performance Confidence in determining the AOP using information on key events Utilization Utility of AOP to address regulatory (or other) issue of concern Relevance Extrapolation Assessment context
AOP-Wiki status As of 24 April, 2016 1 AOP endorsed by OECD 6 AOPs approved by EAGMST (Extended Advisory Group on Molecular Screening and Toxicogenomics) Under WNT (Working Group of the National Coordinators of the Test Guidelines Programme) and TFHA (Task Force for Hazard Assessment) Review 12 AOPs under review by EAGMST 84 under EAGMST development 15 under SAAOP (Society for the Advancement of Adverse Outcome Pathways) development
Modified Bradford Hill considerations Concordance of dose-response relationships between key and end events Dose-response relationships for key events would be compared with one another and with those for endpoints of concern Are the key events always observed at doses below or similar to those associated with the toxic outcome? Temporal association (time) Key events and adverse outcomes would be evaluated to determine if they occur in expected order Consistency and specificity Is the incidence of the toxic effect consistent with that for the key events? i.e., Less than that for the key events? Is the sequence of events reversible if dosing is stopped or a key event prevented? Biological plausibility Is the pattern of effects across species/strains/systems consistent with the hypothesized mode of action? Does the hypothesized mode of action make sense based on broader knowledge (e.g., biology, established mode of action)?
Not all adverse outcomes are relevant to humans Liver tumours induced in mice by phenobarbital Renal tumours in males rats induced by D-limonene Mammary tumours induced in females rats by atrazine Bladder tumours induced in rats by sodium saccharin Phenobarbital in mouse Carcinoma of liver Hence, not all AOPs are relevant to humans, even those in rodents
MOA human relevance framework Problem formulation Key events Hypothesized mode of action (key events) based on Bradford Hill considerations Mode of action (Adverse) effect Assessment specific data generation Critical data gaps identified Level of confidence Qualitative and quantitative human concordance Implications for safety assessment (e.g. dose-response) Assessment specific data generation Critical data gaps identified Level of confidence
AOP and key events Host characteristics (e.g. lifestage, genetics) Other factors (e.g. lifestyle, environment, homeostasis) Host characteristics (e.g. lifestage, genetics) Other factors (e.g. lifestyle, environment, homeostasis) AOP MIE KEY EVENT [S] External dose Molecular target Cellular effects Organ effects Adverse outcome (individual) Adverse outcome (population) ADMT/TK KEY EVENT[S] KEY EVENT[S] Other factors (e.g. lifestyle, environment, homeostasis) Other factors (e.g. lifestyle, environment, homeostasis) Host characteristics (e.g. lifestage, genetics) Host characteristics (e.g. lifestage, genetics)
Information necessary for hazard characterization Information on the toxicodynamic response (AOP) Toxicokinetics of the chemical of interest Chemical-specific dose-response information relevant to human exposure scenarios
Systems-based models From DeWoksin (2007); Schneider & Klabunde (2013)
Application in practice AOPs are chemical-agnostic Risk assessment is chemical-specific Evidence that a given AOP will be engaged at human exposure levels? Human relevance? Necessary key events? Quantitative dose-response relationships In vitro to in vivo extrapolation Adequate coverage of possible AOPs without an unacceptably high false positive rate Learn by experience need to provide confidence to risk manager Parallel assessments for a period of time?