RISK21: Q-KEDRF. ILSI Health and Environmental Sciences Institute

Transcription

1 RISK21: Q-KEDRF ILSI Health and Environmental Sciences Institute

2 Mode of Action 3 Risk / Safety In vivo In vitro 4 Toxicity QSAR/ TTC Matrix Biomonitoring 2 Probabilistic Deterministic Minimal Info Exposure Problem Formulation 1 Conclude

3 Mode of Action In vivo 3 Risk / Safety Dose-response for mode of action, Key Events Dose Response Framework (KEDRF) 4 In vitro Toxicity QSAR/ TTC Matrix Biomonitoring 2 Probabilistic Deterministic Minimal Info Exposure Problem Formulation 1 Conclude

4 Modulating Factors Host factors Genetic variation (e.g. GST polymorphism) Disease/ill-health (e.g. chronic kidney disease) Defense mechanisms (e.g. immune responsiveness) Physiology (e.g. life stage) Lifestyle Diet (e.g. calorie intake) Tobacco Alcohol Exercise Medication (e.g. CYP inhibitors) Illegal drugs Dietary supplements (e.g. anti-oxidants) Environment Co-exposures (e.g. dust, water contaminants)

5 Critical data gaps identified Critical data gaps identified Quantitative KEDRF (Q-KEDRF) Mode of Action/Human Relevance Framework (Meek et al, 2014) Problem formulation Hypothesized mode of action (key events) based on Bradford Hill considerations Adverse effect Mode of action Key events Assessment specific data generation Assessment specific data generation Not relevant Level of confidence Qualitative and quantitative human concordance Level of confidence Implications for risk assessment B2. Which putative Key Events can be identified unequivocally? Are any Key Events represented by an Associative Event? B3. What is the dose response and temporal relationship between the Key Events and the apical event? B1. Use current methodologies, e.g., Margin of Exposure (MOE), on the most Appropriate endpoint Dose-Response and Temporality of Key Events (pathways) B4. What are the Modulating Factors for Key Events of the human dose response? How do the Key Events and their Modulating Factors vary within the human population? DOSE-RESPONSE (Most relevant apical event) B5. Use quantitative dose response analysis to understand species differences with the goal of developing human toxicity criteria based on the MOA

6 Example: Dimethylarsinic Acid (DMA) DMA III (Metabolite) Urothelial Toxicity Regenerative Proliferation Hyperplasia Bladder Tumors SUSTAINED Formation of the reactive metabolite trivalent DMA (DMA III ) Cytotoxicity within the superficial epithelial layer of the urinary bladder Regenerative proliferation Urothelial hyperplasia (Bladder tumors)

7 Dose-time concordance table for DMAIII

8 Dose-response species concordance EVENT OR FACTOR QUALITATIVE CONCORDANCE Animals Humans Concordance QUANTITATIVE CONCORDANCE AND QUANTITATIVE DOSE-RESPONSE Str.* Animals Humans Key Event #1 Metabolism to DMA III DMA III detected in urine following 26 weeks treatment with 100 ppm DMA V Evidence following DMA V exposure too limited to draw conclusions, but DMA III shown to be present following human exposure to ias KEY EVENTS Plausible +/- NA DMA III in urine (mm) Dose of DMA V (mg/kg/d) Key Event #2 Urothelial Cytotoxicity Urothelial toxicity observed in vivo in rats at 2 ppm but not enough for successive key events Potential to occur in humans but unknown if sufficient DMA III formed Plausible +/- NA DMA III in urine (mm) weeks Dose of DMA V (mg/kg/d) 10 weeks Key Event #3 Urothelial Proliferation observed at 0.5 mg/kg/d DMA V Potential to occur in humans but unknown if sufficient DMA III formed Plausible +/- 5 NA Proliferation at 10 weeks (fold change) Dose of DMA V (mg/kg/d) *Str. = strength

9 Dose-response species concordance EVENT OR FACTOR QUALITATIVE CONCORDANCE QUANTITATIVE CONCORDANCE AND QUANTITATIVE DOSE-RESPONSE Key Event #4 Hyperplasia Apical Event Tumors Animals Humans Concordance observed at 2 mg/kg/d or 0.3 to 2 mmol DMA III in urine observed at 5 mg/kg/d DMA V or 0.8 to 5.05 mmol DMA III in urine Potential to occur in humans but unknown if sufficient DMA III formed No data in humans Str.* Animals Humans KEY EVENTS Plausible +/- NA Concordance cannot be made because there is no human data Frequency of Hyperplasia at 10 weeks Dose of DMA V (mg/kg/d) - NA Frequency of Bladder Tumors (2 yr) Dose of DMA V (mg/kg/d) *Str. = strength

10 SUSTAINED Q-KEDRF and RISK21 Matrix DMA III (Metabolite) Urothelial Toxicity Regenerative Proliferation Hyperplasia Bladder Tumors

11 Conclusions High quality D-R data for both KEs and the apical event are needed Which KEs can be unequivocally identified as such? Both the position and steepness of the D-R should be considered MFs need to be taken into account relative to dose levels of interest Quantitative DR of KEs can provide much information about the MOA

12 Thank you Questions welcome