Prof. Dr. Wolfgang Dekant Department of Toxicology University of Würzburg Germany

1. Risk, Hazard, and Innovation Prof. Dr. Wolfgang Dekant Department of Toxicology University of Würzburg Germany dekant@toxi.uni-wuerzburg.de

2. Faksimile aus Paracelsus, 3. Kärntner Defension 1538 Paracelsus (1492 - 1541)Hirschvogel, Nürnberg, 1536 Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

3. Toxicological risk assessment Hazard x Exposure = Risk (Probability of effect) Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

4. Risk characterization of chemicals Risk characterization Identification Assessment • Nature and incidence of adverse effects in animal studies (hazard) • Exposure characteristics • Mode of action • Dose-response and extrapolation • Data quality • Reproducibility and plausibility of effects reported Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

5. Hazard assessment • Regulations mandate targeted animal experiments • Studies need to be performed under “Good Laboratory Practice” and according to specific testing guidelines (OECD, US EPA, ICH) detailing study design (number of animal/group, duration, data generation from weight gain over clinical chemistry to detailed histopathology) • Study design should include at least three dose levels (and untreated control), the highest dose should result in adverse effects within time-frame of experiment • Some endpoints supported by non-animal studies (mainly aspects of genotoxicity) Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

6. Quality Criteria for Toxicology Studies • Reliable without restriction (all raw data available for evaluation, performed along established guideline, clearly defined endpoints with known relation to adversity) • Reliable with restriction (detailed description of methods, observations and results, scientifically acceptable study design and data evaluation) • Not reliable (poorly documented, inadequate methodology, inappropriate data evaluation) • Not assignable (e.g. abstracts, case report) Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

7. Definition of „Adverse Effects“ • An adverse effect is a “change in the morphology, physiology, growth, development, reproduction, or life span of an organism, … that results in an impairment of functional capacity,…..” (WHO/IPCS, 2004). Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

8. Exposure assessment • Often predicted using “conservative” defaults integrated into computer predictions • Measured data on content of chemical in environmental media and assumptions of human behavior using highly “conservative” approach • Direct measurements (biomonitoring) in humans much more appropriate, usually demonstrates much lower exposures as derived from above assessments Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

9. WOE approach in toxicology • The weight of evidence evaluation is a determination of what is a reasonable conclusion in view of all available information.... while exercising one’s best judgement. • Requires detailed justification of conclusions based on the available science Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

10. Extrapolation issues Exposures of animals in toxicity tests usually orders of magnitude above expected or measured human exposures, therefore extrapolations are needed • Dose extrapolation: Effects at high doses in rodents to low doses expected from the human exposure assessment • Species extrapolation: rodents to humans considering toxicokinetics and toxicodynamics • Transformation of “point of departure” (dose descriptor) in animals to a tolerable human exposure (dose) Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

11. NOAEL (mg/kg bw) : SF = ADI TDI (mg/kg bw) PTWI Risk assessment relies on the TDI Concept (WHO 1961) Extrapolation from animals to humans to derive a tolerable-daily-intake (TDI): • Lowest NOAEL • Most sensitive species used in toxicity studies • Application of a safety factor (SF) (usually 100) Human Animal Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany

12. The future ? • Relying only on hazard assessment is often misleading and present hazard assessment procedures require large number of experimental animals • Scientifically, more focus on exposure-based assessments is mandated • Integrated testing strategies providing useful information on more chemicals within a shorter time frame are needed • However, interpretation of such data likely will be difficult and even more controversy Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany