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Risk, Hazard, and Innovation. Prof. Dr. Wolfgang Dekant Department of Toxicology University of Würzburg Germany [email protected]. Faksimile aus Paracelsus, 3. Kärntner Defension 1538. Paracelsus (1492 - 1541) Hirschvogel, Nürnberg, 1536. Toxicological risk assessment . - PowerPoint PPT Presentation
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Prof. Dr. Wolfgang DekantDepartment of Toxicology
University of WürzburgGermany
Risk, Hazard, and Innovation
Paracelsus (1492 - 1541)Hirschvogel, Nürnberg, 1536
Faksimile aus Paracelsus, 3. Kärntner Defension 1538
Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany
Toxicological risk assessment
Hazard x Exposure = Risk (Probability of effect)
Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany
Risk characterization of chemicals
Identification
Nature and incidence of adverse
effects in animal studies (hazard)
Exposure characteristics
Mode of action
Assessment
Dose-response and extrapolation
Data quality
Reproducibility and plausibility of
effects reported
Risk characterization
Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany
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
Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany
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)
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
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
Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany
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
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
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)
NOAEL (mg/kg bw) : SF = ADITDI (mg/kg bw)PTWI
Animal Human
Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany
Prof. Dr. Wolfgang Dekant, Department of Toxicology, University of Würzburg, Germany
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