Prof. Dr. Wolfgang DekantDepartment of Toxicology

University of WürzburgGermany

dekant@toxi.uni-wuerzburg.de

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