Prinzipien der Risikobewertung für chemische Stoffe und andere Stressfaktoren in der Umwelt

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1 Prinzipien der Risikobewertung für chemische Stoffe und andere Stressfaktoren in der Umwelt Prof. Dr. W. Dekant Institut für Toxikologie Universität Würzburg

2 Risikocharakterisierung und Management Risikocharakterisierung Wissenschaftlicher Prozess Risikomanagement Politisches Handeln

3 Risikomanagement und Grenzwerte Eingehende Faktoren: Art und Größe des Risikos freiwillig / aufgezwungen Kosten / Nutzen-Abschätzung vermeidbar / unvermeidbar

4 Risikocharakterisierung Risikocharakterisierung Ermittlung des Risikos Bewertung des Risikos Art und Häufigkeit von Schadwirkungen Bestimmung der Exposition Wirkmechanismen Dosis-Wirkungsbeziehungen (Extrapolation) Qualität der Daten Plausibilität der Daten (wiederholbar?)

5 Human risk assessment process Critical toxic effect characterized by threshold (non-genotoxic) non-threshold (genotoxic) safety factors quantitative risk assessment

6 ADI / TDI Concept of the WHO (WHO 1961) Extrapolation from animal to human: Lowest NOAEL Most sensitive species Safety factor (SF) (usually 100) NOAEL (mg/kg bw) : SF =! ADI! TDI (mg/kg bw)! PTWI! Animal! Human!

7 Safety factor

8 Qualitative factors required for the optimized definition of safety factors Evaluation of animal toxicity studies! number of studies and effects observed! type of toxic effects! time course for toxic effects! tumorigenicity! Evaluation of biochemical endpoints! biotransformation and toxicokinetics! mechanism of action, covalent binding to macromolecules! short-term test for genotoxicity and other non-threshold effects! Evaluation of species differences! interspecies variations in biotransformation and toxicokinetics! influence of anatomical and physiological differences between species on toxic effects!

9 Advantages and disadvantages of safety factors in the risk assessement process Advantages simple application ease of understanding flexibility of use use of expert judgement Disadvantages uncertainties of threshold values and size of safety factor no risk comparison possible slope of dose-response curve not adequately considered experimental NOELs are dependent on group size in the animal toxicity testing and endpoint selected

10 Mechanisms of chemical carcinogenesis

11 Examples of established human carcinogens based on epidemiological observations Chemical or agent Site of tumor formation Chemical or agent Site of tumor formation aflatoxin liver chlornaphazine bladder alcoholic drinks mouth, esophagus chromium lung 4-aminobiphenyl bladder cyclophosphamide bladder benzidine bladder bis(2-chloroethyl)sulfide larynx, lung 2-naphthylamine bladder nickel compounds nasal cavity, lung arsenic skin, lung estrogens endometrium, vagina asbestos lung, pleura, peritoneum phenacetin kidney and lower urinary tract azathioprine reticulo-endothelial polycyclic aromatic skin, scrotum, lung system hydrocarbons benzene bone marrow steroid hormones liver bis(chloromethyl)ether lung tobacco mouth, pharynx, larynx, oesophagus, lung, bladder cadmium prostata vinyl chloride liver chlorambucil bone marrow

12 Advantages and disadvantages of quantitative risk assessement Advantages gives numerical values on risk which may be used for the setting of exposure limits permits the comparison of risks due to different chemicals provides a reasonable basis for the setting of exposure limits by identifying of compounds with high risk Disadvantages extrapolation of data obtained at high doses to low doses, relevant for human exposure using mathematical models, which are not based on cancer biology and pathophysiology mechanistic and kinetic data are not used for the risk estimation process requires expensive and time-consuming lifelong bioassay

13 Uncertainties in quantitative risk assessment and the application of scientifically based methods for the reduction of these uncertainities

14 Possible slopes of dose-response curves in the very low dose range below the ability of experimental determination in cancer bioassays high dose Region low dose region Response supralinear Dose linear sublinear threshold experimental data point

15 Range of concentrations of acrylamide in foodstuff Foodstuffs Concentration (µg/kg) Bread and cake < Crackers < Cereals < Potato-chips < Pommes frites < Coffee, Cocoa

16 Estimated human exposure to acrylamide Mean daily intake µg/kg bw Up to 50 µg/kg bw with specific dietary habits 10-fold below NOAEL for neurotoxicity

17 Toxicology of acrylamide Rapid uptake, distribution and elimination Biotransformation to electrophilic epoxide Neurotoxic in rodents (NOAEL 0.5 mg/kg bw) Carcinogenic in rats Genotoxic in some assays Human epidemiology inconclusive

18 Tumor incidences in rats after oral administration of acrylamide in drinking water (Johnson et al., 1984 and 1986) 35 Male 50 Female Tumor incidences (%) ,5 1 1, ,5 1 1,5 2 Doses (mg/kg/day) Thyroid (adenomas and carcinomas combined) Brain tumors (combined incidencers) Testicular mesothelioma Mammary gland (combined adenomas and carcinomas) Malignang adenocarcinomas in the uterus

19 Tumor incidences in rats after oral administration of acrylamide in drinking water (American Cyanamid Co.) 35 Male 35 Female Tumorincidence (%) ,5 1 1,5 2 2, Dose (mg/kg/day) thyroid (adenomas and carcinomas) mammary gland (adenomas and carcinomas) brain tumors (combined incidences) scrotal mesothelioma

20 Estimated life-time tumor risks for acrylamide Unit risk (1 µg/kg bw/day): US EPA 4 500/10 6 WHO: 700/10 6 Granath et al /10 6 Sanner et al /10 6 Schlatter /10 6

21 Comparison of margins of exposure for acrylamide and other carcinogenic compounds in human diet MOE = dose causing tumors in rodents! human exposure! Acrylamide Ochratoxin A Nitrosamines Benzo[a]pyrene Ethylcarbamate