Prinzipien der Risikobewertung für chemische Stoffe und andere Stressfaktoren in der Umwelt Prof. Dr. W. Dekant Institut für Toxikologie Universität Würzburg
Risikocharakterisierung und Management Risikocharakterisierung Wissenschaftlicher Prozess Risikomanagement Politisches Handeln
Risikomanagement und Grenzwerte Eingehende Faktoren: Art und Größe des Risikos freiwillig / aufgezwungen Kosten / Nutzen-Abschätzung vermeidbar / unvermeidbar
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?)
Human risk assessment process Critical toxic effect characterized by threshold (non-genotoxic) non-threshold (genotoxic) safety factors quantitative risk assessment
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!
Safety factor
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!
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
Mechanisms of chemical carcinogenesis
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
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
Uncertainties in quantitative risk assessment and the application of scientifically based methods for the reduction of these uncertainities
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
Range of concentrations of acrylamide in foodstuff Foodstuffs Concentration (µg/kg) Bread and cake < 30 1 430 Crackers < 30 2 400 Cereals < 30 2 300 Potato-chips < 60 3 680 Pommes frites < 60 3 500 Coffee, Cocoa 151-548
Estimated human exposure to acrylamide Mean daily intake 0.3-0.8 µg/kg bw Up to 50 µg/kg bw with specific dietary habits 10-fold below NOAEL for neurotoxicity
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
Tumor incidences in rats after oral administration of acrylamide in drinking water (Johnson et al., 1984 and 1986) 35 Male 50 Female Tumor incidences (%) 30 25 20 15 10 5 0 40 30 20 10 0 0 0,5 1 1,5 2 0 0,5 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
Tumor incidences in rats after oral administration of acrylamide in drinking water (American Cyanamid Co.) 35 Male 35 Female Tumorincidence (%) 30 25 20 15 10 5 0 0 0,5 1 1,5 2 2,5 30 25 20 15 10 5 0 Dose (mg/kg/day) thyroid (adenomas and carcinomas) mammary gland (adenomas and carcinomas) brain tumors (combined incidences) scrotal mesothelioma 0 1 2 3 4
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. 1999 10 000/10 6 Sanner et al. 2001 5 000/10 6 Schlatter 2002 50-100/10 6
Comparison of margins of exposure for acrylamide and other carcinogenic compounds in human diet MOE = dose causing tumors in rodents! human exposure! Acrylamide 50-1 000 Ochratoxin A 5 000 Nitrosamines 100 000 Benzo[a]pyrene 1 000 000 Ethylcarbamate 1 000 000