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Risikobewertung für chemische Stoffe in der Umwelt
Prof. Dr. W. Dekant Institut für Toxikologie Universität Würzburg
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Risikocharakterisierung und Management
Risikocharakterisierung
Wissenschaftlicher Prozess
Risikomanagement
Politisches Handeln
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Risikomanagement und Grenzwerte
Art und Größe des Risikos
freiwillig / aufgezwungen
Kosten / Nutzen-Abschätzung
vermeidbar / unvermeidbar
Eingehende Faktoren:
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Risikocharakterisierung
Ermittlung des Risikos
Art und Häufigkeit von Schadwirkungen Bestimmung der Exposition Wirkmechanismen
Bewertung des Risikos
Dosis-Wirkungsbeziehungen (Extrapolation) Qualität der Daten Plausibilität der Daten (wiederholbar?)
Risikocharakterisierung
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Human risk assessment process
Critical toxic effectcharacterized by
threshold(non-genotoxic)
non-threshold(genotoxic)
safety factors quantitative risk assessment
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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!
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Safety factor
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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!
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Mechanisms of chemical carcinogenesis
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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 bladderalcoholic drinks mouth, esophagus chromium lung4-aminobiphenyl bladder cyclophosphamide bladderbenzidine bladder bis(2-chloroethyl)sulfide larynx, lung2-naphthylamine bladder nickel compounds nasal cavity, lungarsenic skin, lung estrogens endometrium, vaginaasbestos lung, pleura, phenacetin kidney and lower urinary
peritoneum tractazathioprine reticulo-endothelial polycyclic aromatic skin, scrotum, lung
system hydrocarbonsbenzene bone marrow steroid hormones liverbis(chloromethyl)ether lung tobacco mouth, pharynx, larynx,
oesophagus, lung, bladdercadmium prostata vinyl chloride liverchlorambucil bone marrow
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Uncertainties in quantitative risk assessment and the application of scientifically based methods for the
reduction of these uncertainities
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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 regionth
resh
old
Dose
Res
pons
e
supralinear
linear
sublinear
experimental data point
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Tumor incidences in rats after oral administration of acrylamide in drinking water (Johnson et al.,
1984 and 1986)
0
10
20
30
40
50
0 0,5 1 1,5 2
Male
0
5
10
15
20
25
30
35
0 0,5 1 1,5 2Doses (mg/kg/day)
Tum
or in
cide
nces
(%)
Female
Thyroid (adenomas and carcinomas combined)Brain tumors (combined incidencers)Testicular mesotheliomaMammary gland (combined adenomas and carcinomas)
Malignang adenocarcinomas in the uterus
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Tumor incidences in rats after oral administration of acrylamide in drinking water
(American Cyanamid Co.)
Dose (mg/kg/day)
Male
0
5
10
15
20
25
30
35
0 0,5 1 1,5 2 2,5
Female
0
5
10
15
20
25
30
35
0 1 2 3 4
Tum
orin
cide
nce
(%)
thyroid (adenomas and carcinomas)mammary gland (adenomas and carcinomas)brain tumors (combined incidences)scrotal mesothelioma
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
Estimated life-time tumor risks for acrylamide
Unit risk (1 µg/kg bw/day):
US EPA 4 500/106
WHO: 700/106 Granath et al. 1999 10 000/106 Sanner et al. 2001 5 000/106 Schlatter 2002 50 - 100/106
Prof. Dr. W. Dekant, Institut für Toxikologie, Universität Würzburg
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