Risikobewertung für chemische Stoffe in der Umwelt · aflatoxin liver chlornaphazine bladder...

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


Risikomanagement und Grenzwerte

  Art und Größe des Risikos

  freiwillig / aufgezwungen

  Kosten / Nutzen-Abschätzung

  vermeidbar / unvermeidbar

Eingehende Faktoren:



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?)



Human risk assessment process

Critical toxic effectcharacterized 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 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


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 regionth

resh

old

Dose

Res

pons

e

supralinear

linear

sublinear

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)

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


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


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


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

Risikobewertung für chemische Stoffe in der Umwelt · aflatoxin liver chlornaphazine bladder...

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