Cancer risk estimation of genotoxic chemicals based on target dose and a multiplicative model.
A mechanistic model and associated procedures are proposed for cancer risk assessment of genotoxic chemicals. As previously shown for ionizing radiation, a linear multiplicative model was found to be compatible with published experimental data for ethylene oxide, acrylamide, and butadiene. The validity of this model was anticipated in view of the multiplicative interaction of mutation with inherited and acquired growth-promoting conditions. Concurrent analysis led to rejection of an additive model (i.e. the model commonly applied for cancer risk assessment). A reanalysis of data for radiogenic cancer in mouse, dog and man shows that the relative risk coefficient is approximately the same (0.4 to 0.5 percent per rad) for tumours induced in the three species. Doses in vivo, defined as the time-integrated concentrations of ultimate mutagens, expressed in millimol x kg-1 x h (mMh) are, like radiation doses given in Gy or rad, proportional to frequencies of potentially mutagenic events. The radiation dose equivalents of chemical doses are, calculated by multiplying chemical doses (in mMh) with the relative genotoxic potencies (in rad x mMh-1) determined in vitro. In this way the relative cancer incidence increments in rats and mice exposed to ethylene oxide were shown to be about 0.4 percent per rad-equivalent, in agreement with the data for radiogenic cancer. Our analyses suggest that values of the relative risk coefficients for genotoxic chemicals are independent of species and that relative cancer risks determined in animal tests apply also to humans. If reliable animal test data are not available, cancer risks may be estimated by the relative potency. In both cases exposure dose/target dose relationships, the latter via macromolecule adducts, should be determined.
Granath
F N
FN
Department of Mathematical Statistics, Stockholm University, Sweden.
Vaca
C E
CE
Ehrenberg
L G
LG
Törnqvist
M A
MA
D020106:Acrylamide / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000009:adverse effects; D018736:DNA Adducts; D004202:Disinfectants / Q000008:administration & dosage / Q000009:adverse effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005027:Ethylene Oxide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D015994:Incidence; D016014:Linear Models; D008297:Male; D051379:Mice; D008954:Models, Biological; D009153:Mutagens / Q000008:administration & dosage / Q000009:adverse effects*; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced*; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology; D011829:Radiation Dosage; D051381:Rats; D015203:Reproducibility of Results; D012306:Risk; D018570:Risk Assessment / Q000379:methods*
D002070:Butadienes; D018736:DNA Adducts; D004202:Disinfectants; D009153:Mutagens; D020106:Acrylamide; D005027:Ethylene Oxide