Carcinogenesis thresholds

A Test of the Linear-No-Threshold Dose-Response Relationship for Radiation Carcinogenesis... 

Radiation is carcinogenic. The frequency of death from cancer of the thyroid, breast, lung, esophagus, stomach, and bladder was higher in Japanese survivors of the atomic bomb than in nonexposed individuals, and carcinogenesis seems to be the primary latent effect of ionizing radiation. The minimal latent period of most cancers was <15 years and depended on an individual s age at exposure and site of cancer. The relation of radiation-induced cancers to low doses and the shape of the dose-response curve (linear or nonlinear), the existence of a threshold, and the influence of dose rate and exposure period have to be determined (Hobbs and McClellan 1986). 

Also access to the target may be a factor. For example, DNA repair seems to be very important in some cases of chemical carcinogenesis and will contribute to the presence of a dose threshold. 

The early studies of the kinetics of induction of recessive lethal mutations in Drosophila showed linearity at low doses and no evidence of a threshold. The contention that there is no threshold, or "safe" dose, has dominated genetic thinking on radiation effects and has carried over to chemicals. However, it was long assumed that carcinogenic effects of radiation and chemicals had a threshold. It may be helpful to review some of the recent studies of carcinogenesis. 

In particular, high-dose data usually cannot identify a threshold. A threshold is a dose or exposure below which there is no effect. It is often assumed that there is no threshold for an end point, like a gene mutation, that may involve one molecule of the toxicant and one target molecule in such a case, the dose-response relationship would be linear at low doses. If the observed relationship is linear over the dose range studied and if the fitted line is extrapolated to no effect (or the background frequency of effects) at zero dose, linear kinetics with no threshold are likely. But data are usually not clear. Even such a large carcinogenesis study as the EDqi study conducted by... 

Brown, C.C. Mathematical aspects of dose response studies in carcinogenesis The concept of thresholds. Oncology, 1976,... 

The maternal capacities that provide a homeostatic environment and metabolic deactivation of potential toxicants, along with the repair and regenerative capabilities of the embryo/fetus, are believed to impart a threshold phenomenon to developmental toxicity. The supposition of a threshold implies that a maternal dose exists at which a toxicant will elicit no adverse effect on the conceptus. This is in contrast to the threshold principle of carcinogenesis, which assumes that exposure to any amount of carcinogen, even a single molecule, can potentially lead to cancer. 

No chronic-duration oral MRLs were derived for benzene because of lack of appropriate data on effects of oral exposure to benzene. The NTP (1986) carcinogenesis bioassay was considered. In the NTP (1986) bioassay, male rats were given 50, 100, or 200 mg/kg/day and female rats and mice of both sexes were given 0, 25, 50, and 100 mg/kg/day benzene in com oil for 2 years. The dose of 25 mg/kg/day was a LOAEL for hematotoxicity and immunotoxicity in rats and mice, and is higher than the serious LOAEL of 8 mg/kg/day in the intermediate-duration data base. Therefore, the threshold for hematological and... 

De Flora S (2000) Threshold mechanisms and site specificity in chromium(VI) carcinogenesis. Carcinogenesis 21(4) 533-541. 

Kitano M, Ichihara T, Matsuda T, Wani-buchi H, Tamano S, et al. 1998. Presence of a threshold for promoting effects of phe-nobarbital on diethylnitrosamine-induced hepatic foci in the rat. Carcinogenesis 19 1475-80... 

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