Although structural differences in the AhR have been identified among different species, this receptor operates in a similar manner in animals and humans. Therefore, a common mechanism is likely to underlie the carcinogenic effects of TCDD in humans and animals, and data on animals support a biologic basis of the carcinogenic effects of TCDD in humans. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the magnitude of TCDD exposure that is carcinogenic.

Fewer studies have been conducted on the carcinogenicity of the herbicides. Several studies of the carcinogenicity of 2,4-D, 2,4,5-T, and picloram have been performed in laboratory animals. In general, the results were negative. However, some studies do not meet present-day standards for cancer bioassays, and others produced equivocal results. Thus, it is not currently possible to have confidence in the conclusions regarding the carcinogenicity of these compounds. With respect to genotoxicity, however, most of the evidence indicates that 2,4-D is genotoxic only at very high concentrations. Although 2,4,5-T increased the formation of DNA adducts by cytochrome P450-derived metabolites of benzo[a]pyrene, most available evidence indicates that 2,4,5-T is genotoxic only at high concentrations.

There is some evidence that cacodylic acid (also known as dimethylarsinic acid, DMA) is carcinogenic. DMA may induce DNA modifications that sensitize it to free-radical injury. Other studies concluded that it is a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats; causes pulmonary neoplasms in mice; and causes bladder hyperplasia and tumors in rats. Another exposure study in mice, however, produced negative results.

The evidence suggests that a connection between TCDD and cancer in humans is, in general, biologically plausible. However, differences in sensitivity and susceptibility among individual animals, strains, and species; the lack of strong evidence of organ-specific effects among species; and differences in route, dose, duration, and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism of induction of site-specific cancers by TCDD. Experiments on 2,4-D, 2,4,5-T, and picloram in animals and cells do not provide a strong biologic basis for the presence or absence of carcinogenic effects of these compounds. Some animal data might support a carcinogenic effect of DMA, but these data alone are not sufficient to draw conclusions on the carcinogenicity of this compound in humans.

Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicide or TCDD exposure in Vietnam veterans. Scientists disagree about the extent to which information derived from animals and cellular studies predicts human health outcomes and about the comparability of health effects resulting from high-dose and low-dose exposure. Investigating the biologic mechanisms underlying TCDD's carcinogenic effects continues to be an active field of research, and future updates of this report might