The safety of 2,4-D to farm and forestry workers, commercial applicators and the general public has been of continuing concern because certain epidemiological studies of groups potentially exposed to 2,4-D have suggested a relationship between 2,4-D use and increased risk of soft tissue sarcoma, Hodgkin's disease or non-Hodgkin's lymphoma. This review on 2,4-D is unique in that the approach taken was to integrate data from worker exposure studies, whole animals, metabolic and other relevant laboratory studies with the epidemiological findings to assess the extent to which there is scientific support for the hypothesis that 2,4-D exposure is associated with any increased risk of human cancer. The case-control epidemiological studies that have been the source of the cancer risk hypothesis are inconclusive. Problems in assessing exposure based on patients' memories make these studies difficult to interpret. Cohort studies of exposed workers do not generally support the specific hypothesis that 2,4-D causes cancer. Taken together, the epidemiological studies provide, at best, only weak evidence of an association between 2,4-D and the risk of cancer. Importantly, the cancer hypothesis is not supported by other data. A critical evaluation of the exposure data indicates that exposure to 2,4-D in user groups is intermittent and much lower than the doses tested chronically in long-term animal studies that have not shown evidence of tumor induction. Moreover, the structure of 2,4-D does not suggest it would be a carcinogen. 2,4-D is a simple organic acid, that is largely excreted unchanged, and there is no evidence that it is metabolized to critically reactive metabolites or accumulates in tissues. This evidence is supported by a large body of negative studies on genotoxicity, which taken together with the metabolic studies, clearly indicates that 2,4-D is highly unlikely to be a genotoxic carcinogen. Furthermore, 2,4-D has no known hormonal activity and does not induce proliferative changes in any tissue or organ, indicating that it does not possess any of the characteristics of non-genotoxic animal carcinogens. Thus the available mechanistic studies provide no plausible basis for a hypothesis of carcinogenicity. In this review, data relating to potential neurotoxicity, immunotoxicity and reproductive toxicity also were evaluated. There is no evidence that 2,4-D adversely affects the immune system and neurotoxic and reproductive effects only have been associated with high toxic doses that would not be encountered by 2,4-D users. Historical exposures to 2,4-D by user groups, particularly farmers, forestry workers and commercial applicators, would be higher than those sustained under present rigorous standards for application which involve the use of protective clothing and other measures to reduce exposure. Proposed label changes indicate that in the future exposures will be even further reduced. Viewed in this context, the available data indicate that the potential public health impact of 2,4-D, including the risk of human cancer, was negligible in the past and would be expected to be even smaller in the present and future.
