VOL.: 73 (1999) (p. 59)
Chem. Abstr. Name: 6-Chloro-N-ethyl-N¢-(1-methylethyl)-1,3,5-triazine-2,4-diamine
5.1 Exposure data
Atrazine is a triazine herbicide widely used on a variety of crops, notably maize, sorghum and sugar-cane, for the pre- and post-emergent control of broad-leaved weeds. Occupational exposure may occur through both inhalation and dermal absorption during its manufacture, its formulation and its application by spraying. It is found widely, together with its dealkylated degradation products, in rivers, lakes, estuaries, groundwater and reservoirs. In drinking-water, the levels rarely exceed 1 mg/L. Surveys of various foods and feeds have generally indicated no detectable atrazine residue.
5.2 Human carcinogenicity data
A combined analysis of the results of two cohort studies of agricultural chemical production workers in the United States showed decreased mortality from cancers at all sites combined among the subset of workers who had had definite or probable exposure to triazine. Site-specific analyses in this subset of workers yielded no significant findings; a non-significant increase in the number of deaths from non-Hodgkin lymphoma was seen, but was based on very few observed cases.
A pooled analysis of the results of three population-based case–control studies of men in Kansas, eastern Nebraska and Iowa–Minnesota, United States, in which the risk for non-Hodgkin lymphoma in relation to exposure to atrazine and other herbicides on farms was evaluated, showed a significant association; however, the association was weaker when adjustment was made for reported use of phenoxyacetic acid herbicides or organophosphate insecticides. A sub-analysis of results for farmers in Nebraska, the State in which the most detailed information on atrazine use was available, showed no excess risk for non-Hodgkin lymphoma among farmers who had used atrazine for at least 15 years, after adjustment for use of other pesticides. In a case–control study of non-Hodgkin lymphoma among women in eastern Nebraska, a slight, nonsignificant increase in risk was seen. In all these studies, farmers tended to have an increased risk for non-Hodgkin lymphoma, but the excess could not be attributed to atrazine.
Less information was available to evaluate the association between exposure to atrazine and other cancers of the lymphatic and haematopoietic tissues. One study of Hodgkin disease in Kansas, one study of leukaemia in Iowa–Minnesota and one study of multiple myeloma from Iowa gave no indication of excess risk among persons handling triazine herbicides.
In a population-based study in Italy, definite exposure to triazines was associated with a two- to threefold increase of borderline significance in the risk for ovarian cancer. The study was small, and potential confounding by exposure to other herbicides was not controlled for in the analysis.
5.3 Animal carcinogenicity data
Atrazine was tested for carcinogenicity in one study in mice by oral administration in the diet. No increase in tumour incidence was observed. It was also tested by oral administration in two studies in Fischer rats and in five studies in Sprague-Dawley rats, including a comparison of intact and ovariectomized females of the latter strain. In Fischer rats, no increase in tumour incidence was observed in one adequate study. The incidence of mammary tumours was increased in intact Sprague-Dawley females in four studies, but no increase was seen in ovariectomized Sprague-Dawley females. Atrazine was also tested by intraperitoneal injection in one study in mice; an increased incidence of lymphomas was reported.
5.4 Other relevant data
N-Dealkylation and conjugation with glutathione are the main metabolic pathways for atrazine in various species in vivo. There do not appear to be qualitative differences in the metabolism of atrazine between the strains and species studied that would explain the fact that mammary gland tumours develop in Sprague-Dawley rats but not in Fischer 344 rats or CD-1 mice.
Atrazine has been tested for developmental toxicity in rats and rabbits. No teratogenic effects have been observed. Fetal loss and reduced fetal body weights were seen in rabbits; the incidences of some minor skeletal variants were elevated in exposed fetal rats. No developmental effects were seen in a study of mice and rats exposed to groundwater contaminants that included atrazine.
The evidence from biological assays (e.g. uterine weight, stromal cell proliferation, epithelial cell height) and from in-vitro assays of oestrogen receptors indicates that atrazine does not have intrinsic oestrogenic activity.
Long-term administration of atrazine enhances the onset of reproductive senescence in female Sprague-Dawley (but not Fischer 344) rats, resulting in an earlier onset of persistent oestrus and tissue changes characteristic of long-term exposure to elevated oestrogen levels. Atrazine appears to disrupt neuroendocrine pathways in the hypothalamus by as yet undetermined mechanisms, resulting in attenuation of the luteinizing hormone surge that normally results in ovulation. These hormonal imbalances seen after atrazine administration were associated with an increased incidence and earlier onset of mammary tumours in some but not all studies of carcinogenicity in Sprague-Dawley rats, and not in Fischer 344 rats or CD-1 mice. Ovariectomized Sprague-Dawley rats exposed for two years to the highest dose of atrazine used in the bioassay in which ovariectomized and intact animals were compared did not develop either tumours or other proliferative lesions in the mammary gland.
In contrast to the hormonal changes in Sprague-Dawley rats, reproductive senescence in women is characterized by depletion of the ovarian oocyte content and reduced oestrogen secretion.
No data were available on the genetic and related effects of atrazine in humans. There is weak evidence for genotoxic effects in mammalian cells in vivo and in vitro. Atrazine was mutagenic in Drosophila, yeast and plant cells but was not mutagenic to bacteria. Overall, the results of genotoxicity testing would not appear to bear directly on the strain-specific tumour induction in female Sprague-Dawley rats.
There is inadequate evidence in humans for the carcinogenicity of atrazine.
There is sufficient evidence in experimental animals for the carcinogenicity of atrazine.
Overall evaluationIn making its overall evaluation, the Working Group concluded that the mammary tumours associated with exposure to atrazine involve a non-DNA-reactive, hormonally mediated mechanism. In reaching the conclusion, the following evidence was considered:
(a) Atrazine produces mammary tumours (fibroadenomas, adenocarcinomas) only in intact female Sprague-Dawley rats (not in Fischer 344 rats, CD-1 mice or ovariectomized Sprague-Dawley rats) and does not increase the incidences of other tumour types.
(b) Atrazine affects neuroendocrine pathways of the hypothalamus to accelerate the onset of reproductive senescence in female Sprague-Dawley but not Fischer 344 rats.
(c) Atrazine does not have intrinsic oestrogenic activity.
(d) There are critical interspecies differences in the hormonal changes associated with reproductive senescence.
Therefore, there is strong evidence that the mechanism by which atrazine increases the incidence of mammary gland tumours in Sprague-Dawley rats is not relevant to humans.
Atrazine is not classifiable as to its carcinogenicity to humans (Group 3).For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Vol. 53 (1991)Synonyms
See Also: Toxicological Abbreviations Atrazine (HSG 47, 1990) Atrazine (ICSC) Atrazine (IARC Summary & Evaluation, Volume 53, 1991)