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5.1 Exposure data
Amitrole is a herbicide, which has been used since the 1950s to control a wide range of weeds and grasses along roadsides, in vineyards and in orchards and in other applications, although contact with food crops is avoided. Amitrole is rapidly degraded in the environment, but occupational exposure may occur during its production and application.
5.2 Human carcinogenicity data
In a small cohort study of mortality among Swedish railroad workers who had sprayed herbicides, there was a statistically significant excess of cancers at all sites combined among men exposed to both amitrole and chlorophenoxy herbicides but not among those exposed mainly to amitrole.
5.3 Animal carcinogenicity data
Amitrole was tested in mice by oral administration, skin application and transplacental and perinatal exposure, in rats by oral and subcutaneous administration and in hamsters by oral administration. In mice, thyroid follicular-cell and hepatocellular tumours were produced after oral administration of amitrole. In rats, amitrole administered orally induced thyroid follicular-cell adenomas and carcinomas in males and females and a marginal increase in the incidence of pituitary adenomas in female rats at the highest dose. No carcinogenic effect was observed in hamsters.
In one experiment in rats, amitrole promoted thyroid follicular-cell tumours induced by N-nitrosobis(2-hydroxypropyl)amine.
5.4 Other relevant data
Amitrole is rapidly absorbed from the gastrointestinal tract and lung.
Amitrole caused thyroid gland enlargement (goitre) in rats and mice as a result of diffuse hypertrophy and hyperplasia of thyroid follicular cells. Administration of amitrole to rats under bioassay conditions that caused predominantly benign follicular-cell tumours resulted in alteration of thyroid hormone homeostasis, including increased secretion of thyroid-stimulating hormone. The underlying mechanism for the changes induced by amitrole is interference with the functioning of thyroid peroxidase.
No data were available on the genetic and related effects of amitrole in humans. Amitrole was not genotoxic in appropriate tests in bacteria and cultured mammalian cells or in rats and mice exposed in vivo. Amitrole induced chromosomal aberrations in plants, aneuploidy in some experiments in fungi and transformation of Syrian hamster embryo cells in vitro.
There is inadequate evidence in humans for the carcinogenicity of amitrole.
There is sufficient evidence in experimental animals for the carcinogenicity of amitrole.
Amitrole is not classifiable as to its carcinogenicity to humans (Group 3).
In making its evaluation, the Working Group concluded that amitrole produces thyroid tumours in mice and rats by a non-genotoxic mechanism, which involves interference with the functioning of thyroid peroxidase, resulting in a reduction in circulating thyroid hormone concentrations and increased secretion of thyroid-stimulating hormone. Consequently, amitrole would not be expected to produce thyroid cancer in humans exposed to concentrations that do not alter thyroid hormone homeostasis.
An additional consideration of the Working Group, based on the lack of genotoxicity of amitrole, was that the liver tumours in mice and benign pituitary tumours in rats were also produced by a non-genotoxic mechanism.
Evidence from epidemiological studies and from toxicological studies in experimental animals provide compelling evidence that rodents are substantially more sensitive than humans to the development of thyroid tumours in response to thyroid hormone imbalance.For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations: Vol. 7 (1974); Vol. 41 (1986); Suppl. 7 (1987)
See Also: Toxicological Abbreviations Amitrole (EHC 158, 1994) Amitrole (HSG 85, 1994) Amitrole (ICSC) Amitrole (PDS) Amitrole (WHO Pesticide Residues Series 4) Amitrole (Pesticide residues in food: 1977 evaluations) Amitrole (Pesticide residues in food: 1993 evaluations Part II Toxicology) Amitrole (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental) Amitrole (IARC Summary & Evaluation, Supplement7, 1987) Amitrole (IARC Summary & Evaluation, Volume 7, 1974) Amitrole (IARC Summary & Evaluation, Volume 41, 1986)