An evaluation of the carcinogenic potential of the herbicide alachlor4 to man

Abstract

<jats:p> Chronic bioassays have revealed that alachlor caused nasal, thyroid, and stomach tumours in rats but was not carcinogenic in mice. Significant increases in thyroid and stomach tumours were observed only at doses that exceeded the maximum tolerated dose (MTD). While nasal tumours were found at doses below the MTD, they were small and benign in nature. This publication describes the work undertaken by Monsanto to understand the carcinogenic mode of action of alachlor in the rat and to investigate the relevance to humans. </jats:p><jats:p> The genetic toxicity of alachlor has been investigated in an extensive battery of in vitro and in vivo test systems. In addition, target-specific mutagenicity tests, such as the COMET assay and DNA binding in nasal tissue, were carried out to investigate any possible in-situ genotoxic action. The weight-of-evidence analysis of all available data clearly demonstrates that alachlor exerts its carcinogenicity in the rat by non-genotoxic mechanisms. </jats:p><jats:p> In the rat, alachlor is initially metabolised primarily in the liver through the P-450 pathway and by glutathione conjugation. The glutathione conjugates and their metabolites undergo enterohepatic circulation with further metabolism in the gastrointestinal tract, liver, and then nasal tissue where they can be converted to a diethyliminoquinone metabolite (DEIQ). This electrophilic species binds to the cysteine moiety of proteins leading to cell damage and increased cell turnover. When comparisons of in vitro nasal metabolic capability were made, the rat's capacity to form DEIQ from precursor metabolites was 38 times greater than for the mouse, 30-fold higher than monkey, and 751 times greater than that of humans. This data is consistent with the results of studies showing in vivo formation of DEIQ-protein adducts in the nasal tissue of rats but not mice or monkeys. The lack of DEIQ nasal adducts in mice is consistent with the lack of nasal tumours in that species. When the differences between rat and humans in the capacity for initial glutathione conjugation by the liver and nasal tissue are also taken into account, the rat is found to be even more susceptible to DEIQ formation than man. Based on this, it is clear that the potential for DEIQ formation and nasal tumour development in humans is negligible. </jats:p><jats:p> The mechanism of stomach tumour formation has been studied in the rat. The results demonstrated that the mechanism is threshold-sensitive and involves a combination of regenerative cell proliferation and a gastrininduced tropic effect on enterochromaffin-like (ECL) cells and stem cells of the mucosal epithelium. The absence of a carcinogenic effect in mice and of any preneoplastic effect in monkeys treated with very high doses is indicative of the species-specific aspect of this mechanism of action. </jats:p><jats:p> The results of studies on thyroid tumour production indicate that alachlor is acting indirectly through the pituitary-thyroid axis by increasing the excretion of T4 by enhanced glucuronidation and subsequent biliary excretion. The increased excretion reduces plasma T4 levels and a feedback mechanism leads to increased synthesis of TSH by the pituitary. Chronic stimulation of the follicular epithelium of the thyroid by TSH produces hyperplasia and ultimately tumour formation. This non-genotoxic, threshold-based mechanism is well established and widely considered to be not relevant to humans. </jats:p><jats:p> In this work, the modes of action for the three types of tumours elicited in the rat by alachlor were investigated. All are based on non-genotoxic, threshold-sensitive processes. From all the data presented it can be concluded that the tumours detected in the rat are not relevant to man and that alachlor presents no significant cancer risk to humans. This conclusion is supported by the lack of mortality and tumours in an epidemiology study of alachlor manufacturing workers. </jats:p>

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

“…Given that mouse nasal tissue is less proficient than rat in forming critical metabolites and human nasal tissue is even less proficient than mouse (Heydens et al, 1999), the fact that the mouse is insensitive to chloracetanilide NM carcinogenicity suggests that humans would be unlikely to be responsive. In humans, no association with nasal toxicity or nasal or other tumors (Heydens et al, 1999) has been reported for chloracetanilide compounds.…”

Consensus Diagnoses and Mode of Action for the Formation of Gastric Tumors in Rats Treated with the Chloroacetanilide Herbicides Alachlor and Butachlor

“…2, 2014 CONSENSUS DIAGNOSES AND MODE OF ACTION FOR THE FORMATION OF GASTRIC TUMORS 391 (i.e., parietal, chief, or ECL cells) were not recognizable Thake, Iatropoulos, et al 1995). Parietal cell number measurements in the alachlor gastric tumor promotion study demonstrated that after 1 year of treatment with 126 mg/kg/day, the numbers of parietal cells were profoundly reduced to 7% of the control value (Branch and Thake 1995;Heydens et al 1999;Tatematsu and Thake 1996).…”

“…Since there was substantial morphologic variability within and among the gastric tumors as diagnosed in the original carcinogenicity studies (Daly 1981(Daly , 1983, reevaluations of the gastric tumors from the original bioassays for both alachlor and butachlor were previously conducted in an attempt to identify the tumor type involved and to determine whether the morphologic characteristics of tumors from the two original studies with alachlor and butachlor were comparable (Hard and Iatropoulos 1994;Hard et al 1995;Heydens et al 1999; International Agency for Research on Cancer [IARC] 2003). Also, a series of histochemical and immunohistochemical stains were used to identify features that would aid in identification of the cell/cells of origin.…”

Cytogenetic Effect of the Chloroacetanilide Herbicide Alachlor in Somatic and Germ Cells of the Mouse

“…Although the carcinogenic potential of alachlor and its hazardous effect are reported in a number of previous studies (EPA 1984, 1987, Heydens et al. 1999, Dearfield et al 1999and Genter et al 2002 it is still widely used in agriculture (Lee et al 2004).…”

“…It represents a high health hazard on a toxicological basis being a carcinogen, class B2 (USEPA, 1993). Alachlor caused nasal, thyroid and stomach tumors in rats and was not carcinogenic in mice (Heydens et al 1999). Also, the herbicide induced olfactory mucosal tumors in rats in a highly ordered temporal process (Wetmore et al 1999).…”