28 research outputs found

    Acute Oral Poisoning Due to Chloracetanilide Herbicides

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    Chloracetanilide herbicides (alachlor, butachlor, metachlor) are used widely. Although there are much data about chronic low dose exposure to chloracetanilide in humans and animals, there are few data about acute chloracetanilide poisoning in humans. This study investigated the clinical feature of patients following acute oral exposure to chloracetanilide. We retrospectively reviewed the data on the patients who were admitted to two university hospitals from January 2006 to December 2010. Thirty-five patients were enrolled. Among them, 28, 5, and 2 cases of acute alachlor, metachlor, butachlor poisoning were included. The mean age was 49.8 ± 15.4 yr. The poison severity score (PSS) was 17 (48.6%), 10 (28.6%), 5 (14.3%), 2 (5.7%), and 1 (2.9%) patients with a PSS of 0, 1, 2, 3, and 4, respectively. The age was higher for the symptomatic patients (1-4 PSS) than that for the asymptomatic patients (0 PSS) (43.6 ± 15.2 vs 55.7 ± 13.5). The arterial blood HCO3 ¯ was lower in the symptomatic patients (1-4 PSS) than that in the asymptomatic patients (0 PSS). Three patients were a comatous. One patient died 24 hr after the exposure. In conclusion, although chloracetanilide poisoning is usually of low toxicity, elder patients with central nervous system symptoms should be closely monitored and cared after oral exposure

    Effects of Thiocyanate on Fetal and Postnatal Development and Thyroid Function in Rats.

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    Human exposures to thiocyanate through dietary intake and tobacco smoking are extensive. This compound has antithyroid activity in adults, but the effects of thiocyanate in developing organisms have not been extensively studied. Therefore, research was undertaken in rats to investigate the effects of thiocyanate on: (1) embryonic, fetal and neonatal development; and (2) hypothalamic-pituitary-thyroid axis development. Thiocyanate did not cause significant teratogenicity but did cause fetal growth retardation when administered at 55 and 220 mg/kg on gestational days 6-15. Thiocyanate administration throughout gestation (150/mg/kg/day) also retarded postnatal growth and development. Continued exposure throughout lactation worsened this retardation only slightly. This suggests that thiocyanate impaired postnatal development by interfering with cellular processes primarily during the prenatal period. This phenomenon may be explained by the toxicokinetics of thiocyanate in fetuses and neonates. Thiocyanate peaked at 10.7 mg% in fetal plasma after maternal dosing. In contrast, thiocyanate never exceeded 1.2 mg% in neonatal serum. The relatively low thiocyanate concentrations in these pups may account for the minimal retardation. Thiocyanate exposure during gestation did not significantly alter postnatal serum levels of pituitary and thyroid hormones. Continued thiocyanate administration throughout lactation resulted in significant hormone changes after the compound was withdrawn. On the 56th postnatal day, serum thyroid hormones were elevated and thyrtotropin was decreased. By day 91, thyrotropin was depressed even further, and thyroid hormones returned to normal in most animals. Analysis of the data indicates that the observed hyperthyroidism may have resulted from: (1) hypersensitivity of the thyroid to thyrotropin; and (2) insufficient suppression of thyrotropin secretion by the pituitary in response to elevated thyroid hormone concentrations. The postnatal serum thiocyanate levels required to produce these effects in rat pups were near those observed in babies born to smoking mothers. In addition, the toxicokinetics of thiocyanate in neonatal rats closely resembles the pattern observed in humans. Taken together, these data indicate a potential for thiocyanate to cause long term hypothalamic-pituitary-thyroid axis alterations in human offspring.Ph.D.Public healthUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160146/1/8422250.pd

    Alachlor

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    An evaluation of the carcinogenic potential of the herbicide alachlor(4) to man

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    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. 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. 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 Five 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. 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 gastrin-induced 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. 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. 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
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