Disulfoton toxicity

Signs of disulfoton toxicity, such as muscle tremors, fasciculations, lacrimation, and salivation, in animals are generally observed after a few daily doses, but begin to diminish in severity as exposure to dislllfoton continues (Bombinski and DuBois 1958). This phenomenon is known as tolerance. Tolerance appears to be a reproducible phenomenon that does not depend on the organophosphate insecticide used, the route of administration, or the animal species (Costa et al. 1982b). Several possible mechanisms have been proposed /explain this phenomenon. 

Holcombe, G.W., G.L. Phipps, and D.K. Tanner. 1982. The acute toxicity of kelthane, dursban, disulfoton, pydrin, and permethrin to fathead minnows Pimephales promelas and rainbow trout Salmo gairdneri. Environ. Pollut. 29A 167-178. 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of disulfoton. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

The causes of death in these studies were not specifically mentioned, but disulfoton is a cholinesterase inhibitor, and animals exposed to disulfoton typically exhibit cholinergic signs of toxicity (see Section 2.2.2.4). 

Similarly, in chronic feeding studies, no clinical chemistry or histological evidence of liver toxicity was found in rats (Carpy et al. 1975 Hayes 1985), mice (Hayes 1983), or dogs (Hoffman et al. 1975). However, trends towards increased liver weights in male rats and decreased liver weights in female rats fed disulfoton for 1.5-2.0 years were observed (Carpy et al. 1975). The reason for these opposite trends in male and female rats is not clear. 

Disulfoton causes neurological effects in humans and animals. The mechanism of action on the nervous system depends on the metabolism of disulfoton to active metabolites. The liver is the major site of metabolic oxidation of disulfoton to disulfoton sulfoxide, disulfoton sulfone, demeton S-sulfoxide and demeton S-sulfone, which inhibit acetylcholinesterase in nervous tissue. These four active metabolites are more potent inhibitors of acetylcholinesterase than disulfoton. Cytochrome P-450 monooxygenase and flavin adenine dinucleotide monooxygenase are involved in this metabolic activation. The active metabolites ultimately undergo nonenzymatic and/or enzymatic hydrolysis to more polar metabolites that are not toxic and are excreted in the urine. 

No studies were located regarding absorption in humans or animals after dermal exposure to disulfoton. However, data on lethality, other signs of toxicity, and acetylcholinesterase inhibition in animals after dermal exposure (see Section 2.2.3) suggest that disulfoton can be absorbed from the skin. 

Employees at hazardous waste sites, employees at pesticide mixing and formulating plants, and farm workers are more likely to be exposed to disulfoton than individuals in other occupations. Neurotoxl effects have been observed in occupationally exposed persons. However, no human data were located to identify susceptible subpopulations. Animal data suggest that female animals and young animals are more susceptible to disulfoton toxicosis. Based on the results from animal studies, women and children could also be more susceptible than men to toxic effects of disulfoton. 

The MRL is based on a NOAEL of 0.5 mg/m3 for decreased acetylcholinesterase activity in rats exposed to disulfoton 4 hours/day for 5 days in a study by Thyssen (1978). The NOAEL was adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). Inhibition of erythrocyte cholinesterase activity and unspecified behavioral disorders were observed at 1.8 mg/m, and unspecified signs of cholinergic toxicity were observed at 9.8 mg/m. Similar effects were observed in rats or mice exposed to higher concentrations for shorter duMtions (Doull 1957 Thyssen 1978). The NOAEL value of 0.5 mg/m is supported by another study, in which no significant decrease in the activity of brain, serum, or submaxillary gland cholinesterase was found in rats exposed to 0.14-0.7 mg/m for 1 hour/day for 5-10 days (DuBois and Kinoshita 1971). Mild depression of erythrocyte cholinesterase activity was reported in workers exposed by the inhalation and dermal routes (Wolfe et al. 1978). 

Although some steroids have been reported to reduce the toxic effects of some insecticides, the steroid ethylestrenol decreased the rate of recovery of depressed cholinesterase activity in disulfoton- pretreated rats (Robinson et al. 1978). The exact mechanism of this interaction was not determined. Ethylestrenol alone caused a small decrease in cholinesterase activity, and, therefore, resulted in an additive effect. Rats excreted less adrenaline and more noradrenaline when given simultaneous treatments of atropine and disulfoton compared with rats given disulfoton alone (Brzezinski 1973). The mechanism of action of disulfoton on catecholamine levels may depend on acetylcholine accumulation. In the presence of atropine, the acetylcholine effect on these receptors increases the ability of atropine to liberate catecholamines. 

This section will describe clinical practice and experimental research concerning methods for reducing toxic effects of exposure to disulfoton. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposure to disulfoton. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. 

Developmental Toxicity. No studies were located regarding developmental effects in humans after inhalation, oral, or dermal exposure to disulfoton or in animals after inhalation or dermal exposure. Developmental effects have been found in animals after acute- and intermediate-duration oral exposure to disulfoton. Plasma and erythrocyte cholinesterase depression and increased incidences of incomplete ossified parietal bones and sternebrae were observed in fetuses from rats fed... 

In the first year, the maximum concentrations of sulfoxide and sulfone in soil, seed potatoes, and foliage were approximately 2, 2, and 6 times, respectively, the concentrations of those metabolites measured in the second and third year treatments. These results demonstrated that enhanced microbial degradation of relatively minor insecticidal compounds in the soil can significantly affect insecticide levels in the plant (when these degradation products are the major insecticidal component accumulated). As the sulfoxide and the sulfone metabolites are the major toxicants in the foliage of potato plants grown in disulfoton-treated soil, this reduction in toxicant residues overtime can be expected to reduce insecticide efficacy. 

---