Endosulfan toxicity

The effects of protein deficiency on endosulfan toxicity were studied in Wistar rats (Boyd and Dobos 1969 Boyd et al. 1970). Rats fed a diet totally deficient in protein for 28 days prior to administration of a single oral dose of endosulfan had an LDjq of 5.1 mg/kg of endosulfan. Rats fed a low-protein diet (3.5% protein) for 28 days had an LDjq of 24 mg/kg of endosulfan. Rats fed standard laboratory chow (26% protein) had an LDjq of 102-121 mg/kg. The immediate cause of death in all animals was respiratory failure following tonic-clonic convulsions. This study demonstrated that, while a protein-deficient diet does not affect the nature of the toxic reaction, it may affect the sensitivity of rats to the lethal effects of endosulfan. 

The primary systemic targets of endosulfan toxicity in animals following dermal exposure are the liver and kidney. Adverse hematological effects have also been observed following dermal administration of endosulfan. No studies were located regarding musculoskeletal effects in humans or animals after dermal exposure to endosulfan. 

Gavage dosing of male and female rats with endosulfan (65.3% a-endosulfan, 33.7% P-endosulfan) for 30 days resulted in a greater accumulation of endosulfan in fatty tissue from females than males (Dikshith et al. 1984). The authors speculated that the difference between males and females was a function of more rapid excretion of endosulfan by males than females, and that this could account for the higher sensitivity of female rats to endosulfan toxicity. However, excretion of endosulfan and its metabolites was not directly measured in this study therefore, alternative explanations for the differences in residue content and toxicity caimot be discounted. 

The effects of endosulfan have not been studied in children, but they would likely experience the same health effects seen in adults exposed to endosulfan. Data in adults, mostly derived from cases of accidental or intentional acute exposure (ingestion) to large amounts of endosulfan, indicate that the primary target of endosulfan toxicity is the nervous system. The effects are manifested as hyperactivity and convulsions and in some cases have resulted in death (Aleksandrowicz 1979 Blanco-Coronado et al. 1992 Boereboom et al. 1998 Cable and Doherty 1999 Lo et al. 1995 Terziev et al. 1974). These effects have been reproduced in experimental animals. 

Anand M, Khanna RN, Misra D. 1980a. Electrical activity of brain in endosulfan toxicity. Indian J Pharmacol 12 229-235. 

Ansari RA, Husain K, Gupta PK. 1987. Endosulfan toxicity influence on biogenic amines of rat brain. 

Boyd EM, Dobos I, Krijnen CJ. 1970. Endosulfan toxicity and dietary protein. Arch Environ Health 21 15-19. 

Kiran R, Varma MN. 1988. Biochemical studies on endosulfan toxicity in different age groups of rats. Toxicol Lett 44 247-252. 

Oktay, C., E. Goksu, N. Bozdemrr, and S. Soyuncu. 2003. Unintentional toxicity due to endosulfan A case report of two patients and characteristics of endosulfan toxicity. Vet. Hum. Toxicol. 45(6) 318-20. 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of endosulfan. 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. 

Technical-grade endosulfan contains at least 94% a-endosulfan and (3-endosulfan. The a- and (3-isomers are present in the ratio of 7 3, respectively. The majority of the studies discussed below used technical-grade endosulfan. However, a few examined the effects of the pure a- and (3-isomers. Endosulfan sulfate is a reaction product found in technical-grade endosulfan as a result of oxidation, biotransformation, or photolysis. There is very little difference in toxicity between endosulfan and its metabolite, endosulfan sulfate. However, the a-isomer has been shown to be about three times as toxic as the P-isomer of endosulfan. 

Increased mortality was observed in both male rats (at doses of 20.4 mg/kg/day and above) and male mice (at doses of 0.46 mg/kg/day and above) in a 2-year bioassay conducted by the National Cancer Institute (NCI 1978). The authors attributed the excessive mortality in the male rats to treatment-related toxic nephropathy. The high mortality in male mice was possibly due to fighting since no other treatment-related cause for the deaths could be determined. Survival in females of both species was unaffected by endosulfan (NCI 1978). However, survival was significantly decreased in female rats that consumed 5 mg/kg/day for 2 years (FMC 1959b), and in female mice that consumed approximately 2.9 mg technical endosulfan/kg/day for 2 years (Hack et al. 1995 Hoechst 1988b). In these studies, survival in male rats was not affected at 5 mg/kg/day for 2 years (FMC 1959b) and survival in male mice was not affected at 2.51 mg/kg/day for 2 years (Hoechst 1988b). 

Male rats given a single oral dose of 200 mg/kg of endosulfan had myocardial hemorrhages (Terziev et al. 1974). It is not clear whether this effect was due to a direct effect of endosulfan on the heart or secondary to other toxicity such as damage occurring in response to effects of endosulfan on neural control of the heart. 

Studies in experimental animals indicate that both toxic effects and adaptive effects may be seen in the liver following oral exposure to endosulfan. 

These results demonstrate that immunotoxicity may be a sensitive end point of endosulfan-induced toxicity following exposure to low doses for sufficient durations. The highest NOAEL value and all reliable LOAEL values for immunological effects in each species in each duration category are recorded in Table 2-2 and plotted in Figure 2-2. 

In summary, neurotoxic effects of endosulfan are usually apparent only after acute ingestion of relatively high doses. Cumulative neurotoxicity does not appear to be significant. If the animal survives the acute toxic effects, then no long-term neurotoxic effects are evident from behavioral, gross, and microscopic observations. However, some impairment may occur that can be detected only by specialized neurobehavioral testing. 

No studies were located regarding reproductive toxicity in humans after oral exposure to endosulfan. 

Blood vessels were congested and cardiac ventricles were distended with blood in rats that died as the result of a 6-hour/day, 5-day/week for 30-day exposure to 81 mg/kg/day (males) and 27 mg/kg/day (females) (Hoechst 1985c). However, it is unclear whether these effects were due to a direct action of endosulfan on the blood vessels and heart or were a result of a more general toxic insult (e.g., convulsions). The respective NOAELs for males and females were 27 and 9 mg/kg/day. 

Twenty-two cases of endosulfan poisoning were reported in people exposed while spraying cotton and rice fields the dermal route of exposure was assumed to be the primary route of exposure (Singh et al. 1992). The assumption was based on the fact that those spraying rice fields, and who suffered cuts over the legs with the sharp leaves on the rice plants exhibited the more severe toxicity. Three out of the 22 cases exhibited tremors and 11 presented convulsions all patients recovered. 

Acute exposure to large amounts of endosulfan results in frank effects manifested as hyperactivity, muscle tremors, ataxia, and convulsions. Possible mechanisms of toxicity include (a) alteration of neurotransmitter levels in brain areas by affecting synthesis, degradation, and/or rates of release and reuptake, and/or (b) interference with the binding of those neurotransmitter to their receptors. 

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