toxicological profile for malathion - Agency for Toxic Substances and ...

MALATHION 144
3. HEALTH EFFECTS
The effects of metabolic enzyme inducers on the toxicity of malathion have been examined in several
studies. For example, Brodeur (1967) observed that intraperitoneal administration of 50 mg/kg of
phenobarbital (PB) to rats for 5 days before a single injection of malathion (unspecified purity) produced
maximum protection against the inhibition of cholinesterase activity of malathion in brain, submaxillary
gland, and serum; extension of the PB treatment for 25 days did not confer additional protection. The
PB-induced reduction in anticholinesterase activity was paralleled by an increase in the intraperitoneal
LD50 from 520 to 920 mg/kg. Further experiments showed that PB-induced resistance was due mostly to
induction of a liver carboxylesterase and that inhibition of this enzyme by TOTP resulted in a complete
loss of protection of PB against malathion (Brodeur 1967). In similar experiments in mice, three daily
intraperitoneal treatments with 75 mg/kg of PB did not protect against the toxicity of malathion
(unspecified purity); the control LD50 was 985 vs. 915 mg/kg in PB-pretreated mice (Menzer and Best
1968). No enzymatic assays were conducted in the latter study. In a more recent study, Ketterman et al.
(1987) produced differential induction of cytochrome P-450-dependent monooxygenases, microsomal
carboxylesterases, and cytosolic glutathione-S-transferases, all systems that metabolize malathion. PB
(100 mg/kg) given on days 1, 4, 6, and 7 significantly induced cytochrome P-450 and carboxylesterase
activity, and pretreatment with 2(3)-tert-butyl,-4-hydroxyanisole (BHA), which greatly induced
glutathione-S-transferases, did not protect against malathion (98.5% pure) toxicity. Ketterman et al.
1987) suggested that the lack of protection may have been due to concurrent increases in both activating
and detoxifying pathways.
In addition to studies of interactions with other chemicals, a few studies have examined the influence of
malnutrition on the toxic effects of malathion. For example, Bulusu and Chakravarty (1984) reported that
administration of a single oral dose of malathion to rats kept on a low protein diets for 3 weeks induced
more severe liver effects than those seen in rats maintained on a normal diet and given malathion. This
conclusion was based on the findings of greater decreases in liver AST and ALT activities and greater
increases in liver β-glucuronidase activity in rats maintained on lower protein diets and given malathion
than in rats kept on normal diets and administered malathion. The authors speculated that a combined
effect of malathion and low protein diets on membranes allowed cytoplamic AST and ALT to leak into
the plasm, whereas disruption of lysosome membrane caused β-glucuronidase to be released into the
cytoplasm. Similar results regarding β-glucuronidase activity were reported in a study in which the rats
were maintained on low protein diets and treated with malathion for 3 weeks (Bulusu and Chakravarty
1986). In rats, exposure to malathion during gestation days 6, 10, and 14 increased serum levels of
cholesterol and triglycerides and the levels of cholesterol, triglycerides, and phospholipids in brain, liver,
kidney, and uterus, and these effects were intensified in rats maintained on a low protein diet