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

MALATHION 130
3. HEALTH EFFECTS
plasma or RBC cholinesterase activity. However, administration of 0.34 mg malathion/kg/day for
56 days caused a maximum depression of 25% in plasma cholinesterase approximately 3 weeks after
cessation of treatment. A similar depression in RBC cholinesterase was observed, but occurred later. No
clinical manifestations of toxicity were noted throughout the study.
The high selective toxicity of malathion is due to its rapid hydrolysis by carboxylesterase in mammals
and the general lack of this enzyme in most insect pests. This enzyme is inhibited by several of the
impurities that accompany technical malathion as well as other organophosphorus esters including ethylp-nitrophenyl
thionobenzenephosphonate (EPN) and triorthotolyl phosphate (TOTP). The effective dose
of malathion preparations depends greatly on the carboxylesterase inhibition, which in turn is determined
by the level of impurities. Experimental inhibition of most carboxylesterase by TOTP dramatically
lowered acute LD50 of malathion preparations, from 1,600 to 20 mg/kg in one case and from 415 to
7.5 mg/kg in another (Main and Braid 1962) in male Sprague-Dawley rats.
3.5.3 Animal-to-Human Extrapolations
Malathion exerts most of its toxic effects through cholinergic disruption both in humans and in other
mammalian species. Data obtained with rodent models are clearly relevant to humans as they share basic
physiology both in the function of the nervous system and in the metabolic pathways. Because of these
similarities, basic clinical signs of poisoning are similar in humans and in rodents when they are exposed
to sufficient doses of malathion. In details, however, extrapolation of animal data to humans becomes
difficult due mainly to differences in pharmakokinetics. The situation is exacerbated by the unique
dependence of malathion toxicity on the degree of hydrolysis by carboxylesterases.
In humans, hepatic carboxylesterase activities appear similar to those in rat liver. Unlike rats, however,
humans lack detectable levels of malathion carboxylesterase in the serum; the enzyme is also absent in
human erythrocytes (Main and Braid 1962). Further confirmation of the general absence of malathion
carboxylesterase in the serum of healthy humans was provided by Talcott et al. (1982). About 30% of
blood donors had detectable levels of malathion carboxylesterase activity in serum, activity ranging from
0.1 to 7.2 units/mL; no relation to age, sex, or race was noted. Positive correlations between serum ALT
and malathion carboxylesterase were noted among 46 hospital patients. In addition, the two enzymes in
the serum of a patient hospitalized for acetaminophen poisoning were observed to rise and decline in
parallel, with the peak being reached on day 4. These data suggest that the low level of malathion
carboxylesterase found in some human serum is a reflection of liver damage. The lack of malathion