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

MALATHION 105
3. HEALTH EFFECTS
for acute toxicity has not been determined. The overriding factor that makes the mammalian
toxicokinetics of malathion unique is the rapid hydrolytic cleavage of carboxylic ester linkages that
counters the buildup of the neurotoxic metabolite malaoxon. The impact of carboxylesterase on acute
toxicity is evident in the rat in which the oral LD50 of malathion may be as low as 7.5 mg/kg when
carboxylesterase is artificially suppressed (Dauterman and Main 1966; Main and Braid 1962) and as high
as 10,000 mg/kg when carboxylesterase is fully active in the absence of interfering impurities. A similar,
though less dramatic, effect of carboxylesterase inhibition has also been observed for malaoxon toxicity
(Dauterman and Main 1966).
Malathion also undergoes various other forms of biotransformation. Both malathion and malaoxon are
subject to phosphate linkage hydrolysis as well as glutathione-linked cleavage, both of which are
detoxicative. Carboxylesterase is quite active in rat blood, but not in human blood (Main and Braid
1962). In contrast, in both species, the enzyme is highly active in the liver. Since the blood enzyme in
the rat apparently plays a major role in keeping the toxicity of this insecticide low, whether rats serve as a
correct toxicokinetic model for humans is uncertain, particularly in view of the observed inter-specific
variations. The efficient carboxylesterase hydrolysis masks various other pathways of biotransformation,
and makes studies of toxicokinetics difficult. Further confounding the toxicokinetics is the varying
amounts of impurities in commercial formulations, which inhibit carboxylesterase to varying degrees
depending on the formulation. As a result, toxicokinetics depends not only on variations in the recipient
sensitivity, but also on the purity of the malathion preparation at hand.
3.4.1 Absorption
Absorption of malathion has been studied either indirectly by following the urinary output of metabolites
or directly by studies of disappearance of malathion from the site of application, typically by using
malathion radiolabeled with 14 C at various parts of the molecule, including the methoxy, succinyl, and
ethyl groups. Though many of these studies also provide information regarding elimination, studies
concerning elimination as evidence of absorption are presented in this section, while other studies more
directly addressing elimination are reviewed in Section 3.4.4, Elimination and Excretion.