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

MALATHION 128
3.5.2 Mechanisms of Toxicity
3. HEALTH EFFECTS
The acute toxicity of malathion is basically similar to that of other phosphorothioate insecticides as the
inhibition of target neural acetylcholinesterase arises from the metabolic activation of the parent
compound. It is unique among organophosphates, however, since it is not possible to define an
unequivocal LD50 for a given population of a test species. Preparations of malathion contain varying
composition and amounts of impurities, many of which inhibit carboxylesterase and potentiate the
toxicity of malathion (Lin et al. 1984b; Pellegrini and Santi 1972; Talcott et al. 1977, 1979c; Toia et al.
1980; Verschoyle et al. 1982). However, only isomalathion among the impurities inhibits human liver
carboxylesterase (Talcott et al. 1979b). The existing literature is inadequate to describe the complex
dynamics of malathion biotransformation following the initial exposure, but clearly, the toxicity of
malathion is dependent upon the simultaneous reactions of the carboxylesterase hydrolyzing
malathion/malaoxon and of the impurities inhibiting carboxylesterase. Conceivably, when impurities are
low and carboxylesterase is very active, malaoxon may not build up to an effective level at the target as
noted in the preceding section. The typical cholinergic mechanism of toxic action, however, likely
accounts for the toxicity of most malathion formulations.
Inhibition of the target acetylcholinesterase by organophosphorus insecticides and other neurotoxic
organophosphorus esters involves phosphorylation of the serine moiety at the active site of the enzyme,
the reaction that parallels the acetylation during the normal hydrolysis of acetylcholine.
Besides the neural acetylcholinesterase, other serine hydrolases are also similarly inhibited. Most
notably, acetylcholinesterase in the erythrocyte and cholinesterase (pseudocholinesterase) in serum are
usually affected when the animal is exposed to a sufficient dose of malathion. Although the toxicological
consequences of this inhibition are unknown, it is regarded as a useful marker of malathion exposure (see
Section 3.8.2).
In the case of dimethyl phosphorus esters such as malathion, esterase inhibition by phosphorylation
appears more reversible than in the case of their higher alkyl homologs. This is due to dephosphorylation
rather than the true reversal of reaction, and represents a step in a series of displacement reactions in the
hydrolysis of malaoxon by acetylcholinesterase (O'Brien 1967).
This step is sufficiently slow to suppress the normal action of acetylcholinesterase, but does occur at a
measurable pace. For example, serum cholinesterase of New Zealand White rabbits was significantly