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

MALATHION 127
3. HEALTH EFFECTS
Pharmacokinetics of malathion is uniquely influenced by the high degree of carboxylester hydrolysis in
mammalian tissues, though other pathways of metabolism also operate, contributing to the ready
excretion of absorbed doses. Aldridge et al. (1979) observed that about 10,000 mg/kg of purified
malathion (an LD50 dose) caused little evidence of poisoning in female Lac:P rats for the first 6 hours of
malathion ingestion, and most fatalities occurred 20–40 hours following the dose. Clearly, in the absence
of impurities to inhibit carboxylesterase activity, rapid detoxification in rats precludes the buildup of an
effective level of malaoxon at the target site for hours.
In technical malathion, pharmacokinetics of malaoxon is a complex function of malathion level,
carboxylesterase titer, concentration of carboxylesterase inhibitors including isomalathion and malaoxon,
malathion dose level, and exposure frequency. A glimpse of this complexity may be seen in the multiple
role that just one of the malathion impurities (isomalathion) plays, competing with malathion for
glutathione (Malik and Summer 1982), and reducing the hydrolytic metabolism of both malathion and
malaoxon by inhibiting carboxylesterase (Talcott et al. 1979b). The level of malaoxon will also affect the
activity of carboxylesterase (Main and Dauterman 1967), which in turn affects the levels of malathion and
malaoxon. Such interaction of malathion would be dose-dependent, but this relationship has not been
examined.
The source organ of malaoxon molecules that interact with the target has not been elucidated. While
overall kinetic constants for the process of oxidative metabolism of malathion have been derived (Lechner
and Abdel-Rahman 1986; Rabovsky and Brown 1993), rates of malaoxon production for individual
organs and tissues remains unknown. The fact that the liver has the highest capacity to activate malathion
to malaoxon cannot be taken as evidence that malaoxon that reaches specific targets originates in the liver
in view of the complexity found in parathion (Nakatsugawa 1992). Thus, other organs of lesser activative
capacity may be significant sources of malaoxon reaching the target, especially in view of the high
hepatic level of carboxylesterase that can counter the activation in this organ (Talcott 1979).
Pharmacokinetics of malaoxon in humans must reflect the absence of serum carboxylesterase (Main and
Braid 1962; Talcott et al. 1982), which may be as important as the hepatic carboxylesterase in the rat.
This is not the only difference between the species; the rat liver, but not the human liver, has a substantial
capacity to demethylate malathion in addition to hydrolyzing at carboxylester linkages (Matsumura
1966).