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

MALATHION 162
3. HEALTH EFFECTS
response relationships, to test other organophosphates to determine specificity, and to test cells from
occupationally and accidentally (or intentionally) exposed subjects.
Effect. There are no biomarkers of effect specific for malathion. As an organophosphate pesticide,
malathion in sufficient amounts, produces typical signs and symptoms of cholinergic stimulation. Plasma
and RBC cholinesterase levels are widely used as biomarkers of exposure to organophosphates, but alone,
their levels do not predict whether adverse health effects will occur except in cases of significant
inhibition (Maroni 2000). Because baseline data for plasma and RBC cholinesterase are not usually
available for nonoccupationally exposed individuals, additional studies of normal values by age and sex
are needed for assessing potential adverse effects.
Absorption, Distribution, Metabolism, and Excretion. Among the areas of absorption,
distribution, metabolism, and excretion, the greatest data needs seem to lie in metabolism. The most
unique feature of malathion toxicokinetics (i.e., the extremely rapid hydrolysis at the carboxylester
linkages) is still poorly understood. Since carboxylesterase activities are the major determinant of the
malathion and malaoxon levels in vivo, many aspects of this enzyme need to be studied. Although it is
known that carboxylesterase exists in more than one form, details remain unknown. The question of
whether the same carboxylesterase hydrolyze both malathion and malaoxon is still unanswered. It is also
unknown whether the reported variable α/β ratio of monocarboxylic acid metabolites is due to the
variation in the enzyme or to variable contributions of different isozymes.
Less urgent toxicologically, but relevant, is the nature of the enzyme that yields dicarboxylic acid from
either of the monocarboxylic acids. Beyond the isozyme question, kinetic data on these enzymes would
also contribute to our understanding of toxicokinetics. Knowledge of Km and Vmax values of isozymes in
various organs would greatly facilitate construction of useful PBPK models. Though the importance of
malaoxon in the acute toxicity of malathion is unquestionable, generation, distribution, and metabolism of
malaoxon has been little studied. This likely reflects the technical difficulty imposed by the
overwhelmingly active carboxylesterase that prevents quantitation or even detection of malaoxon. Such
difficulties may be overcome by inhibiting carboxylesterase in vitro as was demonstrated by the increase
in cytochrome P-450 binding of malathion and malaoxon in the presence of bis-(p-nitrophenyl)phosphate,
a carboxylesterase inhibitor (Stevens and Greene 1973). In vivo studies of distribution and metabolism
may also benefit from similar strategies. Suppression of carboxylesterase in Sprague-Dawley rats in vivo
has been accomplished with TOTP.