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

MALATHION 125
3. HEALTH EFFECTS
Target Tissues. This model does not attempt to estimate the level of active toxic molecular species at
the target tissues or at any other tissue. Instead, the goal of the model, for which validation and
optimization have been conducted, is to predict the dose based on the end product of metabolism. While
the model incorporates kinetic constants for metabolic processes, the main elements that controlled the fit
of output with actual data appear to be skin permeability constants (Dong et al. 1996), and for the purpose
of this model, other internal elements appear less important and hence less suited for predictions of target
tissue levels of the toxicant.
Species Extrapolation. Although some parameters and constants have been adapted from rodent data,
the model has been formulated for human simulation from the outset and reverse extrapolation to animals,
while useful, has not been tested.
Interroute Extrapolation. This model has been optimized solely for the purpose of estimating dermal
doses. As stated above under “Target Tissues”, internal elements have not been optimized. Further
validation and adjustments will be needed for the model to be useful in oral or inhalation routes of
exposure.
3.5 MECHANISMS OF ACTION
The typical acute neurotoxic action of malathion is cholinergic. It involves the inhibition of the neural
acetylcholinesterase by its active metabolite, malaoxon (Ecobichon 1994). The inhibition occurs due to
the similarity of malaoxon to the neurotransmitter acetylcholine. Mimicking acetylcholine, malaoxon
first binds to the active serine residue of acetylcholinesterase, undergoes a double displacement reaction
involving the serine hydroxyl group, and yields dimethyl-phosphorylated acetylcholinesterase. Since the
phosphorylated acetylcholineterase is stable within the time frame of poisoning, the inhibition prevents
the normally extremely rapid hydrolysis of neurotransmitter acetylcholine, prolonging the impulse
transmission.
The expression of toxic signs depends on which of the divisions of nervous systems is affected. Thus,
commonly observed cholinergic signs of poisoning including salivation, lacrimation, perspiration, and
constriction of the pupils are due to the stimulation of muscarinic acetylcholine receptors in the
parasympathetic autonomic synapse at exocrine glands and eyes. Other consequences of stimulating