Application for the Reassessment of a Hazardous Substance under ...

3 TOXICOLOGICAL HAZARD PROFILE – INTRODUCTIONDichlorvos exerts its toxic effects by inhibiting neural acetylcholinesterase inhumans and animals. Throughout the central and peripheral nervous systemscholinergic synapses contain this enzyme, which is responsible for hydrolyzingacetylcholine released from the pre-synaptic terminal. Dichlorvos chemicallyreacts with the active site of acetylcholinesterase and inhibits enzyme activity.Inhibition of neural acetylcholinesterase allows acetylcholine to accumulate in thesynapse, resulting in increased firing of the postsynaptic neuron or increasedneuroeffector activity. Increased cholinergic activity in the parasympatheticautonomic nervous system (muscarinic receptors) can include increasedsalivation, lacrimation, perspiration, miosis, nausea, vomiting, diarrhea, excessivebronchial secretions, bradycardia, frequent micturition, and incontinence.Increased neuroeffector activity on skeletal muscles (nicotinic receptors) caninclude muscle fasciculations, cramps, muscle weakness, and depolarization-typeparalysis. Effects on central nervous system (predominantly muscarinic) includedrowsiness, fatigue, mental confusion, headache, convulsions, and coma. Theseclassical symptoms of organophosphate neurotoxicity increase in severity andrapidity of onset in a dose-dependent manner (Ecobichon 1991). (Originals notsighted in APVMA, 2008a)Erythrocytes also contain acetylcholinesterase, erythrocyte (or RBC)acetylcholinesterase. Both neural and erythrocyte acetylcholinesterase areproduced by the same gene (Taylor et al., 1993). Erythrocyte and neuralacetylcholinesterase in in vitro systems are inhibited to roughly the same extent byexposure to dichlorvos (Hayes 1982). Erythrocyte acetylcholinesterase is used as asurrogate measurement of the inhibition of neural acetylcholinesterase. The liverproduces a cholinesterase that circulates in the blood. This cholinesterase, calledserum (or plasma) cholinesterase, is also inhibited by dichlorvos and is anothermarker for exposure. Usually, this enzyme is inhibited by dichlorvos at lower levelsof exposure than required to inhibit neural or erythrocyte acetylcholinesterase(Hayes 1982). (Originals not sighted; ATSDR, 1997)Dichlorvos has high acute toxicity in experimental animals. Clinical signs of toxicityoccur soon after dosing and are typical of organophosphate poisoning (exophthalmus,salivation, lachrymation, tremors, dyspnoea, convulsions and death). Survivors recovercompletely within 24 hours (Durham et al., 1957; Lamb 1992). The time to peak effectin rats following oral dosing is 15-60 minutes (Tyl et al., 1990a; Lamb 1992; Lamb1993b). (Originals not sighted; APVMA, 2008a)There is an extensive genotoxicity database for dichlorvos. Negative results werereported in in vivo host-mediated, dominant lethal, sister chromatid exchange andmicronucleus assays (except on skin after local application at cytotoxic doses).Dichlorvos was reported not to induce in vivo chromosomal aberrations in bone-marrowcells, spermatocytes or spermatogonia (Dean & Thorpe, 1972a; Moutschen-Dahmen etal., 1981; Degraeve et al., 1984b), DNA strand breaks (Wooder & Creedy, 1979) orunscheduled DNA synthesis (Mirsalis et al., 1989; Bedford, 1991). (Originals notsighted; WHO, 1993)Dichlorvos reassessment – application Page 160 of 436