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

The APVMA (2008a) summarised:―Numerous in vitro and in vivo experiments have tested the genotoxic potential ofdichlorvos, with the majority of data generated between 1972 and 1990 andpublished in the open scientific literature. In the current submission, sevenunpublished genotoxicity studies were evaluated, which showed that dichlorvoswas genotoxic in vitro but not in vivo. These findings are consistent with theextensive genotoxicity database for dichlorvos.―Dichlorvos is mutagenic and DNA-reactive in bacteria and other microorganismsin vitro, in both the presence and absence of exogenous metabolic activation(although effects were commonly reduced in the presence of exogenous metabolicactivation). Dichlorvos is also mutagenic and clastogenic in a range ofmammalian cells exposed in vitro, including induction of UDS but notchromosomal aberrations or SCE in cultured human cells. In contrast, the majorityof in vivo studies, including tests for induction of UDS, SCE, micronucleusformation, chromosomal aberrations and dominant lethal mutations, have yieldednegative results. These negative in vivo genotoxicity results can be explained bythe rapid metabolism and inactivation of dichlorvos, which appears to preventsystemic exposure to intact dichlorvos at concentrations likely to lead to directmolecular interactions.―Tungul et al. (1991) described micronucleus formation in mouse epidermalkeratinocytes after direct application of dichlorvos to the skin, confirming thatdichlorvos has genotoxic potential at localised high concentrations and in theabsence of metabolism. Pletsa (1999) reported a 3-fold increase in the mutationfrequency in the liver of transgenic mice following repeated intraperitonealinjection of dichlorvos. In this same study, a single injection failed to have aneffect, while neither single nor repeated administration generated methylatedDNA adducts or increased the frequency of mutations in other tissues. Thesefindings are consistent with increased tumours (mostly papillomas) observed inthe forestomach of mice, where tissue was exposed to high concentrations ofunchanged dichlorvos (NCI 1977; Chan 1989).―The extensive genotoxicity database indicates that in the absence of metabolism,dichlorvos is mutagenic and clastogenic at the point of contact, where unchangeddichlorvos may be in direct contact with tissue. There is no evidence thatdichlorvos has any systemic genotoxic potential. Scenarios of prolonged exposurein the absence of metabolic activity are unlikely in the general population giventhe current patterns of use. Chronic inhalational exposure (the most likelyexposure route in humans) failed to cause tumours (Blair et al., 1974) or tomethylate nucleic acids in rats (Wooder et al., 1976). The failure of dichlorvos tomethylate DNA or RNA in vivo has been attributed to its phosphorylatingreactivity, leading to highly efficient biotransformation (Wright et al., 1979).Furthermore, the consistently negative in vivo genotoxicity findings consequentwith rapid metabolism indicate that dichlorvos is unlikely to pose a genotoxic riskto humans.‖ (Originals not sighted; APVMA, 2008a)Dichlorvos reassessment – application Page 190 of 436