Dichlorvos (DDVP) Risk Characterization Document - California ...

In mice, there were dose-related increases in the incidences of forestomach papilloma in the males,
and of forestomach papilloma and carcinoma in the females (Chan, 1989; Table 7). The increased
incidences of forestomach papilloma appeared to be due irritation from gavage administration
(Benford et al., 1994). No other DDVP-related lesions were observed in this study (Chan, 1989). The
NTP considered the results for the male and female mice to be "some evidence" and "clear evidence",
respectively, of oncogenicity.
Supporting evidence for the potential oncogenicity of DDVP was provided by studies with rats given
DDVP in water (Enomoto, 1978), mice fed DDVP in the diet (NCI, 1977b), and DDVP increased
growth rate of tumors in Fischer 344 rats with leukemia transplants (Dieter et al., 1989). There were
increased incidences of pituitary adenomas and mononuclear cell leukemia (Enomoto, 1978), and
esophageal tumors (carcinoma and papilloma) (NCI, 1977b). There are limitations to the
interpretation of these studies (as discussed in III.D. CHRONIC TOXICITY section) and the data are
not appropriate for quantitative risk assessment.
Results from other chronic studies can not be used as weight of evidence because of various protocol
deficiencies. For example, the dog studies (Markiewicz, 1990; Jolley et al., 1967) were only for 1-2
years; therefore the duration of exposure was not a significant percentage of the lifetime. The
exposure of rats and mice to DDVP was not continuous in the studies conducted by Horn et al. (1988).
There were no individual data in the NCI (1977a) study with rats fed DDVP in the diet. An inadequate
number (25 instead of 50) of animals was exposed to DDVP in the study by Witherup et al. (1967).
Results from the in vitro genotoxicity studies also indicated a potential for DDVP to induce DNA and
gene damage in some systems including mammalian cells. Positive responses were detected in the
mouse lymphoma forward mutation assay and in the unscheduled DNA synthesis assay. However,
results from the micronucleus, dominant lethal, and in vivo sister chromatid exchange assays were
negative for genotoxicity. Alkylation of tissue DNA was detected in mice exposed to DDVP by
intraperitoneal injection, but not in rats exposed to DDVP by inhalation. The difference in results may
be due to experimental design and species difference. DDVP is considered a weak alkylating agent
as determined by its reaction with 4-(p-nitrobenzyl)pyridine in vitro (Bedford and Robinson, 1972).
Studies conducted in the presence and absence of liver activating system showed the genotoxicity of
DDVP was reduced due to the inactivation of DDVP by liver enzymes. Pharmacokinetics studies with
several species, including human, and using several routes of exposure, showed that DDVP was
rapidly and completely metabolized (III.A. PHARMACOKINETICS). Toxicity studies by Casida et al.
(1962) have shown that DDVP was more toxic than the metabolites. Dichloroacetaldehyde, a
metabolite, when fed to mice has been reported to induce dominant lethal mutations (Fischer et al.,
1977). The significance of its formation in vivo and its mutagenic effect is unknown.
Dichloroacetaldehyde was not detected in the rat urine (Hutson et al., 1971).
Therefore, DDVP was considered by DPR to be potentially oncogenic in humans based on positive
results in 2 animal species from the NTP study (Chan, 1989), supporting results from other studies,
and evidence of potential genotoxic effects. The potential oncogenic risk for DDVP was evaluated
using a quantitative approach. A non-threshold dose-response relationship was assumed to be linear
at the low dose range. A linearized multistage model, Global 86, (Howe et al., 1986) was used to
extrapolate the dose-response relationship obtained from experimental animal data at high dose
levels to low dose range which is generally more typical of human exposures . Both the maximum
likelihood estimate (MLE, q 1 ) and the 95% upper confidence limit (q 1 *) of the linear term of the
multistage model were presented as estimates of the oncogenic potency. The human oncogenic risk
at a low dose range was calculated by multiplying the potency by the potential exposure dosage.
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