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

may be involved in the alkylation of DNA. In vitro studies showed that dichloroacetaldehyde caused
gene mutations in bacteria and dominant lethal mutations in mice (Aquilina et al., 1984).
Therefore, in the absence of adequate data to evaluate the oncogenicity of DDVP by the inhalation
route and in the presence of data from the gavage study (Chan, 1989) indicating potential
oncogenicity, DDVP is assumed to be oncogenic by the inhalation route. The potency factor derived
for mononuclear cell leukemia (a systemic effect) in rats (Chan, 1989) was used to assess human
exposures.
Oral
Evidence of DDVP oncogenicity by the oral route was identified in rats and mice (Chan, 1989) (Tables
4 and 7). In 2.9 and 5.7 mg/kg-day male rats, there were dose-related increases in the incidences of
pancreatic adenoma and mononuclear leukemia. The results showed positive trends and were
considered significantly (p @ 0.05) different from the concurrent controls based on Fisher's Exact test.
In females, there were also dose-related increases in the incidences of pancreatic adenoma,
mononuclear cell leukemia, and mammary gland tumors; even though the pair-wise comparison
(except for mammary gland tumors found at 2.9 mg/kg-day) and trends were not statistically
significant (at p @ 0.05). The NTP considered the increased incidences of pancreatic adenoma and
mononuclear cell leukemia in male rats as some evidence of carcinogenicity 1 . In female rats, the
increased incidences of mammary gland and pancreatic tumors were considered to be equivocal
evidence of carcinogenicity.
For pancreatic adenoma, there is evidence of progression to a malignant stage (McConnell et al.,
1986). The NTP proposed that pancreatic adenoma and carcinomas should be combined for the
evaluation of oncogenicity. These results were, however, confounded by the use of corn oil as the
vehicle, as high incidences of pancreatic adenomas were found in the controls. Corn oil has been
shown to induce pancreatic tumors in F344/N male rats (Eustis and Boorman, 1985; Haseman et al.,
1985). In this study, DDVP may be a promoter rather than a direct carcinogen (Chan, 1989;
Mennear, 1988). Consistent with the report by Haseman et al. (1985) for other compounds, corn oil
did not have any effect in the females. Other studies have also shown an enhancement of toxicity and
oncogenicity of organic compounds by corn oil (Condie et al., 1986, and Bull et al., 1986). However, a
recent report by Huff and Hasemen (1991) showed that corn oil has little or no influence on the
oncogenicity and that the previous finding may be due to a difference in body weight.
The control incidences (11/50 and 17/50 for males and females, respectively) of mononuclear cell
leukemias were within the range (1/50 to 22/50) of historical controls for NTP carcinogenesis studies
conducted during that period (Stefanski et al., 1990). Comparison of concurrent control data with the
historical control data confined to the testing period is appropriate because the background rate of
certain tumor types, including leukemia, in F344 rats has been steadily increasing (Huff and
Haseman, 1991). Possible reasons for the shift were: changes in histopathology diagnostic criteria
over time, changes in the amount of tissue examined, intra- and interlaboratory variability, and dietary
factors.
1/ The descriptions of the evidence classification from the NTP are:
Clear evidence - there is a dose-related increase of malignant neoplasms, a combination of
malignant and benign neoplasms, or marked increase of benign neoplasm if there is an
indication that such tumors have the ability to progress to malignancy.
Some evidence - there is a chemically-related increase in the incidence of neoplasms
(malignant, benign, or combined) but have less strength than clear evidence.
Equivocal evidence - there is a marginal increase of neoplasms that may be chemically
related.
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