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

E. GENOTOXICITY
Summary: DDVP was genotoxic in some in vitro systems, including assays with Salmonella TA 100
strain and Schizosaccharomyces pombe, mouse lymphoma forward mutation assay, and unscheduled
DNA synthesis assay using human epithelial cells. However, DDVP was not genotoxic in the
micronucleus, dominant lethal, in vivo chromosomal aberrations, and in vivo sister chromatid
exchange assays. Studies conducted in the presence and absence of a liver preparation (S-9
fraction) showed that the decrease in genotoxicity in the presence of the preparation may be due to
the inactivation of DDVP by liver esterases. Methylated DNA was detected in tissues of mice given
DDVP by intraperitoneal injection, but not in rat tissues when DDVP was given by inhalation.
Gene Mutation
Data from mutagenicity assays of DDVP in microbial systems showed mutagenic effects (Gilot-
Delhalle et al., 1983; and Braun et al., 1982). DDVP at 5 uM or more per plate was positive in only
TA100, one of five strains of Salmonella, in the absence of liver enzymes from the NMRI mouse
(Braun et al., 1982). DDVP (99% purity; 1.5, 4, or 14 mM) was mutagenic to Schizosaccharomyces
pombe only in the absence of S9 fraction from mice pretreated with phenobarbital (Gilot-Delhalle et
al., 1983). These studies were considered unacceptable to DPR because of inadequate protocol
description and/or results. The only negative mutagenicity study was in E. coli B/r WP2 (Dean, 1971).
This study was unacceptable to DPR because no data or dose levels were stated.
Positive mutagenic response in the mammalian system was observed in two studies (Ford et al.,
1986; and NTP, 1985). The mutagenic effect of DDVP (97.5% purity, 0.004 to 0.5 ul/ml) in L5178Y
TK +/- mouse lymphoma cells was examined in the presence and absence of Aroclor 1242 and 1254-
induced rat liver S-9 preparation (Ford et al., 1986). A dose-related increase in the mutation
frequency was observed in cells treated with DDVP (0.043 to 0.24 ul/ml) in the absence of liver
preparation. The results from experiments in the presence of the liver preparation showed the
increase in mutation frequency was lower than those obtained in the absence of the preparation. The
decrease in response may have been due to the rapid degradation of DDVP by the liver enzymes.
This study was acceptable to DPR.
In the National Toxicology Program (NTP) study, DDVP (purity not specified) was tested at 0, 6.25,
12.5, 25, 50, 100, 200, or 250 nl/ml in mouse lymphoma L5178Y TK +/- cells (NTP, 1985). In the
absence of the liver S-9 preparation, there was a concentration-related increase in the mutation
frequency at the three lowest exposures (6.25 to 25 nl/ml). Cytotoxicity was observed at
concentrations equal to and greater than 50 nl/ml. The effect of S-9 preparation on mutation was not
tested. This study was unacceptable to DPR because metabolic activation was not studied and DDVP
purity was not reported.
Structural Chromosomal Aberration
There was no evidence of micronucleus formation when DDVP (98.4% purity; 0, 4, 13, or 40 mg/kg)
was given to mice by intraperitoneal injection twice at 24 hour interval and sacrificed at 30, 48, or 72
hours (SDS Biotech Corp. 1985). This study was acceptable to DPR.
DDVP has not been shown to induce dominant lethal effects. In the only acceptable study, DDVP
(97.% purity; 0. 8, 16, or 32 mg/kg-day) were administered by intraperitoneal injection to male CD-1
mice for 5 days and mated weekly for 8 weeks (Ford and Killeen, 1987). In two unacceptable studies
of similar protocols, no dominant lethal effects were observed when CD-1 mice were exposed to
DDVP (>97% purity; up to 10 mg/kg-day) by intraperitoneal injection for 5 consecutive days (Ford et
al., 1985; Putman, 1985). These studies were unacceptable because of inadequacies in the protocols
and/or report of the data.
41