10 Genotoxicity of Permethrin

No data are available in the literature on the genotoxicity of permethrin in humans.

GENE MUTATIONS

Several investigators have tested permethrin for its ability to produce mutations in Ames reverse mutation assay using Salmonella typhimurium tester strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100, with and without metabolic activation (Litton Bionetics, 1975; Longstaff, 1976; Simmon, 1976; Callander, 1989). The concentrations of permethrin tested ranged from 1 to 2,500 µg per plate. The results of these studies showed that permethrin was not mutagenic in the Ames Salmonella test. Permethrin was also not mutagenic in Escherichia coli WP2 uvrA mutation assay (Newell and Skinner, 1976; Simmon, 1976). In one host-mediated assay, permethrin (200 mg/kg of body weight) was orally administered to ICR mice, and the indicator organisms, S. typhimurium G46, were injected intraperitoneally and harvested from the abdominal cavity of mice 3 hr after treatment. The study did not reveal any mutagenic effect (Shirasu et al., 1979). In another host-mediated assay employing a similar test system, trans-permethrin at 600 and 3,000 mg/kg of body weight and cis-permethrin at 21 and 54 mg/kg of body weight gave negative results (Miyamoto, 1976).



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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms 10 Genotoxicity of Permethrin No data are available in the literature on the genotoxicity of permethrin in humans. GENE MUTATIONS Several investigators have tested permethrin for its ability to produce mutations in Ames reverse mutation assay using Salmonella typhimurium tester strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100, with and without metabolic activation (Litton Bionetics, 1975; Longstaff, 1976; Simmon, 1976; Callander, 1989). The concentrations of permethrin tested ranged from 1 to 2,500 µg per plate. The results of these studies showed that permethrin was not mutagenic in the Ames Salmonella test. Permethrin was also not mutagenic in Escherichia coli WP2 uvrA mutation assay (Newell and Skinner, 1976; Simmon, 1976). In one host-mediated assay, permethrin (200 mg/kg of body weight) was orally administered to ICR mice, and the indicator organisms, S. typhimurium G46, were injected intraperitoneally and harvested from the abdominal cavity of mice 3 hr after treatment. The study did not reveal any mutagenic effect (Shirasu et al., 1979). In another host-mediated assay employing a similar test system, trans-permethrin at 600 and 3,000 mg/kg of body weight and cis-permethrin at 21 and 54 mg/kg of body weight gave negative results (Miyamoto, 1976).

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms Permethrin has also been tested for its genotoxicity with Saccharomyces cerevisiae D4, with or without metabolic activation, at concentrations ranging from 0.0001 to 5.0 µg per plate, and the results showed that permethrin was not mutagenic to S. cerevisiae D4 (Litton Bionetics, 1975). Permethrin was not mutagenic in Drosophila melanogaster sex-linked recessive lethal mutation assay (Mehr et al., 1988). Clive (1977) studied the mutagenicity of permethrin (purity not stated) in mouse lymphoma L5178Y TK+/TK− assay at concentrations ranging from 1 to 125 mg/mL, with and without metabolic activation. There was no evidence of mutagenicity in this study. Pluijmen et al. (1984) showed that permethrin was not mutagenic to V79 Chinese hamster cells, with or without metabolic activation. CHROMOSOMAL EFFECTS The results of investigations of clastogenic effects of permethrin are inconsistent. In one study, D. melanogaster males were administered permethrin in a feeding solution at 5 ppm for 3 days before mating with untreated mus-302 DNA-repair defective females. The F1 male progeny were screened for partial or complete chromosomal loss. The results of this investigation were negative (Woodruff et al., 1983). The utility of this study is questionable because the assay is not commonly used for chromosomal aberrations and its sensitivity is unknown. Furthermore, the findings are questionable because only low doses of permethrin were tested. Anderson and Richardson (1976) tested permethrin for its ability to induce micronuclei in Alderley Park rats. Male rats (12 controls and 8 per treatment group) were injected intraperitoneally with permethrin (94% pure, cis/trans ratio, 40:60) once or in five daily doses of 0, 600, 3,000, or 6,000 mg/kg. There were eight animals per test group and 12 animals in the control group. Rats were killed 24 hr after the single injection and 6 hr after the final dose with multiple injections. Bone-marrow cells from each animal were analyzed, and the results of this investigation showed that permethrin was not clastogenic. Hoellinger et al. (1987) reported a slight but significant (p < 0.01)

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms increase in micronuclei in bone-marrow cells (1,000 cells analyzed) of female Sprague-Dawley rats (0.71% vs. 0.25%) that were administered permethrin by gavage at doses of 139 mg/kg (purity, 91%; cis/trans ratio unknown). The subcommittee considers this study inadequate because only one dose was tested in six animals. In another study, 10 male CFLP mice per group were administered permethrin (purity unknown; cis/trans ratio unknown) orally once at 150 mg/kg or in five daily doses at 45.2 mg/kg (Paldy, 1981). The animals were killed 24 hr after the final dose but only 100 bone-marrow cells from each animal were examined (the standard practice is to analyze 1,000 bone-marrow cells) for chromosomal aberrations—breaks, chromatid-type gaps, isogaps, and chromosome-type deletions with acentric fragments and translocations. The results showed that single and repeated administration produced these chromosomal effects. In both experiments, permethrin produced chromosomal aberrations in 5% of the cells as compared with 2% in controls. According to Paldy (1981), this result is on the borderline of statistical significance; the “p” value was not provided, however. The subcommittee considers the study to be inadequate because the study is published only as an abstract without details of protocols. Furthermore, only 100 bone-marrow cells were examined and the investigator observed mainly chromatid gaps and breaks; their significance is unknown. Barrueco et al. (1992) tested permethrin for its ability to induce sister chromatid exchanges (SCEs), micronuclei, and chromosomal aberrations in cultured human peripheral blood lymphocytes from two human donors. Permethrin was tested at concentrations of 5-200 µg/mL in the absence and presence of rat liver S9 mix. Small increases in the SCE frequencies were found that were statistically significant, but they might not be biologically meaningful since there was no dose-effect relationship and the increase in SCEs was not always reproducible. Permethrin increased the occurrence of micronuclei over controls when it was assayed at concentrations of 10-100 µg/mL in the absence of S9 mix. The effect was statistically significant. However, in the presence of S9 mix, the increase in micronuclei was not statistically significant in lymphocytes from both human donors. Permethrin was found to increase the frequency of chromosomal aberrations at concentrations of 75-150 µg/mL in the absence of S9 mix. In

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms the presence of S9 mix, the increase in frequency of chromosomal aberrations was not statistically significant. The chromosomal aberrations induced by permethrin in this study were mainly chromosome type. The authors concluded that permethrin did not induce SCEs and recommended that additional studies should be conducted to confirm the positive results in the chromosomal-aberration and micronuclei assays using the cultured human lymphocyte. Additional studies should consider the influence of the metabolic activation system and the duration of treatment on the induction of clastogenic effects of permethrin (Barrueco et al., 1992). Herrera et al. (1992) studied the induction of SCEs in cultured human lymphocytes from two human donors. They found that permethrin at concentrations of 50 or 100 µg/mL induced SCEs in the absence of rat liver S9 mix; however, the increases in frequency of SCEs were not dose-related. There were differences between the two donors in the SCE assays carried out in the presence of liver S9 mix—one showed no increase in SCEs and the other showed an increase in SCEs that was not dose-related. The authors concluded from this that “permethrin induces a slight genotoxic effect that cannot always be detected.” Herrera et al. (1992) also studied the induction of micronuclei in cultured human lymphocytes of two human donors. The lymphocytes were exposed to permethrin at concentrations of 0, 10, 25, or 50 µg/mL in the absence of S9 mix. Permethrin was positive in the micronucleus test when it was assayed in the absence of S9 mix. However, in the presence of S9 mix and permethrin concentrations of 0, 25, 50, 75, 100, or 200 µg/mL, the increase in number of micronuclei, observed in some cases, was not statistically significant. The authors concluded that “a definitive conclusion on the genotoxicity of the pyrethroid insecticide can only be possible when more experimental tests are available. ” Barrueco et al. (1994) tested permethrin for its ability to induce structural chromosomal aberrations in human lymphocyte cultures and Chinese hamster ovary (CHO) cells. Permethrin was tested in the range of 50-200 µg/mL in human lymphocyte cultures and in the range of 20-100 µg/mL in CHO cells. A short-term (2-3 hr) exposure and a long-term (20-24 hr) exposure were used in each study. The short-term exposure was conducted in the presence and absence of S9 mix. Permethrin induced dose-dependent increases in chromosomal aberrations in human lymphocytes and CHO cells in the absence of S9 mix. In the presence of

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms S9 mix, the clastogenicity was not statistically significant. In both cultures, permethrin induced primarily chromosome-type aberrations. Permethrin has been studied for dominant lethal effects in two studies. In one study, 15 male CD-1 mice in each group were administered permethrin (purity, 95.3%; cis/trans ratio, 40:60) orally on GDs 7-12 at 0, 15, 48, or 150 mg/kg per day. Each male was mated with two virgin females weekly for 8 consecutive weeks. The pregnant mice were killed on GD 12. There was no dose-related effect on pregnancy or early fetal deaths. Thus, permethrin had no dominant lethal effect on male mice (McGregor and Wickramaratne, 1976b). However, this study was flawed because there was no explanation for deaths of 5% of the females and the number of pregnant females per interval was insufficient. In the second dominant-lethal-effects study, 10 male CD-1 mice in each group were administered permethrin (purity unknown; cis/trans ratio, 25:75) orally at 0 or 452 mg/kg per day (1/5 LD50) for 5 days. Each male was mated with three virgin females weekly for 6 weeks. The results of the investigation showed no evidence of dominant lethal effect of permethrin (Chesher et al., 1975b). OTHER GENOTOXIC EFFECTS In DNA damage studies, Trueman (1988) studied the induction of unscheduled DNA synthesis in primary rat hepatocytes in culture. Rat hepatocytes were exposed to 93.5% permethrin at concentrations of 10−9-10−2 molar. There was no evidence of induced DNA repair as measured by unscheduled DNA synthesis in primary cultures of rat hepatocytes exposed in vitro. Permethrin was negative in the E. coli pol A assay, the Bacilus subtilis rec assay, the S. cerevisiae D3 mitotic recombination assay, and the unscheduled DNA synthesis in human lung fibroblasts (Garrett et al., 1986). CONCLUSIONS Studies conducted to determine the potential of permethrin to produce gene mutations in microbial and mammalian systems were all negative. Studies conducted to determine the potential of permethrin to produce

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms chromosomal damage provided an array of results. Of the two in vivo studies conducted in the micronucleus assay, one was negative and the other was inadequate. Three in vitro studies in which clastogenicity of permethrin was investigated provided evidence of potential clastogenicity of permethrin. Small, statistically significant elevations in sister chomatid exchanges, micronuclei, and chromosomal aberrations in human lymphocyte cultures were reported. Chromosomal aberrations were also reported in Chinese hamster ovary cells. All three in vitro studies were performed in one laboratory by the same investigators. Other genotoxicity tests of permethrin (dominant lethal test and tests for DNA damage in microbial and mammalian cells) were negative. The subcommittee believes that the weight of evidence suggests that permethrin does not produce gene mutations but is a potential clastogen in certain in vitro systems. Three in vitro studies from one laboratory showed small, statistically significant increases in clastogenic effects of permethrin. The subcommittee recommends that these studies be repeated by other investigators to determine if the positive findings of permethrin's clastogenicity can be confirmed. If these findings are confirmed, the clastogenicity of permethrin should also be studied in vivo with an adequate number of animals and dosages of permethrin.