9 Reproductive and Developmental Toxicity Of Permethrin

Several reproductive and developmental toxicity studies have been conducted with permethrin administration in diet or by gavage. No studies were found that used dermal exposure, but any effect would be expected to be less because of lower absorption in dermal exposure than in oral exposure. The oral studies include six experiments in rats, two in mice, and two in rabbits in which permethrin was given during part or all of organogenesis, and fetuses were examined at term or, in some cases, postnatally. Three three-generation reproduction studies were conducted in rats. Several chronic toxicity studies were also reviewed for information on reproductive organ weight or histopathology. As a whole, the data available suggest little or no effect of permethrin on developmental or reproductive end points, except at fairly high doses. There were observations of developmental or reproductive effects in single studies, but those alterations were not confirmed in other similar studies.

Most of the following descriptions of studies were developed from information in the World Health Organization's (WHO's) Environmental Health Criteria (IPCS, 1990) and the California Environmental Protection Agency's Risk Characterization Document (CEPA, 1992). In addition, clarifying information on several studies was obtained from Dr. John Doherty, Office of Pesticide Programs, U.S. Environmental Protection Agency (EPA), who reviewed many of the original studies on permethrin for that office.



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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms 9 Reproductive and Developmental Toxicity Of Permethrin Several reproductive and developmental toxicity studies have been conducted with permethrin administration in diet or by gavage. No studies were found that used dermal exposure, but any effect would be expected to be less because of lower absorption in dermal exposure than in oral exposure. The oral studies include six experiments in rats, two in mice, and two in rabbits in which permethrin was given during part or all of organogenesis, and fetuses were examined at term or, in some cases, postnatally. Three three-generation reproduction studies were conducted in rats. Several chronic toxicity studies were also reviewed for information on reproductive organ weight or histopathology. As a whole, the data available suggest little or no effect of permethrin on developmental or reproductive end points, except at fairly high doses. There were observations of developmental or reproductive effects in single studies, but those alterations were not confirmed in other similar studies. Most of the following descriptions of studies were developed from information in the World Health Organization's (WHO's) Environmental Health Criteria (IPCS, 1990) and the California Environmental Protection Agency's Risk Characterization Document (CEPA, 1992). In addition, clarifying information on several studies was obtained from Dr. John Doherty, Office of Pesticide Programs, U.S. Environmental Protection Agency (EPA), who reviewed many of the original studies on permethrin for that office.

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms RAT STUDIES Kohda et al. (1976a) treated Sprague-Dawley rats with permethrin at 0, 10, 20, or 50 mg/kg per day orally on gestation days (GDs) 9-14. Two-thirds of the animals were killed on GD 20, and the rest were allowed to deliver, were weaned, and then killed at 6 weeks of age. Parental females fed 50 mg/kg showed neurotoxicity and slight body-weight decreases, but no mortality. Fetal loss at the high dose was also slightly increased, and there was an increase in nonossified sternebrae. No other effects were seen either prenatally or postnatally. McGregor and Wickramaratne (1976a) treated CD rats with permethrin at 0, 22.5, 71, or 225 mg/kg per day on GDs 6-16. No effects on any maternal or developmental end points were seen at GD 20 when animals were killed and uterine contents examined. Metker et al. (1977) treated Sprague-Dawley rats with 4, 41, or 83 ppm in the diet on GDs 6-16. Animals were killed on GD 20, and no effects on adults or offspring were noted. James (1974a) administered permethrin (cis/trans ratio, 25:75) to Wistar rats by gavage at 0 or 200 mg/kg on GDs 6-16. Animals were killed on GD 20; no effects were seen in either maternal or developmental end points. Hodge (1988) administered permethrin dissolved in corn oil by gavage to Alpk:Apf Sprague-Dawley rats (24 in each group) at doses of 0, 15, 50 or 150 mg/kg per day on GDs 7-16. Maternal toxicity was seen at 150 mg/kg, and reduced fetal body weight and delayed ossification were seen at 150 mg/kg. The maternal and developmental NOAELs were 50 mg/kg. Spencer and Berhane (1982) treated Sprague-Dawley rats (five to eight in each group) with 0, 500, 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, or 4,000 ppm in the diet on GDs 6-15. Laparotomies were done on GD 6 to count implantation sites (after iv injection with Chicago blue dye), and animals were killed on GD 20. Other animals were treated similarly and killed on GD 16 for assay of placental protein and glycogen content. Although a reduction in placental glycogen content was seen at 2,000 ppm and above and protein content was reduced at 2,500, 3,000 and 4,000 ppm, there was no consistent dose-related effect in offspring observed on GD 20. There was an increase in the

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms resorption rate in all treated groups, but the increase was not dose-related and might have been due to an unusually low incidence in controls. Schroeder and Rinehart (1977) conducted a three-generation reproduction study in Long-Evans rats (10 males and 20 females in each group) with two litters in each generation. Animals were exposed to permethrin at 0, 20, or 100 ppm (cis/trans ratio, 40:60) in the diet (0, 1, or 5 mg/kg per day). The only observation was a decrease in the F2 mating index in both controls and treated groups, but no dose-related effects were seen in the study. No histopathological examination was done in this study. Hodge et al. (1977) also conducted a three-generation study (two litters per generation) in Wistar rats (12 males and 24 females in each group) with 0, 500, 1,000, or 2,500 ppm in the diet (0, 25, 50, or 125 mg/kg). Tremors and other clinical signs were seen mostly in the high-dose group or F0 females. In both generations, there was a dose-related increase in the occurrence of buphthalmos (enlargement of the eye) and pupillary membrane (a mesodermal layer attached to the iris during embryonic development) in offspring at weaning. The pupillary-membrane incidence in the 0-, 500-, 1,000-, and 2,500-ppm groups was 0 of 1,252, 2 of 1,241, 18 of 1,383, and 19 of 1,408, respectively, and the buphthalmos incidence was 0 of 121, 1 of 120, 14 of 130, and 15 of 131, respectively. The incidence was significantly increased at 1,000 and 2,500 ppm, although the highest incidence was less than 2% of pups, approximately 11% of litters. These effects were similar to those seen in adult animals exposed to permethrin (see Chapter 7). The earliest litter affected was the second F2 at 500 ppm, the first F2 at 1,000 ppm, and the second F1 at 2,500 ppm. Thus, there was some progression toward earlier litters affected as the dose was increased. The CEPA document noted that this defect can be genetically determined, but no evidence for that was found in the pedigree of the animals used in the study. However, they did not rule out a genetic-chemical interaction. In F3b offspring, dose-related centrilobular hypertrophy and cytoplasmic eosinophilia were seen in the liver at all doses (looked at only in the F3b offspring). No other effects of permethrin exposure were seen. No histopathological examination was performed in this study. A third three-generation study with two litters in each generation was

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms conducted by James (1979) in Wistar COBS rats. Twenty males and 20 females in each group were fed permethrin (cis/trans ratio, 25:75) in the diet at doses of 0, 5, 30, and 180 mg/kg of body weight. No effects were reported in any group. No histopathological examination was performed in this study. MOUSE STUDIES Kohda et al. (1976b) treated ICR mice with 0, 15, 50, or 150 mg/kg orally on GDs 7-12. Two-thirds of the animals were killed on GD 18, and the rest went to term, delivered, and weaned their young; pups were killed at 6 weeks of age. No effects were seen on any maternal, developmental, or postnatal end points. James (1974b) treated CD-1 mice with 0 or 400 mg/kg per day by oral gavage on GDs 6-15, and killed the animals on GD 18 to examine the offspring. No effects were seen. RABBIT STUDIES Richards et al. (1980) treated Dutch rabbits by gavage with permethrin at 0, 600, 1,200, or 1,800 mg/kg in 0.5% Tween 80 on GDs 6-18 and killed the animals on GD 29. Maternal body-weight gain was reduced, and there was increased hair loss at 1,200 and 1,800 mg/kg. Embryo lethality was also increased at the two highest doses, and fetal weight was decreased at 1,800 mg/kg. James (1974c) treated Dutch belted rabbits (six to seven per group) with permethrin at 0 or 400 mg/kg per day in a corn oil gavage on GDs 6-18. No effects were noted in the permethrin-exposed animals. OTHER STUDIES Since the multigenerational studies did not include data on specific reproductive toxicity, such as organ weights, histopathology, or semen measurements, other data were reviewed to determine whether there

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms might be more specific effects of permethrin, particularly on male reproductive function. Data summaries of the chronic toxicity studies and the dominant-lethal-effects studies using permethrin exposure were reviewed in an attempt to find more specific information. There are several issues that should be considered in evaluating these data, however. In the chronic toxicity studies, data were usually collected at the end of 1-2 years when pathology of aging is often seen in the testis. Also, histopathological examinations at the time these studies were done were most likely conducted after formalin fixation, which does not result in adequate testicular morphology. Current procedures recommend Bouin's fixation for testes. The following summarizes data available from these studies. Ishmael and Litchfield (1988) conducted chronic toxicity studies in Alpk:AP (Wistar-derived) rats and Swiss-derived mice fed permethrin (cis/trans ratio, 40:60) in the diet for 104 weeks. The concentrations used for rats were 0, 500, 1,000, or 2,500 ppm, and those used for mice were 0, 250, 1,000, or 2,500 ppm. Testis weights were recorded at 52 and 104 weeks in rats and at 26, 52, and 98 weeks in mice; no effects were noted. It is not clear from the paper whether testis histopathological examination was done. A chronic toxicity study was conducted by Tierney and Rinehart (1979) in CD-1 mice (75 of each sex per group) (see Table 9-1). Permethrin was given at 0, 20, 500, or 2,000 ppm in the diet to male mice and 0, 20, 2,500, or 5,000 ppm in the diet to female mice. At the end of the 2-year study, testis weight was reduced and testicular hypoplasia histologically was noted; increased mortality occurred in males at the 2,000-ppm (300-mg/kg) dose. There was also reduced testis weight and increased mortality in males at 500 ppm (75 mg/kg); testis weight was not significantly reduced at 20 ppm (3 mg/kg), but there was a clear dose-related change among the three permethrin doses. The study was considered unacceptable by CEPA because of poor animal husbandry, but EPA audited the study and found it acceptable. Another chronic toxicity study submitted to EPA by Wellcome (Life Science Research, 1980) was a dietary feeding study in which Charles River Wistar rats were fed permethrin at 0, 10, 50 and 250 mg/kg of body weight per day (cis/trans ratio, 25:75). At the end of the study (104 weeks), histopathological examination was performed on a number

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms TABLE 9-1 Reproductive and Developmental Toxicity in Tierney and Rinehart Study   % Reduction Relative to Controls Testis Weight Reduction 20-ppm Group 500-ppm Group 2,000-ppm Group Absolute 7 15 38 Relative to body weight 7 12 35 of tissues, including male and female reproductive organs (using H & E staining and presumably formalin fixation). No effects were noted. Several subacute and subchronic toxicity studies are cited in the WHO document (IPCS, 1990), and several other chronic toxicity studies are reviewed in the WHO document (IPCS, 1990) and the CEPA document (CEPA, 1992). These reviews do not indicate testis-weight or histopathological results, but very little detail of what was done in the studies is given. Two dominant-lethal-effects studies were performed in mice, and both were negative but poorly conducted. One study had small numbers of animals in each group (McGregor and Wickramaratne, 1976b), and the other study used only a single dose (Chesher et al., 1975b). CONCLUSIONS Data on the reproductive and developmental toxicity of orally administered permethrin suggest that there are few toxic effects and that these tend to be at high doses. No data are available from dermal exposure studies, but oral dosing would be expected to maximize any effects, since dermal absorption is poor. Where toxic effects have been reported, other similar studies have not confirmed those effects. There is also disagreement among the studies on the doses at which toxicity was observed. In the rat developmental toxicity studies, for example, Kohda et al. (1976a) reported maternal and developmental toxicity at 50 mg/kg per day on GDs 9-14 and a NOAEL of 20 mg/kg per day. On the other hand, Hodge (1988) reported maternal and developmental toxicity at 150 mg/kg per day (given orally on GDs 7-16) and a NOAEL of 50 mg/kg

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms per day, and McGregor and Wickramaratne (1976a) reported no effects at doses as high as 225 mg/kg per day on GDs 6-16. There were some differences in the strain of rat used in these studies, and the cis/trans mixture was not always specified; that might explain in part the inconsistencies in the data. NOAELs from the mouse and rabbit studies (400 mg/kg per day and 600 mg/kg per day, respectively) were much higher than those from the rat studies. In the three-generation studies, Hodge et al. (1977) reported an increase (albeit small) in buphthalmos and persistent papillary membrane in weanling rats following continuous exposure to permethrin at 1,000 and 2,500 ppm (50 and 125 mg/kg per day); the NOAEL was 500 ppm (25 mg/kg per day). In contrast, James (1979) reported no effects from doses as high as 180 mg/kg per day given in the diet. It is possible that buphthalmos and persistent papillary membrane might have occurred in the James (1979) study but were not observed because they are subtle changes and have a very low incidence. Schroeder and Rinehart (1977) used such low doses (5 mg/kg per day was the highest dose used) that the defects were unlikely to have occurred in their study. Given the available data and the uncertainties concerning possible differences in observation of pups among the studies, the NOAEL of 25 mg/kg per day from the Hodge et al. (1977) study will be used as the NOAEL for developmental toxicity on the basis of the three-generation studies. Liver hypertrophy similar to that seen after adult exposures (see Chapter 7) was not considered a developmental effect but was significantly increased in F3b weanling pups at all doses in the Hodge et al. (1977) study (the LOAEL was 25 mg/kg per day). As for the possibility of an effect of permethrin on male reproductive function, few data are available. No histopathological examinations were done in any of the three-generation studies, and there was no indication that organ weights were measured. Few data on testis weight and histopathology were available from chronic toxicity studies (usually at the end of the 2-year study when pathology due to aging is often seen). Also, it is assumed that formalin fixation and H & E staining were probably used for histological examination because the studies were conducted in the late ‘70s and early ‘80s, when this was the standard procedure. Current procedures include Bouin's fixation of testes to obtain good histological results. One chronic toxicity study in mice (Tierney

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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms and Rinehart, 1979) did note an effect on testis weight and testicular hypoplasia at doses of 500 and 2,000 ppm (75 and 300 mg/kg per day; NOAEL of 20 ppm or 3 mg/kg per day). There was also increased mortality at the two higher doses. However, no such effects in rats or mice were noted by Ishmael and Litchfield (1988) using concentrations of permethrin up to 2,500 ppm in feed. The Life Science Research (1980) study also reported no effects of permethrin in rats on testis weight or histopathology at doses of up to 250 mg/kg per day. Thus, information on male reproductive effects is minimal at best, and the most conservative NOAEL was 3 mg/kg per day. The NOAEL of 3 mg/kg per day based on testicular effects and the daily intake of 6.8 × 10−5 mg/kg per day from wearing permethrin-impregnated BDUs provide a MOS of approximately 44,000. Because the daily lifetime dose for garment workers is less than that for military personnel (3 × 10−5 mg/kg per day), the MOS for garment workers is 100,000. Given the lack of reproductive or other types of toxicity (except for the liver) in most of the reproductive and developmental toxicity studies available on permethrin and a MOS of approximately 44,000 or more from the most sensitive toxic end point (decreased testicular weight), the possibility of male reproductive effects or other reproductive and development effects occurring from wearing permethrin-impregnated BDUs or working with treated fabric seems remote. It should be noted, however, that no data are available from dermal exposure studies. Furthermore, there is disagreement among different studies on the doses at which toxicity was observed, and there are no specific studies on either male reproductive effects or human reproductive toxicity.