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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms 11 Carcinogenicity of Permethrin No data are available in the literature on the carcinogenicity of permethrin in humans. Evidence of permethrin's possible carcinogenicity in humans is derived from bioassays in rodents. Permethrin has been tested for its carcinogenicity in seven chronic carcinogenicity studies using mice and rats. These studies have been reviewed in detail by the U.S. Environmental Protection Agency (EPA, 1989a) and the California Environmental Protection Agency (CEPA, 1992). CARCINOGENICITY STUDIES IN MICE Four mouse carcinogenicity studies have been conducted with permethrin; in all four studies, permethrin was administered to mice in their diet. ICI Mouse Study Hart and co-workers (1977) conducted a chronic carcinogenicity study for Imperial Chemical Industries (ICI). Seventy Alderley Park (Swiss-derived) mice of each sex per group were administered permethrin (purity, 94.0-98.9%; cis/trans ratio, 40:60) at 0, 250, 1,000, or 2,500 ppm
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms (0, 37.5, 150, or 375 mg/kg of body weight per day) for 98 weeks. A slight increase was reported in lung adenomas in males at the highest dose tested (2,500 ppm), which was not statistically significant. There were no carcinomas observed in any of the male groups; in female mice, one carcinoma was reported in each treatment group. Table 11-1 presents the lung adenoma incidences for this study. There was a slight decrease in growth of animals administered the two highest doses of permethrin. Nononcogenic effects noted at doses of 1,000 ppm and above included minimal changes in liver enzyme activity, increases in liver weight, and histopathological changes in the liver (eosinophilia of hepatocytes). Hepatic aminopyrine N-demethylase activity increased significantly in male and female mice in the highest-dose group. A decrease in vacuolation of the proximal tubular epithelium of the kidney was also noted at all doses of permethrin in male mice. At the highest dose tested (2,500 ppm), mortality increased in both sexes. This study was conducted at an adequate dose for determining the oncogenic potential of permethrin. EPA determined that the NOEL for this study was 250 ppm (37.5 mg/kg per day) on the basis of the liver effects. The subcommittee concluded that this study is negative for carcinogenicity. FMC Mouse Studies A mouse carcinogenicity study was conducted for FMC Corporation by Bio-Dynamics Laboratory (Hogan and Rinehart, 1977; Rapp, 1978). CD-1 mice (75 of each sex per group) were fed permethrin (purity unknown; cis/trans ratio, 40:60) for 2 years. During the first 5 months, TABLE 11-1 Adenomas in Mouse Lungs in ICI Mouse Study Dose, ppm in diet (mg/kg/day) Males Females Incidence Percent Incidence Percent 0 (0) 11/70 15.7 11/70 15.7 250 (37.5) 6/70 8.6 8/70 11.4 1,000 (150) 13/70 18.6 10/70 14.3 2,500 (375) 17/70a 24.3 15/70 21.4 a Fisher's exact test p = 0.145 (not significant).
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms two dose changes were made. From weeks 1 to 19, the animals were fed permethrin at 0, 20, 100, and 500 ppm of diet. At week 19, the 500-ppm dose was increased to 5,000 ppm and maintained for 2 weeks before returning to 500 ppm. At week 21, the 100-ppm dose was increased to 4,000 ppm and maintained for the remainder of the dosing period. Table 11-2 shows the doses used in this study. Because of the changes in dosing, 506 animals were not classified correctly. There was a statistically significant increase in mortality in male and female mice at the highest dose (4,000 ppm). In surviving male animals, growth was inhibited at 4,000 ppm. The liver weight was higher than it was in control animals in both male and female animals at a dose of 500 ppm of diet or more. Although there was no direct effect with respect to hepatic neoplasms, it was noted that hepatocellular hypertrophy, pleomorphism, and degeneration occurred in treated mice with increased frequency and appeared to show a dose-response relationship. No oncogenic effects were observed in the test animals. EPA (1989a) determined that this study was invalid because of test-diet feeding errors for a significant portion of the study and because of misplaced animals and failure to positively identify misplaced animals. In the second FMC mouse study, permethrin (purity, 94.5-96.7%; cis/trans ratio, 40:60) was administered to groups of 75 male and 75 female Charles River CD-1 mice for 2 years (Tierney and Rinehart, 1979; Rapp, 1980). Male mice were fed permethrin at 0, 20, 500, or 2,000 ppm in diet (equivalent to 0, 3, 71, or 286 mg/kg per day); female mice were fed permethrin at 0, 20, 2,500, or 5,000 ppm (0, 3, 357, or 714 mg/kg per day). Survival decreased at high doses in male mice, and liver weight increased at both mid and high doses. The sporadic histopathological changes observed were not deemed to be related to the test substance. TABLE 11-2 Permethrin Dosage Regimen in FMC Mouse Study 1 Permethrin Oral Dose, mg/kg of diet Week Control Group 1 Group 2 Group 3 1 0 20 100 500 19 0 20 100 5,000 21 0 20 4,000 500
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms The evidence of carcinogenicity was strongest in this study (Table 11-3). The following results were reported: Statistically significant increases in liver adenomas in male mice at all doses and a significant dose-related trend; statistically significant increases in combined liver adenomas and carcinomas at mid and high doses in males were also observed. Highly statistically significant increases in liver adenomas in female mice at mid and high doses (both were outside historical control range) and a significant dose-related trend; statistically significant increases in combined liver adenomas and carcinomas at mid and high doses and a significant dose-related trend. Statistically significant increases in lung adenomas and combined adenomas and carcinomas at all doses in females; carcinomas were significantly increased at the highest dose tested only, but were increased at all doses. Significant dose-related trends for lung adenomas, carcinomas, and combined adenomas and carcinomas in females were observed. Incidences of lung tumors in male mice (adenomas, carcinomas, or both) not statistically significant at any dose and no dose-related trend. Burroughs Wellcome Mouse Study In the Burroughs Wellcome study, permethrin (cis/trans ratio, 25:75) was administered to groups of 75 male and 75 female (100 mice of each sex for control) CFLP-strain Swiss-derived mice at 0, 10, 50, or 250 mg/kg per day for 92 weeks (James et al., 1980). There were statistically significant increases in benign lung tumors at the highest dose in females and a significant dose-related trend. Malignant lung tumors were observed in treated animals (one in the mid- and two in the high-dose group), and none were seen in controls. The tumor incidences were, however, within the historical range ( Table 11-4). Non-neoplastic effects noted at the highest dose tested (250 mg/kg per day) were slightly increased liver and kidney weights. However, these mice were not tested at a high enough dose to assess the carcinogenic potential of permethrin. The NOEL for chronic toxicity in this study was 250 mg/kg per day (EPA, 1989a; CEPA, 1992).
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms TABLE 11-3 Incidence of Lung and Liver Tumors in the FMC Mouse 2 Study After Administering Permethrin in the Diet for 2 Yearsa,b Male Female Tumor 0 ppm 20 ppm 500 ppm 2,000 ppm 0 ppm 20 ppm 2,500 ppm 5,000 ppm Alveolar cell 16/72 15/69 15/67 17/68 9/71d 17/65e 24/68f 29/69g adenoma (22%)c (22%) (22%) (25%) (13%) (26%) (35%) (42%) Alveolar cell 7/48 5/53 13/54 4/31 6/66h 7/61 11/59 15/62e carcinoma (15%) (9%) (24%) (13%) (9%) (11%) (19%) (24%) Lung tumors 23/72 20/69 28/67 21/68 15/71d 24/65e 35/68g 44/69g combined (32%) (29%) (42%) (31%) (21%) (37%) (51%) (64%) Hepatocellular 6/64h 17/63f 15/63e 17/56f 2/64d 4/60 22/61g 28/65g adenoma (9%) (27%) (24%) (30%) (3%) (7%) (36%) (43%) Hepatocellular 16/67 12/64 19/64 8/59 4/49 3/54 3/47 2/50 carcinoma (24%) (19%) (30%) (14%) (8%) (6%) (6%) (4%) Liver tumors 22/67 29/64 34/64e 25/59 6/64d 7/60 25/61g 30/65g combined (33%) (45%) (53%) (42%) (9%) (12%) (41%) (46%) aThe incidence was expressed as the number of tumor-bearing animals per animals at risk. bThe Army used different denominators for risk assessment. cThe number in parentheses is the incidence in percentage. dSignificant trend at p < 0.001 based on a dose-weighted chi-square trend test. eSignificantly different from the control group (p < 0.05) based on the Fisher's exact test. fSignificantly different from the control group (p < 0.01) based on the Fisher's exact test. gSignificantly different from the control group (p < 0.001) based on the Fisher's exact test. hSignificant trend at p < 0.01 based on a dose-weighted chi-square trend test.
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms TABLE 11-4 Mice with One or More Adenomatous Tumors in the Lungs in the Burroughs Wellcome Mouse Study Dose, mg/kg/day Males Females Incidence Percent Incidence Percent 0 26/99 26.3 3/96 3.1 10 14/75 18.7 5/71 7.0 50 17/73 23.3 7/74 9.5 250 16/74 21.6 15/74a 20.3 Historical controlb 20.4 (7.5-30.0%) aStatistically significantly different from control group, p < 0.05. bHistorical control data (mean and percentage range) derived from nine studies containing 807 female CFLP control mice and mice affected with lung adenomas and carcinomas. Source: EPA, 1989a. CARCINOGENICITY STUDIES IN RATS Permethrin has also been tested for its carcinogenicity in rats. Two of these studies were considered negative for permethrin's carcinogenicity and the third study was considered equivocal by EPA (EPA, 1989a). ICI Rat Study In the ICI rat study, Wistar rats (60 of each sex per group) were fed permethrin (purity 93.1-98.9%; cis/trans ratio, 40:60) at 0, 500, 1,000, or 2,500 ppm (0, 25, 50, or 125 mg/kg per day) for 2 years. No carcinogenic effects were noted at any concentration (Richards et al., 1977; Ishmael and Litchfield, 1988). Signs of poisoning, such as tremors and hyperexcitability, were noted during the first 2 weeks of dosing in the animals that received the highest dose. There was no mortality attributable to permethrin, and growth and food consumption were unaffected. There were no effects on hematological, ophthalmological, urological, or other clinical chemistry measurements. Liver aminopyrine N-demethylase activity was increased in all permethrin-treated animals. Bone-marrow smears of the animals
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms showed no unusual findings. Gross and microscopic examination of tissues and organs was performed after 1 and 2 years, and all animals that died with neoplastic changes were examined. Kidney weight was also increased, predominantly in males, at all doses. Examination of the sciatic nerve showed no effects attributable to permethrin. Liver weights were higher in male and female rats that received permethrin for 1 year at 2,500 ppm (25 mg/kg) than in the control animals. After 2 years, the liver weight and liver-to-body-weight ratios were higher in all permethrin-treated males than in the corresponding controls. In the females, higher values of absolute and relative liver weights, compared with the controls, were recorded only in the group of animals given 1,000 mg/kg. Hepatocyte vacuolation was seen at 1 year in males fed at only the highest dose and in females at all doses. The smooth endoplasmic reticulum showed significant increases at 52 weeks in males and females at all doses. At the end of the study, notable endoplasmic reticulum increases were detected only at the highest doses, although insignificant increases were noted at all doses in males and females. The NOEL for liver effects was 500 ppm (25 mg/kg per day) and the LOEL was 1,000 ppm (50 mg/kg per day) (EPA, 1989a; CEPA, 1992). FMC Rat Study Long-Evans rats (60 males and 60 females per group) were fed permethrin (purity unknown; cis/trans ratio, 40:60) at 0, 20, 100, or 500 ppm (0, 1, 5, 25 mg/kg per day) for 2 years (Braun and Rinehart, 1977). Two independent evaluations of the histopathological data from this study concluded that there was no carcinogenic potential for permethrin. Although there was a dose-dependent increase in gross liver weight in both males and females, those values were small and not statistically significant. The initial examination of lung tissue from males suggested that there was a dose-related increase in lung tumors (Table 11-5), although the difference was not statistically significant at any dose, nor was there a significant dose-related trend. The lung tissue from all males was reexamined after step-sectioning at 250 µm intervals. The incidence from the second reading (8 of 60, 5 of 55, 9 of 60, and 9 of 59 at 0, 20, 100,
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms TABLE 11-5 Incidence of Pulmonary Tumors in FMC Rat Study After Administering Permethrin in the Diet for 2 Yearsa Dose, ppm Sex and Tumor 0 20 100 500 Males Adenoma 1/59 3/55 4/57 5/56 (2%)b (5%) (7%) (9%) Adenocarcinoma 0/59 0/55 2/57 0/56 (0%) (0%) (3%) (0%) Combined 1/59 0/55 6/57 5/56 (2%) (5%) (11%) (9%) Females Adenoma 1/56 0/58 2/58 2/57 (2%) (0%) (3%) (4%) aThe incidence was expressed as the number of tumor-bearing animals per animals at risk. bThe number in parentheses represents the incidence in percentage. and 500 ppm, respectively) was not statistically significant either. In their analysis of the data, EPA adjusted the incidence by the amount of lung tissue examined. The adjusted incidence at mid and high doses was marginally significant (p = 0.10) by pair-wise comparison with concurrent controls. EPA (1989a) concluded that the evidence for lung tumors in these male rats was equivocal, and considering a maximum tolerated dose (MTD) was not reached, this finding was significant. The major deficiency in the study was that there was no clear evidence of toxicity even at the highest dose tested. CEPA (1992) assigned a NOEL of greater than 500 ppm (25 mg/kg per day), whereas EPA assigned a LOEL of 100 ppm (5 mg/kg per day) based on increased liver weights. There was no mortality, and the animals did not reveal adverse effects on growth, food consumption, or behavior attributable to the administration. Hematological, clinical chemistry, and urinalysis measurements were performed at either 6 months or 1 year and at the end of the study. There were no compound-related effects on a wide variety of parameters examined, and ophthalmological examination indicated no abnormalities.
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms Burroughs Wellcome Rat Study Seventy-five Wistar rats of each sex per group were given permethrin (purity unknown; cis/trans ratio, 25:75) in the diet at 0, 10, 50, or 250 mg/kg per day for 103 weeks in a Burroughs Wellcome study. No evidence of carcinogenicity of permethrin was reported in the study (McSheehy et al., 1980). Hepatocytic hypertrophy was observed histopathologically in both sexes at mid and high doses. The NOEL and LOEL were 10 and 50 mg/kg per day, respectively, based on liver hypertrophy (CEPA, 1992). The major deficiencies were the lack of information regarding the diet analysis and purity of the test article. TUMOR PROMOTION STUDIES: SHIMKIN MOUSE LUNG BIOASSAY Groups of 16 male and 16 female strain A/J mice were given permethrin at 0, 285, 475 (females only), 713.5, or 1,425 mg/kg (cis/trans ratio, 40:60) for 3 days a week for 8 weeks. Animals in the positive control group were given urethane (1,000 mg/kg). Animals were sacrificed after 24 weeks and examined for lung tumors (Cunnick, 1985). The frequency of lung tumors in the permethrin-treated mice was equivalent to the corn oil and untreated control groups. Urethane produced the expected tumor-promoting response. No evidence that permethrin promoted lung tumors was seen in this study. CONCLUSIONS Evidence of permethrin's possible carcinogenicity in humans is derived from bioassays in rodents. Permethrin has been tested in seven chronic toxicity studies, three studies in rats and four in mice. The three rat studies were negative for carcinogenicity; however, the studies were not conducted at doses high enough to adequately assess the oncogenic potential of permethrin. In spite of some deficiencies in some of the mouse studies, two of the four showed evidence of carcinogenic-
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms ity. In the second FMC mouse study, the primary findings were as follows: in males, statistically significant (p < 0.01) increases in liver adenomas at all doses were observed, along with a statistically significant (p < 0.01) dose-related trend. (Tumor frequencies were above the historical control range at all nonzero doses.) In females, statistically significant (p < 0.01) increases in lung adenomas and carcinomas combined were observed at the mid and high doses, along with a statistically significant (p < 0.01) dose-related trend. In addition, lung adenomas and carcinomas separately showed statistically significant (p < 0.01) dose-related trends. In the Burroughs Wellcome mouse study, there was a statistically significant (p < 0.01) increase in lung tumors in females at the highest dose as well as a statistically significant (p < 0.01) dose-related trend. Permethrin was also tested in Shimkin mouse lung bioassay to determine if permethrin is a tumor promoter. This assay did not show any evidence that permethrin promoted lung tumors, however the Shimkin assay is not a definitive mouse oncogenicity assay. Based on the weight of evidence from animal studies, the subcommittee concluded that permethrin is a possible human carcinogen. CARCINOGENICITY RISK ASSESSMENT Hazard Identification The U.S. Army (1989) based its quantitative risk assessment for permethrin on the 24-month chronic feeding study in CD-1 mice that was described above in the second FMC study. This study was selected for carcinogenic risk assessment because it showed the most significant increase in tumors. The oral carcinogenic potency factor (upper 95% confidence limit) was calculated on the basis of the combined adenomas and carcinomas of the lung in females. That is the same set of data that EPA used to calculate its carcinogenic potency factor (unit risk) for permethrin (EPA, 1988), and which it subsequently confirmed as an appropriate basis for quantitative risk assessment (EPA, 1989b). CEPA (1992) likewise identified the combined lung tumors in female mice observed in the second FMC mouse study as the most relevant for assessing carcinogenic risk to humans from exposure to permethrin.
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms TABLE 11-6 Combined Lung Adenoma and Carcinoma in Female CD-1 Mice Concentration, ppm (mg/kg/day) Tumor Incidence 0 (0) 15/74 20 (2.7) 24/74 2,500 (333) 35/75 5,000 (667) 44/75 The tumor incidence data used by the Army for dose-response modeling are shown in Table 11-6. Dose-Response Assessment The U.S. Army (1989) calculated a human-equivalent carcinogenic potency factor of 0.016 (mg/kg/day)−1 and EPA calculated a value of 0.018, even though both used the linearized multistage model for dose extrapolation (EPA, 1986) on the same data and both extrapolated to humans on the basis of body surface area (body weight)2/3 (EPA, 1986). That slight difference in estimated potency is the result of modest differences in procedure. Whereas the Army used all the animals that were examined at each dose to fit the dose-response model, EPA included only those animals that were still at risk at the time of observation of the first tumor in any group. Also, the Army used 70 kg and 0.03 kg as representative human and mouse weights, respectively, and EPA used 60 kg and 0.025 kg. CEPA calculated a human oncogenic potency factor of only 0.011 (mg/kg/day) −1. The data modeled by CEPA were the same as those used by EPA, except for the denominator of the lowest-dose group. However, CEPA's dose scaling differed from that of the Army and EPA in several respects, including extrapolation to humans on the basis of (body weight) 3/4. CEPA's report did not appear to give sufficient details to permit reproducing the calculations on dose scaling. Based on the available information, there is no compelling reason to use a carcinogenic potency factor other than the U.S. Army's (1989) calculated value of 0.016 (mg/kg/day)−1.
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms Risk Characterization An upper bound on the lifetime carcinogenic risk is estimated by multiplying the carcinogenic potency factor by the estimated average daily lifetime dose. The same carcinogenic potency factor applies for each exposure group; only the lifetime daily exposure value differs from group to group, depending on the particular exposure scenario (see Chapter 2 for details on exposure assessment). No adjustment has yet been made to account for the fact that the carcinogenic potency factor, 0.016 (mg/kg/day)−1, is based on the oral administered dose rather than the internal absorbed dose. To use this potency factor in conjunction with the calculated human internal dose resulting from dermal exposure, it should be adjusted upward by an oral absorption factor for the experimental animals. Following CEPA (1992), a 70% oral absorption rate for the experimental animals is assumed. (The absorption rate of 70% for permethrin was estimated from rat pharmaco-kinetic studies.) Dividing 0.016 (mg/kg/day)−1 by 0.7 gives a revised potency factor of 0.023 (mg/kg/day)−1. Military Nonfield Personnel The upper bound on lifetime carcinogenic risk is estimated to be 2.3 × 10−2(mg/kg/day)−1 × 6.8 × 10−5 mg/kg/day = 1.6 × 10−6. The calculated risk is 2.7 times higher than the Army's value of 6 × 10−7 (U.S. Army, 1989) (see Appendix A) because of the upward adjustment in dose that resulted from the Army's revised exposure factors (18 hr/day for 10 years vs. 16 hr/day for 6 years) and the upward adjustment in carcinogenic potency that resulted from the inclusion of an oral absorption factor (70% vs. 100%). That value is somewhat lower than the values calculated by CEPA for both the general public and park and forestry workers. However, CEPA's exposure scenarios were completely different from the Army 's—inhalation being the primary route of exposure for CEPA.
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms Military Field Personnel Unless topically applied DEET is shown to enhance appreciably the absorption of permethrin from impregnated uniforms, the upper-bound lifetime carcinogenic risk for field personnel will be estimated to be the same as the risk for nonfield personnel, i.e., 1.6 × 10 −6. Garment Workers The upper bound on lifetime carcinogenic risk due to dermal exposure associated with handling impregnated fabric is estimated to be 2.3 × 10−2 (mg/kg/day)−1 × 3.0 × 10−5 mg/kg/day = 6.9 × 10−7. That calculated upper bound is less than half the value estimated for military personnel. It characterizes the carcinogenic risk to garment workers, provided that dermal contact of hands and forearms with treated fabric is the only relevant source of exposure to permethrin. It does not account for the possibility that workers might be exposed to permethrin via airborne particles of treated fabric. Conclusions An upper bound on the lifetime carcinogenic risk to military personnel wearing permethrin-impregnated uniforms is estimated to be 1.6 × 10−6. That value applies to non-field and field personnel, assuming that topically applied DEET does not enhance dermal absorption of permethrin. As stated earlier, somewhat less than 5% of the skin would be exposed to have overlapping exposure to DEET and permethrin. If the recommended pharmacokinetics studies are done and the results of those studies indicate an enhanced absorption of permethrin from simultaneous exposure to DEET, that would mean higher exposure of permethrin in soldiers wearing permethrin-impregnated BDUs and applying DEET to skin areas not covered by BDUs. In that case, carcinogenic risk should
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Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms be reevaluated to determine if the revised carcinogenic risk is acceptable. Thus, based on current data, permethrin impregnation of uniforms is not considered to pose a serious carcinogenic hazard to either field or non-field military personnel. However, if it is possible to have two sets of uniforms, treated and untreated, then it is recommended that only uniforms worn by field personnel be made from permethrin-impregnated fabric. The estimated upper-bound lifetime carcinogenic risk to garment workers, 6.9 × 10−7, is less than half the calculated upper-bound risk to military personnel. However, that value does not reflect any possibility that workers might be exposed to permethrin via airborne particles of fabric, and, therefore, it might not represent a true upper bound on the overall carcinogenic risk to garment workers.
Representative terms from entire chapter: