12 Summary of Recommendations
The Subcommittee to Review Permethrin Toxicity from Military Uniforms conducted a health assessment of wearing BDUs impregnated with permethrin. This assessment was performed by evaluating the toxicity of permethrin in humans and animals and by evaluating the potential exposure of soldiers to permethrin from wearing permethrin-impregnated BDUs. The toxic end points evaluated were acute and subchronic toxicity, dermal and ocular toxicity, neurotoxicity, liver and other organ toxicity, immunotoxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. In addition, the report includes discussion on pharmacokinetics, exposure assessment, and carcinogenic risk assessment of permethrin.
The subcommittee's conclusions and recommendations are listed below. The recommendations are intended to provide additional toxicity data and related data on permethrin that will enable risk assessors to evaluate the risk of wearing permethrin-treated BDUs with more confidence. The subcommittee recommends further research in exposure assessment, pharmacokinetics, dermal toxicity, neurotoxicity, immunotoxicity, and genotoxicity. The subcommittee, however, does not recommend further research for other toxicity end points, because it believes that information available on those end points is adequate to address the question of safety of wearing or sewing permethrin-impregnated BDUs.
The subcommittee considered the dermal route to be the only relevant route of exposure to permethrin from wearing permethrin-impregnated BDUs. At present, there is no information to indicate that significant exposure will occur by any route other than dermal absorption. The average lifetime dermal dose for military personnel from wearing permethrin-impregnated BDUs (permethrin impregnation at a concentration of 0.125 mg/cm2) was calculated to be 6.8 × 10−5 mg/kg per day. The average daily lifetime internal dose for garment workers was calculated to be 3.0 × 10−5 mg/kg per day, less than half the daily dose calculated for military personnel. That dose is only for dermal exposure from direct contact with permethrin-treated cloth and does not include possible exposure to permethrin by inhalation or ingestion of permethrin-impregnated airborne particles. Thus, the above estimated internal dose of 3.0 × 10−5 mg/kg per day possibly represents a lower bound on the overall exposure of garment workers to permethrin.
The subcommittee recommends that studies be conducted to collect data on representative permethrin-exposure factors to produce a more complete and accurate risk characterization for garment workers.
Wearing permethrin-impregnated BDUs and applying DEET to exposed skin provide nearly 100% protection against bites of insects and other arthropods. DEET's enhancement of the dermal penetration of a variety of chemicals suggests that the use of DEET in conjunction with permethrin might facilitate the dermal absorption of permethrin. Research specifically on the interaction of DEET and permethrin has not been conducted and represents an area of uncertainty regarding the dermal absorption of permethrin. Facilitated absorption of permethrin by DEET is a possible concern for military personnel who apply DEET to the exposed skin and wear permethrin-treated BDUs. Although the area of skin with potentially overlapping coverage is small and is assumed to be of minor importance, the magnitude of the effect is not known with certainty.
The subcommittee recommends that the Army conduct a human pharmacokinetic study with combined exposure to permethrin and DEET. Specifically, this study would involve three groups of volunteers: a group wearing untreated uniforms (control); a group wearing uniforms treated with permethrin; and a group wearing uniforms treated with permethrin and using DEET for skin protection. Urine samples would be collected from these individuals over a specified time, and the appearance of the permethrin metabolite 3-(2,2-dichlorovinyl)-2,-2-dimethylcyclopropane carboxylic acid (CVA), could be quantitated by mass spectrometry. An increase in CVA in the urine of the DEET-permethrin group would suggest a potential interactive effect.
The subcommittee also recommends that military personnel apply DEET only to areas of the skin not covered by BDUs to reduce potential interactive effects of DEET on permethrin absorption. The interactive effects can probably be minimized if the areas of the body covered by permethrin-impregnated BDUs are not also covered by DEET.
Review of the available information on dermal toxicity of permethrin indicates that permethrin might be a skin sensitizer at high doses in guinea pigs, although the Draize repeat insult patch test in 184 human subjects did not cause any dermal sensitization. However, several subjects described a transient burning, stinging, or itching sensation. The results of the photochemical irritation studies showed that permethrin does not cause phototoxicity (photo irritation). Therefore, the weight of evidence indicates that exposure to permethrin from wearing permethrin-impregnated BDUs at the recommended concentrations (0.125 mg/cm2 of fabric) is unlikely to cause skin sensitization or other skin effects in humans.
A few persons might be hypersensitive to permethrin-treated BDUs and thus develop skin sensitization. The subcommittee recommends that the Army monitor soldiers for hypersensitivity when they begin to wear permethrin-treated BDUs on a regular basis.
Permethrin is neurotoxic at high doses in animals. It produces a variety of neurotoxic effects, some of which are tremors, salivation, paresthesia, splayed gait, depressed reflexes, and tiptoe gait; reversible axonal injury occurs at very high doses. Although animal data clearly demonstrate the neurotoxic properties of high doses of permethrin, human data are needed to substantiate that finding.
The subcommittee recommends that data be collected on neurotoxicity of permethrin in humans from epidemiological studies of workers or from accidental human exposures.
No human data or in vivo animal data are available to evaluate the immunotoxic potential of permethrin in humans. The only two laboratory studies reported in the literature that were conducted in in vitro systems are inconclusive about the immunotoxological effects of permethrin.
The subcommittee recommends that immunotoxicological studies be performed in laboratory animals to ascertain the immunotoxic properties, if any, of permethrin in the mammalian species. These studies should follow the recommendations for conducting additional research as presented in the 1992 National Research Council report entitled Biologic Markers in Immunotoxicology.
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 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 the clastogenic effects of permethrin. These results have not been independently confirmed by other investigators. 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.