Animal Studies On Unexplained Illnesses Among Gulf War Veterans
Chemical Technical Summary for Public Health
and Public Safety Professionals
Agency for Toxic Substances and Disease Registry
December 6, 2004
Many of those involved in the first Gulf War have complained of neurological symptoms of unknown etiology (Abou-Donia et al. 1996a,b; Hoy et al. 2000b). It has been proposed that one possible factor that could be related to these symptoms is the simultaneous exposure to multiple agents used to protect the health of these service men and women. Among a number of chemicals of concern are the anti-nerve agent pyridostigmine bromide (PB), the insecticide permethrin, and DEET, by which exposure occurred by clothing treated with permethrin, dermal treatment with DEET, and oral dosages of PB as prophylactic treatment. Studies of exposure to these agents have been conducted in animals to determine whether these agents are responsible for Gulf War veterans' unexplained illnesses.
In an acute oral toxicity study of PB, permethrin, and DEET, the toxicity of DEET alone and in combination with the other two chemicals was evaluated in adult male rats. Technical grade DEET was used for the formulation at a concentration consistent with the most often cited LD50 value. The rats treated with these high oral doses of DEET were lethargic and showed signs of respiratory distress. Control animals treated with propylene glycol alone were unaffected (McCain et al. 1997). It is difficult to draw useful conclusions about human exposure risk from this study, as the doses used in the rat were very high. For a human to experience an equivalent exposure, the person would have to ingest nearly seven 2-ounce tubes of 33% DEET.
A percutaneous absorption study investigating mixtures of chemicals allegedly involved in Gulf War veterans' unexplained illnesses showed that DEET did not have an enhancement effect on the potential toxicity of permethrin (Riviere et al. 2001). These experiments were conducted in vitro using inert silastic and dermatomed pig skin flow-through diffusion cells as well as the isolated perfused porcine skin flap. It was also observed that none of the other study chemicals, including permethrin, had any effect on DEET dermal absorption. This research is also supported by the work of Baynes et al. (1997), which found that DEET did not enhance deposition of carbaryl into the skin, and found that no permethrin was absorbed in rat, mouse, or pig skin when applied dermally as a mixture with DEET.
Animals treated with DEET in combination with either PB or permethrin were found to exhibit hyperexcitability, and hens treated with DEET and permethrin showed a transient leg weakness between 9 and 14 days post-dose (Abou-Donia et al. 1996a). Intermittent diarrhea, shallow breathing, and decreased activity were observed in hens treated with DEET and PB, as well as altered stance progressing to an unsteady gait. In the group that was treated with all three compounds, signs were evident within 15 minutes of the first dose. They included severe diarrhea, rapid shallow breathing and moderate inactivity. Mild to severe neuropathological changes were observed along with an increase in the number of enlarged axons in the dorsal, lateral, and ventral spinal cord columns (Abou-Donia et al. 1996a). Administration of two of the three chemicals used in this study caused much greater toxicity than one of the chemicals alone. The addition of the third study chemical further increased the observed toxicity in hens. It is proposed that this enhanced toxicity occurs because all three chemicals compete for metabolism by liver and plasma esterases, resulting in a delayed metabolism of the toxic parent compounds (Abou-Donia et al. 1996a).
Hoy et al. (2000b) evaluated the co-administration of DEET by gavage, pyridostigmine bromide (PB) by gavage and permethrin intraperitoneally in Sprague-Dawley rats. When the drugs were given individually, no significant effects were noticed. When PB/DEET and permethrin/DEET were administered together, locomotion rates in males and females changed. There were no significant effects noted when all three drugs were given simultaneously. It was concluded that lasting behavioral effects can be caused by relatively low doses of the drugs administered together, which might explain some of the unexplained symptoms of Gulf War veterans. Hoy et al. (2000a) also found that DEET and permethrin caused significantly depressed locomotion rates in male rats and that PB, and DEET caused locomotor effects synergized by permethrin (Hoy et al. 2000a).
In summary, research has shown a possible relationship between concurrent exposure to permethrin, pyridostigmine bromide, and DEET and the development of neurotoxicity and behavioral effects in laboratory animals. Whether exposures of service personnel were comparable to those that induced neurological changes in laboratory animals is still unclear. Whether the toxic effects seen in laboratory animals can be extrapolated to humans is similarly unclear. More research is needed on the possible synergistic toxic potential of these chemicals and on the actual usage patterns of troops in the first Gulf War.