Evaluation of immunotoxicity induced by single or concurrent exposure to N, N-diethyl-m-toluamide (DEET), pyridostigmine bromide (PYR), and JP-8 jet fuel

Abstract

Approximately 5,000 to 80,000 of the US service personnel involved in the Persian Gulf War have complained of a variety of nonspecific symptoms since their return in 1991. These symptoms have been collectively labeled Gulf War Illness and include muscle fatigue, general malaise, myalgia, impaired cognition, ataxia, headaches, fever, joint pain, skin rash, gastrointestinal disturbances, sleep disturbances, and respiratory difficulties. Exposures of military and service personnel were diverse and included the prescribed anti-nerve gas agent pyridostigmine bromide (PYR), N.N-diethyl-m-toluamide (DEET) insect repellent, and environmental exposures to jet fuel. Thus, studies in our laboratory were undertaken to determine if concurrent exposure to these agents, singly or in combination, would contribute to significant alterations in immunological function and disease susceptibility. To assess immune status, eight-week old B6C3F1 female mice were exposed for 14 days to single compounds or tertiary mixtures of 15.5 mg/kg DEET, 2 mg/kg PYR, and 500 mg/kg JP-8 (termed low dose), or 31 mg/kg DEET, 5 mg/kg PYR, and 1,000 mg/kg JP-8 (termed high dose). Immunosuppression was assessed 24 h after the last exposure. No remarkable alterations were evident in hematological parameters, spleen and thymus organ weight and total cellularity, natural killer (NK) cell activity, cytotoxic T-cell activity, or mitogen-induced lymphocyte proliferation after exposure to either single or tertiary mixtures at low or high doses. A few changes in CD4/CD8 flow cytometric lymphocyte subpopulations were detected after exposure to the tertiary mixture at the high dose. Delayed type hypersensitivity (DTH) was decreased by 88% after exposure to the high-dose mixture, and suppression of antibody-specific IgM immune responses (plaque-forming cell, PFC) occurred after exposure to all single and tertiary mixtures at both dose levels. In the PFC response, antagonism was apparent in the mixture, while coexposure to these agents resulted in a synergistic effect in the DTH response. Susceptibility to B16F10 tumor or Listeria monocytogenes challenge was not affected after single or tertiary exposures. These data suggest that combined exposure to DEET, PYR, and JP-8 does not profoundly alter many immunological endpoints, but does selectively target functional endpoints such as the PFC and DTH response. This should be considered when assessing human health risks in the military environment.

Pyridostigmine Bromide (PYR) Alters Immune Function in B6C3F1 Mice

“…[48] Furthermore, a reduction in antibody responses is not likely attributed to a reduction in splenic B-cells. [49,50] Major deficiencies were not apparent in antigen presenting macrophages, and T-and B-cells suggesting that the cytokine network coordinating IgM antibody responses may be a factor in contributing to the observed decrease in primary IgM responses.…”

Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations

“…Hydrocarbons represent one of the largest chemical exposures to the US military as it is used for fueling military vehicles and dust control on road surfaces [15–17]. JP-8 (Jet Fuel) is a hydrocarbon mixture that is most commonly used by the military [16, 18, 19]. Over 2 million military and civilian personnel are exposed to an estimated 60 billion gallons of JP-8.…”

Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations

“…Apart from mild symptoms, permethrin and DEET generally do not show adverse in vivo or in vitro toxic effects [5]. However, some reported toxicological effects of a mixture of permethrin and/or DEET include uterine enlargement, atrophy of male secondary sex organs [6], testicular cancer [7], neurological disorders and behavioral changes [8–10], oxidative stress in brain [11], DNA damage [12] and immunotoxicity [13]. Previous studies with permethrin used higher doses (10-800 mg/kg) [6] and only F0 generations were studied [14, 15].…”