The effects of concurrent exposure to pyridostigmine, permethrin, and DEET on multiple fixed-ratio and fixed-interval schedules of reinforcement in rats have also been studied (van Haaren et al., 2001). Exposure to either pyridostigmine or permethrin decreased fixed-ratio and fixed-interval response rates, and DEET decreased both response rates but only at the highest dose. Synergistic effects were observed only on fixed-interval response rate. Those rates were decreased after concurrent exposure to half the dose of pyridostigmine and half the dose of permethrin that alone affected fixed-interval response rate. The rates were also decreased after concurrent exposure to half the effective dose of pyridostigmine and half the effective dose of DEET. In addition, the permeability of the blood-brain barrier of the rat was unaffected by permethrin and slightly decreased by DEET but substantially reduced by a combination of the two (Abou-Donia et al., 2001).
Lindane belongs to a class of insecticides known as the organochlorines. Lindane is the γ-isomer of 1,2,3,4,5,6-hexachlorocyclohexane (HCH). The insecticidal activity of HCH was discovered in 1942.
Use of most organochlorine compounds has been banned since the 1970s in many countries, including the United States, because of their environmental persistence (such as DDT), their ability to bioconcentrate, and their biomagnification (Ecobichon, 2001). Lindane is used for treatment of ectoparasites on humans and animals, and it is used by humans as a lotion and a shampoo (Kwell®) (Facts and Comparisons, 2001; Woolley et al., 1985).
Technical HCH is comprised of four major isomers, α-, β-, γ-, and δ-HCH, in which the concentration of lindane (the γ-isomer) can range from 12 to 99%. Lindane is the most toxic of the isomers; its insecticidal activity is 28–10,000 times higher than that of the others (Ullmann, 1972). Although it is a misnomer, “benzene hexachloride” is a common name used in the United States for the mixture of HCH isomers. The structure of lindane is shown in Figure 3.4.
Lindane is rapidly absorbed from the gastrointestinal tract. It is much more slowly absorbed dermally (Dick et al., 1997). Once absorbed, it can be metabolized by dehydrogenation, dehydrochlorination, and hydroxylation in the liver. The metabolites of lindane are less acutely toxic than lindane, so those metabolic pathways are considered detoxification pathways (Fitzloff et al., 1982). It is excreted as glucuronide, sulfate, and mercapturic acid conjugates (Copeland et al., 1986).