studies may be useful in determining human toxic responses, it is unsound to assume that toxic outcomes will be consistent across species.

Enhanced Absorption

Buchholz and colleagues (1997) examined the influence of PB on the CNS uptake of permethrin, at doses and durations relevant to human exposure, and found that oral PB actually reduced the amount of permethrin reaching the central nervous system. Such data, although limited, do not support a role for either decreased metabolism or enhanced penetration into the brain as the basis for enhanced toxicity. Little information regarding the influence of PB on absorption of other agents, or vice versa, is available; however, DEET has been used as a transdermal carrier for drug delivery (Hussain and Ritschel, 1988).

Interference with Metabolic Disposition

Simultaneous exposure to multiple therapeutic agents has repeatedly demonstrated the capacity for one drug to interfere with the metabolism of a second agent. This interaction may facilitate or impair biotransformation, the outcome of which is to diminish or exaggerate the pharmacological or toxicological actions of the chemical. Further, both pyrethroids and carbamates are known to rely to some extent on the cytochrome P-450 system for their metabolism, and possibilities exist for interactions to have toxic outcomes (Casida et al., 1983; Eiermann et al., 1993; Selim et al., 1995). However, direct experimental evidence for such interactions is lacking.

Penetration into the Brain

The brain is protected from many classes of xenobiotics by the blood– brain barrier (BBB), a layer of endothelial cells that prevents the movement of many chemicals from the circulation into the brain. Since the nervous system in the periphery is not afforded similar protection, PB would be expected to manifest its pharmacological and toxicological actions primarily in the peripheral nervous system.

The BBB is a specialized structure responsible for the maintenance of the central neuronal microenvironment, playing a pivotal role in tissue homeostasis, fibrinolysis and coagulation, vasotonus regulation, the vascularization of normal and neoplastic tissues, and blood cell activation and migration during physiological and pathological processes. Regulation of blood–tissue exchange is accomplished by individual endothelial cells. A pivotal function of endothelial cells is to regulate the selective transport and metabolism of substances from the blood to the brain. Because of the existence of tight junctions between adjacent endothelial cells, nonspecific paracellular ionic leakage across the BBB is thought to be minimal. It should be pointed out, however, that not all of the CNS



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