creatine phosphokinase, and aspartate aminotransferase, these indices of myopathy (Hoffman et al., 1989) were unaccompanied by morphological evidence of PB-induced toxicity.
A single study in rats has been reviewed that reports the reproductive toxicity of PB (Levine et al., 1989; Levine and Parker, 1991). No teratogenic effects were noted even after 90 days’ exposure to doses ranging up to 60 mg/kg per day. Although there was a suggestion of postimplantation loss at the highest dose tested (which also resulted in 10 percent mortality), other fertility indices and offspring were unchanged in perinatal and postnatal studies.
In skin sensitization studies, 44 percent of guinea pigs exposed to 50 percent PB alone exhibited positive responses. Addition of dermal penetration enhancers (surfactants) such as sodium lauryl sulfate increased the incidence of positive responses to greater than 80 percent (Harris and Maibach, 1989).
Excess ACh resulting from ChE inhibition might be expected to exacerbate bronchial asthma by causing increased respiratory secretions and bronchoconstriction. Dogs administered PB doses of 2–5 mg/kg exhibited dose-dependent increases in airway resistance and decreases in tidal volume (Caldwell et al., 1989). Since these doses are much higher than those given to humans, no complications of PB administration in asthmatics were predicted. However, there have been reports of human studies (discussed later in this chapter) and anecdotal reports suggesting a possible dose-dependent outcome in asthmatics (Ram et al., 1991; Gouge et al., 1994).
The autonomic, parasympathetic innervation of the heart is concerned principally with the regulation of heart rate and atrioventricular conduction and exerts this influence via cholinergic synapses much like those found elsewhere in the nervous system. Inhibition of AChE at these synapses results in prolonged residence time of ACh, leading to slowing of the sinoatrial firing rate (bradycardia), along with prolongation of phase four conduction parameters. Recent studies in cats indicate that the magnitude of the bradycardia resulting from PB does not correlate with the degree of AChE inhibition, but rather reflects the extent of muscarinic agonist actions (Yamamoto et al., 1996; Stein et al., 1997).