possess the R allele than in controls, and although the arylesterase activity was somewhat lower, the total paraoxonase activity was higher. Since PON1 does not appear to be involved in the metabolism of PB (Haley et al., 1999) the relationship between this polymorphism and PB toxicity is unclear. The authors suggest that PB, having inhibited BuChE, leaves individuals only PON1 as a defense against organophosphates and that this last line of defense is deficient in genetically predisposed individuals. Although this is an intriguing possibility, direct experimental evidence for a contributory role of polymorphisms in the combined toxicity of PB and organophosphates is lacking and requires additional investigation.

HUMAN STUDIES

This section reviews what is known about the use of PB and potential adverse health outcomes from the literature on patients (clinical studies), healthy volunteers, and epidemiologic studies. In some cases, the patient or healthy-volunteer studies include populations of veterans, as do the epidemiologic studies reviewed by the committee. Several of the studies review general health outcomes, whereas others focus on specific organ systems.

Clinical Studies

There are a large number of clinical studies, principally related to the use of PB as a test of hypothalamic pituitary function or growth hormone response and in the treatment of myasthenia gravis. In addition, a smaller number of clinical studies (i.e., case reports and case series) are available that describe the effects of PB when used in patients. These studies are discussed below.

Clinical Studies of PB and Growth Hormone

Studies have been done on normal subjects and patients with a variety of chronic disorders who were given PB as a test of hypothalamic pituitary function, usually of growth hormone (GH) response to PB and one or more other GH-releasing stimuli. Typically, these have been acute studies using relatively low doses of PB, which offer the opportunity to investigate not only the pituitary responses to, but also the adverse effects of, small doses of PB in humans.

Insight into the acute hormonal effects of PB is available from an abundant literature that describes its use as a clinical test of pituitary GH reserve. Normally, the synthesis and secretion of growth hormone are regulated by two hypothalamic peptides: GH-releasing hormone (GHRH), which has a stimulating role, and somatostatin, which has an inhibitory role. In normal humans, GHRH and its analogues stimulate GH secretion in a dose-dependent fashion (Giustina et al., 1990; Cordido et al., 1993, 1995; Penalva et al., 1993; Arvat et al., 1995, 1997a,b), but its release is substantially modulated by cholinergic neurotrans-



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