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One report showed adverse effects after consumption of bagels to which 60 times the normal amount of niacin had been added inadvertently (CDC, 1983). Most of the data on the adverse effects of excess niacin intake are from studies and case reports involving patients with hyperlipidemia or other disorders who were treated with pharmacological preparations containing immediate-release nicotinic acid or slow- or sustained-release nicotinic acid. The Tolerable Upper Intake Level (UL) developed here applies to all forms of niacin added to foods or taken as supplements (e.g., immediaterelease, slow or sustained-release nicotinic acid, and niacinamide [nicotinamide]). Adverse effects such as nausea, vomiting, and signs and symptoms of liver toxicity have been observed at nicotinamide intakes of 3,000 mg/day (Rader et al., 1992) compared with intakes of nicotinic acid of 1,500 mg/day (McKenney et al., 1994). The generic term niacin may be considered interchangeable with nicotinic acid. As described below, the critical adverse effect selected was flushing to the extent that it results in a change in the dosing pattern or withdrawal from treatment.

Vasodilatory Effects (Flushing). The term flushing covers a burning, tingling, and itching sensation as well as a reddened flush primarily on the face, arms, and chest. Flushing occurs in many patients treated with nicotinic acid therapeutically. It is often accompanied by pruritus, headaches, and increased intracranial blood flow (Miller and Hayes, 1982). Occasionally, it is accompanied by pain (Bean and Spies, 1940). Case reports and clinical trials have reported flushing effects at oral doses of 30 to 1,000 mg/day within 30 minutes to 6 weeks of the initial dose (CDC, 1983; Estep et al., 1977; Henkin et al., 1990; McKenney et al., 1994; Sebrell and Butler, 1938; Spies et al., 1938). Although flushing is a transient effect, it often results in patients deciding to withdraw from treatment.

In a study of the flushing effects of nicotinic acid and other pyridine compounds in humans, Bean and Spies (1940) suggest that pyridine compounds without a carboxyl radical in the 3 position of the pyridine ring do not produce flushing effects. Nicotinamide, which does not have a carboxyl radical in the 3 position, does not appear to be associated with flushing.

Flushing appears to be more closely related to a continuous rise in plasma nicotinic acid concentrations than to the absolute dose. Tolerance to nicotinic acid-induced flushing can develop whereby the effects are minimized when the dose is slowly increased over time (Stern et al., 1991). Flushing effects can also be reduced somewhat by taking niacin with food (Knodel and Talbert, 1987). Flush-



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