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Adverse Effects in Animals. Histidine given acutely by intraperitoneal injection or intravenously has been shown to result in changes in the concentration of brain amino acids (Oishi et al., 1989) and histamine (Schwartz et al., 1972). Young rats (4 to 5 weeks old) treated with an inhibitor of histidinase exhibited reduced locomotor activity after an intra-peritoneal injection of histidine (250 mg/kg of body weight) (Dutra-Filho et al., 1989). Pilc and coworkers (1982) reported "bizarre behavior" in rats dosed intraperitoneally with histidine (400 to 800 mg/kg of body weight). These effects have not been examined in rats fed L-histidine and are of minimal use in deriving a UL for the chronic exposure of humans to oral L-histidine.

Feeding low-protein diets supplemented with L-histidine for 3 to 4 weeks resulted in significant body weight losses after only several days in rats. However, the effects became less as increasing levels of high-quality protein were added to the diet (Benevenga and Steele, 1984).

Short-term feeding studies (7 to 46 days) in rats have shown growth retardation, hepatomegaly, and hypercholesterolemia at L-histidine levels of approximately 2 to 4 g/kg body weight/d (Harvey et al., 1981; Hitomi-Ohmura et al., 1992; Ohmura et al., 1986; Solomon and Geison, 1978). Harvey and coworkers (1981) reported significantly reduced concentrations of copper and zinc in the plasma and reduced liver concentrations of copper after feeding diets containing 8 percent L-histidine (~4 g/kg body weight/d) for 46 days. Hypercholesterolemia was eliminated by the simultaneous feeding of an L-histidine- and copper-supplemented diet, supporting the hypothesis that the histidine-induced hypercholesterolemia was a result of changes in copper status. Feeding mice 1.3 g L-histidine/kg body weight/d for 21 days resulted in an increase in the absorption and utiliza-

722 DIETARY REFERENCE INTAKES

tion of zinc with higher concentrations of zinc in liver, muscle, spleen, and pancreas (van Wouwe et al., 1989).

The long-term toxicity and carcinogenicity of L-histidine mono-hydrochloride (HMHC) was studied in 50 male and 50 female rats (Ikezaki et al., 1996). Male rats were fed diets containing 0.47 and 0.96 g/kg body weight/d of HMHC for 104 weeks; female rats were fed 0.56 and 1.1 g/kg body weight/d for the same period. No significant treatment-related increases in any tumors were reported when compared to matched controls. No neoplastic changes were reported in controls or treatment groups. In male rats fed 0.96 g of HMHC/kg body weight/d, increases in red blood cell counts, hemoglobin concentrations, and hematocrit were reported. No evidence of sperm granulomas were observed in male rats fed either 1.6 g of HMHC/kg body weight/d for 13 weeks or 0.97 g/kg body weight/d for 104 weeks (Ikezaki et al., 1994, 1996).

Adverse Effects in Humans. Pinals and coworkers (1977) treated 30 rheumatoid arthritis patients and 30 controls daily with capsules containing 4.5 g of L-histidine for 30 weeks in a double-blind trial followed by 19 patients receiving this dosage for 10 additional months in a period of open treatment. It is not clear which adverse effects were examined; however, the authors concluded that no adverse effects of the histidine therapy were noted. In a similar double-blind treatment design, Blumenkrantz and co-workers (1975) treated 42 patients (16 chronic uremic and 26 undergoing maintenance dialysis) with oral doses of 4 g/d of L-histidine for 17.5 weeks. No adverse effects were reported; however, it was not evident from the report which adverse effects were examined.

Studies on the effects of L-histidine on taste and smell acuity in humans have produced conflicting results. Henkin and coworkers (1975) reported decreased taste and smell acuity in six patients given 8 to 65 g of histidine/d for up to 24 days. In view of the increased urinary excretion of zinc and a decreased concentration of serum zinc, the authors postulated that the effects of histidine administration were due to a zinc-deficient state. In a study of eight healthy men given 4 g/d of histidine for 2 weeks, no effects on smell or taste acuity were reported (Schechter and Prakash, 1979). Similarly, Geliebter and coworkers (1981) failed to find any effect of L-histidine on taste and smell after oral dosing of L-histidine between 24 and 64 g/d for 4 weeks. Even at the lower dose (4 g/d), adverse effects such as headaches, weakness, drowsiness, and nausea were reported, while at the highest doses (24 and 64 g/d) anorexia, painful sensations in the eyes, and changes in visual acuity were reported in two females.

Zlotkin (1989) reported an approximate 70 percent increase in urinary zinc excretion in infants on TPN when the fluid contained 165 mg of

PROTEIN AND AMINO ACIDS 723

histidine/kg body weight/d compared to 95 mg/kg body weight/d in controls. Although the study examined parental administration, it provides further evidence that excess histidine intake in humans can lead to histidine/zinc interactions that might lead to a zinc-deficient state.

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