The Contribution of cocoa additive to cigarette smoking addiction

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Page 98 of 207 RIVM report 650270002 Tryptophan Animal LD50 oral rat: 1.6 g/kg (3, 5). LD50 intraperitoneal rat: 1.63 g/kg body weight (21). LD50 intraperitoneal mouse: 4.8 g/kg body weight (21). Local tolerance Human No data available Animal No data available Repeated dose toxicity Subacute No data available Semichronic Human Tryptophan-containing products have been associated with the eosinophilia-myalgia syndrome in humans, but contamination of tryptophan during the manufacturing process may have been responsible. Evidence pointed to contamination coming from a single manufacturer and the syndrome was probably caused by a bacitracin-like peptide. Tryptophan probably promoted this disorder. Tryptophan dosage ranged from 150 mg/day to 8.4 g/day, with duration of tryptophan use ranging from 2 weeks to 8 years induced the eosinophilia-myalgia syndrome in humans (25). Chronic Animal Chronic administration of tryptophan doses below the LD50 reduced the food intake and the growth of rats, due to amino acid imbalance. Large groups of rats and mice were given greatly elevated amounts of tryptophan (2.5 % or 5% (w/w) in food, equivalent to 6.25 or 12.5 g/kg BW and 0.94 or 1.88 g/kg BW respectively for mice and rats) in their diets for most of their lives (104 – 105 weeks). In this study neither cancer incidence was increased nor gross microscopic changes in the tissue were observed at autopsy (10). A potential side effect of chronic tryptophan use includes the risk of diabetes mellitus. Since xanthurenic acid, which is increased on tryptophan loading, has diabetogenic action in animnals, tryptophan may promote glucose intolerance. In addition there is some evidence that photooxidation of tryptophan and some of its metabolites, such as kynurenine, may be involved in cataract formation (10, 25). Carcinogenicity Human While tryptophan itself seems to be relatively safe, during heating several pyrolysis products are formed which are mutagens, carcinogens and comutagens. No details are available on tryptophan data from this study (10). It has been suggested that long-term tryptophan use may promote bladder cancer. Elevated urinary levels of tryptophan metabolites has been reported in both bladder cancer patients relative to controls, and in patients who had recurrence of cancer
RIVM report 650270002 Page 99 of 207 Tryptophan relative to those who did not (10, 25). Animal The National Toxicology Programme tested rats and mice via feed (2.5 % or 5 % w/w tryptophan). No evidence of carcinogenicity was seen in either species of either sex. However in another study when tryptophan was administered subcutaneous to rats (2 years, 20 mg per week), malignant tumours in the uterus, mammary gland fibroadenomas, salivary gland adenomas, mesenteric reticulosarcomas and reticuloleukosis were observed (21). Tryptophan (6 g/day) is a promoter or cocarcinogen of urinary bladder tumors in dogs treated with an initiating dose of 4-aminobiphenyl or 2-naphthylamine for 0.3 – 7 years (15, 28). Based on longterm studies on rats (80 weeks) with 2% tryptophan diet and vitamin B6 intake, it was concluded that tryptophan promoted tumor formation when vitamin B6 intake was marginal but not when vitamin B6 was adequate. Using pellets with crude tryptophan pyrolysates, 3-amino-1,4-dimethyl-5H-pyrido(4,3b)indole (Trp-1) or 3-amino-1-methyl-5H-pyrido-(4,3-b)indole (Trp-2), high incidence of transitional cell carcinomas in the bladders of female mice were found after 40 weeks. In another study when a pellet diet containing Trp-1 and Trp-2 (0.2 %) were fed to mice for up to 621 days, a high incidence of hepatocellular carcinomas was observed in the female mice (28). Reproduction toxicology Human No data available Animal Tryptophan, given as 1.8 % of the diet to pregnant hamsters, caused significant reduction in embryo and neonate survival and in neonatal weight of the pups (10). Mutagenicity Human No data available Animal Indole derivates (tryptophan derivates included) which are present in cigarette smoke were shown to have a strong mutagenicity effect to Salmonella typhimurium TA100 and TA98 after nitrite treatment (29). Tryptophan reduces sister chromatid exchange incidence in rats treated with cyclophosphamide (21). Other Critical assessment In human tryptophan alone seems to produce no more side effects than placebo when given at a moderate dose (3 g per day). Nausea, headache, lightheadedness and drowsiness have been reported as side effects of acute tryptophan exposure in human. The LD50 in rats is high. Animal studies have indicated that tryptophan may act as a co-carcinogen or tumor promoter. During heating several pyrolysis products are formed which are mutagens, carcinogens and comutagens. Tryptophan is probably
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The Contribution of cocoa additive to cigarette smoking addiction

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