The Contribution of cocoa additive to cigarette smoking addiction

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Page 132 of 207 RIVM report 650270002 Tyramine No data are available on respiratory pharmacokinetics of tyramine in man, but as MAO also occur in the lungs, probably tyramine is also metabolised by inhalation. The major route of catabolism for tyramine is one of enzymatic Ldeaminohydroxylation, and oxidation of the hydroxyl moiety and glycine conjugation. Conclusion There are no pharmacokinetic data available on respiratory intake of tyramine, but the lung MAO will metabolise inhaled tyramine. TOXICOLOGY Acute toxicity Human Small amounts of pressor amines, which are normally considered to be harmless, in foods can lead to a hypertensive crisis in patients on monoamine oxidase inhibitor (MAOI) drug regimens, which is often termed the ‘cheese reaction’ Consumption of 6 mg of tyramine may produce a mild crisis whereas 10 to 25 mg may produce severe headaches with intracranial hemorrhage and its sequelae (30). Animal Acute oral toxicity in Wistar rats is > 2000 mg/kg (1) LD50 i.v. mice, rabbits 229, 300 mg/kg, respectively (1) LDLo i.p. mice 800 mg/kg (1) LDLo s.c. cat, mice is 30, 225 mg/kg, respectively (1) No-observed-adverse-effect level (6 wk) in Wistar rat 2000 ppm in diet (180 mg/kg/day) (1) LD50 icv-mice: 30 mg/kg (31) LDLo scu-cat: 30 mg/kg (31) Local tolerance Human No data available. Animal No data available. Repeated dose toxicity Subacute The acute and subacute toxicity of tyramine has been examined in Wistar rats. Tyramine caused a dose-related increase in blood pressure after intravenous administration. In 6-wk studies tyramine was administered in the diet to groups of 10 male and 10 female rats. Tyramine was given at levels of 0, 18, 180, 900 mg/kg body weight/day in the first study and at levels of 0 or 900 mg/kg body weight/day in a second study. Decreased body weights associated with diminished food intake were generally seen. The no-observed-adverse-effect level was 2000 ppm (180 mg/kg body weight/day) for tyramine (32). Semichronic No data available. Chronic
RIVM report 650270002 Page 133 of 207 Tyramine No data available. Carcinogenicity Human No data available. Animal A variety of foodstuffs including soy sauce, vegetables and smoked foods showed direct-acting mutagenicity in bacteria upon nitrite treatment. The direct-acting mutagenic products of phenolic compounds with nitrite were all diazo derivatives. The diazo compound formed from tyramine with nitrite was proved to be carcinogenic in rats (33, 34). A mutagenic nitrosation product of tyramine, 4-(2aminoethyl)-6-diazo-2,4-cyclohexadienone (3-diazotyramine, 3-DT) preferentially induced tumors of the oral cavity. Squamous-cell carcinomas of the mucosa of the oral cavity floor developed in 19 out of 28 male F344 rats administered 0.1% (w/v) 3- DT in their drinking water. Tyramine and nitrite are found at fairly high concentrations in various foods. This demonstration of the carcinogenicity of 3-DT indicates that although the implications of 3-DT for human cancer are not clear, other nitrosable mutagen precursors need to be tested as possible risk factors in human cancer (35). Reproduction toxicology Human No data available. Animal No data available. Mutagenicity Human No data avaialble. Animal The mutagenic effects of tyramine have been thouroughly investigated, especially reaction products of tyramine with nitrites. In one study no mutagenicity of tyramine was found, but most studies indicated mutagenicity of tyramine. Using the L5178Y mouse lymphoma cell thymidine kinase locus and the Salmonella his locus assays, the mutagenic potentials of tyramine and several catecholamines were examined. In the mouse lymphoma assay tyramine was inactive. Mutagenic responses in Salmonella were also negative (36). Content of tyramine was determined in salted and dried small fish and its mutagenicity after nitrosification was assayed. Results showed content of tyramine in the fish correlated significantly with mutagenicity (r = 0.993, and P < 0.01) (37). The acute cytogenetic effect of tyramine, precursor of the mutagen present in soy sauce, was studied on mouse bone marrow cells in vivo by the micronucleus test. The incidence of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow cells gradually increased and reached a maximum level 24 h after intraperitoneal injection of tyramine and decreased within 36 h. A dose-dependent increase in MNPCE was clearly observed for tyramine. Compared to the values for the untreated control, significant positive results were obtained with 0.5 mmole tyramine/kg (68.5
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