The Contribution of cocoa additive to cigarette smoking addiction

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Page 34 of 207 RIVM report 650270002 Caffeine combination with known carcinogens resulted in decreased incidences of lung tumours in mice treated with urethane, of mammary tumours in rats treated with diethylstilboestrol and of skin tumours in mice treated with either ultraviolet light or cigarette-smoke condensate (1). Reproduction toxicology Human Total caffeine intake, as determined from various sources including coffee, tea, cola and drugs, was positively associated with the proportion of low-birthweight babies after controlling for smoking and other potential confounders (1). For spontaneous abortion, five studies were evaluated; the combined odds ratio was 1.36 (95% confidence interval 1.29-1.45), indicating that mothers who consumed caffeine had a higher risk of spontaneous abortion than those who did not. The birth weight of the babies showed a statistical correlation with the caffeine consumption during pregnancy (28). In human some conflicting results were reported about the effects of caffeine and coffee consumption on fertility. Some studies did not show any correlation between caffeine intake and fertility and other studies showed a threshold and negative doseresponse correlation between caffeine intake and fertility (29). Animal Caffeine in a dose of 25 mg/kg body weight administered by oral gavage to pregnant rats on days 8-9 of gestation caused delayed neuraltube closure in rat embryos; also the development of the heart, eyes and limbs were reduced. From the various recent studies on the reproductive toxicity of caffeine, it is evident that administration of caffeine during pregnancy affects the normal differentiation of foetal ovaries and testis resulting in significant foetal and post natal growth retardation and an increase in post natal mortality and impaired brain differentiation resulting in delayed closure of the neural tube (8). Mutagenicity Human Cultured human lymphocytes from volunteers on a regime of 800 mg caffeine daily for four weeks, resulting in caffeine blood levels as high as 29.6 µg/ml after four weeks showed no significant increase in the frequency of chromosomal damage. Drinking coffee or tea to result in a total caffeine intake corresponding to that in five cups of coffee per day [exact amount not stated] was associated with increased micronucleated reticulocytes and micronucleated mature erythrocytes in splenectomized but otherwise healthy individuals after adjustment for smoking. Drinking decaffeinated coffee was not associated with an increase in the number of micronucleated cells. Although it has been suggested that caffeine may induce gene mutations in mammals and man, direct evidence in vivo is limited. The indirect evidence is based largely on extrapolation from results in lower organisms, in which there is no doubt about the mutagenic action of caffeine, and from cultured mammalian cells, in which caffeine is clastogenic at high concentrations (1). Animal Using dominant lethal method, no significant increase in dominant-lethal mutations (embryonic deaths) were found, whether expressed as early deaths per pregnant female or as mutation index in animals consuming caffeine in drinking water at 3.6, 13.4, 49 and 122 mg/kg for 8 weeks. Although males consuming the two highest
RIVM report 650270002 Page 35 of 207 Caffeine levels of caffeine produced fewer pregnancies, litter sizes of females were not reduced (5). Caffeine can enhance the teratogenic effect of ionizing radiation in mice (30). However, intraperitoneal injections of caffeine prior to, subsequent to, and following X-rays did not enhance the mutagenicity of the radiation (5). Other Caffeine interacts in different ways with DNA structure and metabolism. Non-DNA targets that are important to the genotoxic and related effects of methylxanthines are (i) cytochrome P450s, (ii) cAMP metabolism, (iii) DNA metabolism, chromatin structure and function and (iv) nucleotide pools (1). Caffeine increased the mutagenic effect of UV light on E. Coli (5). In mammal in vivo experiments, most of the experiments showed negative test in the micronucleus test and only three significant positive tests were observed; in each case the doses were in the toxic range (1). Critical assessment The toxicity of caffeine after acute or chronic administration to humans and animals is low. Caffeine intake has been associated with lower birth weights and increased incidence of spontaneous abortion in man. In animals relatively high doses of caffeine affected normal prenatal development. Conclusion Toxic effects of caffeine are observed at high doses. It is unlikely that exposure to caffeine through smoking leads to toxicologically relevant systemic caffeine levels. No data on the toxicological effects of caffeine exposure through inhalation are available. Therefore the influence of exposure to caffeine through smoking cannot be established. INTERACTIONS Chemical Heating/combustion of bulk amounts may release toxic and corrosive gas/vapour: nitrous gasses, carbon monoxide, carbon dioxide; caffeine is able to react with (strong) oxidants (3). The photo-oxidation of caffeine in presence of peroxydiphosphate (PDP) in aqueous solution at natural pH (similar to 7.5) was performed. On the basis of the experimental results and product analysis, 3 probable mechanisms have been suggested in which PDP is activated to phosphate radical anions (PO4. 2- ) by direct photolysis of PDP and also by the sensitizing effect of caffeine. The phosphate radical anions thus produced react with caffeine by electron transfer reaction, resulting in the formation of caffeine radical cation, which deprotonates in a fast step to produce C8-OH adduct radicals. These radicals might react with PDP to give final product 1,3,7-trimethyluric acid and PO4 2- - radicals, the latter propagates the chain reaction (31). Caffeine displays complex formation with hydroxylic derivatives through the hydrogen bonding at the carbonyl functions (32). In vivo Caffeine can enhance the teratogenic effect of ionizing radiation in mice. Also for a variety of pharmaceutical agents (acetazolamide, mitomycin C, hydroxyurea, 5-
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The Contribution of cocoa additive to cigarette smoking addiction

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