The Contribution of cocoa additive to cigarette smoking addiction

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Page 56 of 207 RIVM report 650270002 Serotonin TOXICOLOGY The toxicity data on serotonin that are available in the literature are mostly related to increased endogenous serotonin or its metabolites level by metabolic or medication effect. Acute toxicity Human Acute toxicity of serotonin is displayed when the endogenous serotonin level or its metabolites is raised by exogenous factors (drugs (serotonin reuptake inhibitor, monoamine oxidase inhibitor), food (banana or walnuts) in combination with alcohol, tryptophan) or by serotonin hyperproduction in the body (carcinoid tumor). The most common clinical symptoms observed are: nausea, vomiting, headache, diarrhea and uremic anorexia (11, 35, 36). The serotonin syndrome (SS) is a toxic reaction to a (relative) hyperserotonergic condition in the brainstem and the spinal cord. Motoric restlessness and anxiety, fever, diaphoresis, and myoclonus characterize the syndrome. The syndrome is probably an extreme form of well-known adverse effects. A particular high risk is seen at combination treatments with monoamine oxidase inhibitors and serotonergic agents (37). Animal sc-rat LD50: 285 mg/kg (38) iv-rat LD50: 30 mg/kg (38) oral-mouse LD50: 60 mg/kg (38) ipr-mouse LD50: 160 mg/kg (38) sc-mouse LD50: 601 mg/kg (38) iv-mouse LD50: 81 mg/kg (38) ims-mouse LD50: 750 mg/kg (38) iv-guinea-pig LD50: 12,8 mg/kg (38) Local tolerance Human No data available Animal No data available Repeated dose toxicity Subacute No data available Semichronic No data available Chronic Serotonin is a vasoactive amine, which has been suggested to be a mediator in a wide number of vascular pathologies in human. Alterations in peripheral serotonin have been related to a major risk in suffering vascular diseases in the diabetic population. Also, the valvular thickening seen in carcinoid heart syndrome could be associated with serotonin. The mechanism of the plaque formation is poorly understood, and may involve either kinins or serotonin and its metabolite, 5-hydroxyindoleacetic acid. Its role in hemostasis and thrombosis is not clear. It does amplify aggregation induced by other aggregating agents and in certain individuals can induce aggregation alone.
RIVM report 650270002 Page 57 of 207 Serotonin It has also been shown to constrict coronary arteries in patients with coronary artery disease (13, 39). Furthermore, serotonin is involved in the hypothalamic control of pituitary secretion, in sleep/arousal states, in regulation of circadian rhythms and inhibition of food intake. Disturbances of these serotoninergic systems have been linked to clinical depression and obsessive-compulsive disorder (13). No data are available on repeated dose toxicity of animals. Carcinogenicity Human No data available Animal Serotonin have mitogenic effect on vascular smooth muscle cells and on megakaryocytopoiesis (at serotonin concentration of 100 nmol/L) (40, 41), which is mediated by the 5-HT2 receptors. However, no data are available on the carcinogenicity effect of serotonin. Reproduction toxicology Human No data available Animal Serotoninergic pathways are involved in the neuroendocrine regulation of the sex hormones (42, 43). Serotonin was intraperitoneally injected to adult male rats. Serotonin injected with a single dose for 2 h (10 mg kg -1 bodyweight) showed an inhibition of serum concentrations of luteinizing hormone (LH) and of inhibin and testicular interstitial fluid (IF) volume and intratesticular testosterone concentrations. After four daily injections of serotonin (10 mg kg -1 ), the testis weight was decreased, and IF volume was increased nearly three-fold. Testis concentrations of inhibin and serum testosterone were reduced, whereas serum concentrations of both LH and folliclestimulating hormone (FSH) were elevated. Although serotonin also inhibited pituitary LH release and Leydig cell steroidogenesis, these effects appeared to play only a minor role in the induction of spermatogenic damage (44). Several serotonin reuptake inhibitors caused craniofacial malformations by inhibition of serotonin uptake into craniofacial epithelia of whole mouse embryo in culture (45). Mutagenicity Human No data available Animal No data available Other
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