The Contribution of cocoa additive to cigarette smoking addiction
The Contribution of cocoa additive to cigarette smoking addiction The Contribution of cocoa additive to cigarette smoking addiction
Page 12 of 207 RIVM report 650270002 Theobromine STELUSA: no data available. LTEL: no data available. TLV-C: no data available. TLV-CARCINOGENICITY: no data available. MAK-REPRODUCTION: no data available. Others: The levels of theobromine in the plasma of humans might be quite high following the combined exposure of man to theobromine directly in cocoa diets and indirectly through biotransformation of ingested caffeine in vivo to form theobromine (9). Reference value: Six nursing mothers ingested 113 g of Hershey's milk chocolate containing 240 mg of theobromine. Samples of plasma, saliva, and breast milk were assayed for theobromine. Peak theobromine concentrations of 3.7 to 8.2 µg/ml were found in all fluids at 2 to 3 hour after ingestion of chocolate (11). Theobromine disposition was measured twice in 12 normal men, once after 14 days of abstention from all methylxanthines and once after 1 week of theobromine (6 mg/kg/day) in the form of dark chocolate. The serum theobromine ranged from 5 – 15 µg/ml (12). CLASS EG Carc. Cat.: No data available. IARC-category: 3 (4) CEC: No data available. Critical assessment Comparison of smoking related daily consumption with daily consumption of theobromine (mg) from other sources: SMOKING DRINKING OR EATING 25 cig. 3 3 3 3 (1 % cocoa) tea chocolate chocolate cocoa drinks drinks bars of 60 g drinks . THEOBROMINE 4.75 (6) 138 (13) 195 (13) 864 (12) 750 (4) Little is known about pyrolysis/combustion products. 810 (14) 765 (9) (15, 16) 360 Conclusion The daily intake of theobromine from cigarettes is marginal compared with the intake of theobromine from other sources, like teas, chocolate drinks and sweets. So, the plasma concentration reached after ingestion of theobromine from tea or chocolate sources is expected to be significantly higher, than after intake from cigarettes. However, the different route of application via smoking as compared to other sources should be taken into account. Therefore, local effects of theobromine on the respiratory system might be a point of concern. . .
RIVM report 650270002 Page 13 of 207 Theobromine PHARMACODYNAMICS Mechanism of action The methylxanthines affect many physiological systems of the body through the mediation of the central nervous system. The probable biochemical basis being the ability of methylxanthines to inhibit phosphodiesterase breakdown of cAMP leading to the accumulation of the latter. Theobromine produces central stimulation because of its effect on the brain cortex. Theobromine has stimulatory effects on the brain, heart, gastric secretion and urine flow (9). The action of theobromine on the smooth muscle may depend on the balance between effects of cAMP and cGMP accumulation rather than cAMP alone. Two adenosine receptor sites (A1 and A2) are affected by methylxanthines and therefore these components antagonized the effect of adenosine. Adenosine acts like an inhibitor to neurotransmitter release and this could explain the mechanism of the methylxanthines on the CNS. Theobromine, was tested in mice, to determine whether it could function in vivo as an adenosine receptor antagonist, in keeping with its reported in vitro effects as a blocker of agonist binding to the adenosine A-1 receptor. Theobromine doses, which themselves had no direct effects on spontaneous locomotor activity, completely blocked N6-cyclohexyladenosine (CHA) induced suppression of locomotor activity but were without effect on ethylcarboxyamido adenosine (NECA) induced decreases in motor activity. In contrast to the specific antagonism, theobromine blocked the hypothermia induced by both of these adenosine analogs. These results demonstrate that theobromine is an active in vivo adenosine receptor antagonist and that the antagonism of CHA-sensitive systems occurs even though theobromine does not stimulate spontaneous locomotor activity. Thus, the behavioral stimulant effects of methylxanthines may be more related to effects on NECAsensitive systems, which are not blocked by theobromine (17). Theobromine is also an inhibitor of cholinesterase. Theobromine protected sensitized guinea pig against anaphylactic shock induced by aerosolized antigen by inhibition of the release of a slow reacting substance (SRS) of anaphylaxis and some reduction in histamine release. The methylxanthines have an active vasodilator action on the coronary vessels and on the vessels of the lungs and the legs. The protrombin time and plasma coagulation time in humans were considerably shortened by theobromine. Theobromine also inhibited and reversed platelet aggregation induced by ADP in vitro. The hepatic drug metabolizing microsomal enzymes were stimulated in the rat. Theobromine is less effective than other methylxanthines like caffeine and theophylline on different organs (18). Pulmonary system breathing frequency: 1-Substituted theobromine is a respiratory stimulant in mice and stimulates respiration of the isolated diaphragm of the rat (18). Tidal volume: No data available. Lung compliance: No data available. Airway resistance: Theobromine has a vasodilation effect in the lungs (18) and a bronchodilatory effect (19). The airway resistance by inhalation of theophylline aerosol, a theobromine derivate, was investigated. A dose of 15 mg theophylline aerosol showed significant decrease of the airway resistance after 60 min. of administration. The airway resistance decrease was not significant immediately or after 30 min of theophylline administration (20). Theobromine is significantly less active as a bronchodilator than theophylline. (7, 18)
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Page 12 <strong>of</strong> 207 RIVM report 650270002<br />
<strong>The</strong>obromine<br />
STELUSA: no data available.<br />
LTEL: no data available.<br />
TLV-C: no data available.<br />
TLV-CARCINOGENICITY: no data available.<br />
MAK-REPRODUCTION: no data available.<br />
Others:<br />
<strong>The</strong> levels <strong>of</strong> theobromine in the plasma <strong>of</strong> humans might be quite high following the<br />
combined exposure <strong>of</strong> man <strong>to</strong> theobromine directly in <strong>cocoa</strong> diets and indirectly<br />
through biotransformation <strong>of</strong> ingested caffeine in vivo <strong>to</strong> form theobromine (9).<br />
Reference value:<br />
Six nursing mothers ingested 113 g <strong>of</strong> Hershey's milk chocolate containing 240 mg <strong>of</strong><br />
theobromine. Samples <strong>of</strong> plasma, saliva, and breast milk were assayed for<br />
theobromine. Peak theobromine concentrations <strong>of</strong> 3.7 <strong>to</strong> 8.2 µg/ml were found in all<br />
fluids at 2 <strong>to</strong> 3 hour after ingestion <strong>of</strong> chocolate (11).<br />
<strong>The</strong>obromine disposition was measured twice in 12 normal men, once after 14 days<br />
<strong>of</strong> abstention from all methylxanthines and once after 1 week <strong>of</strong> theobromine (6<br />
mg/kg/day) in the form <strong>of</strong> dark chocolate. <strong>The</strong> serum theobromine ranged from 5 – 15<br />
µg/ml (12).<br />
CLASS<br />
EG Carc. Cat.: No data available.<br />
IARC-category: 3 (4)<br />
CEC: No data available.<br />
Critical assessment<br />
Comparison <strong>of</strong> <strong>smoking</strong> related daily consumption with daily consumption <strong>of</strong><br />
theobromine (mg) from other sources:<br />
SMOKING DRINKING OR EATING<br />
25 cig. 3 3 3 3<br />
(1 % <strong>cocoa</strong>) tea chocolate chocolate <strong>cocoa</strong><br />
drinks drinks bars <strong>of</strong> 60 g drinks .<br />
THEOBROMINE 4.75 (6) 138 (13) 195 (13) 864 (12) 750 (4)<br />
Little is known about pyrolysis/combustion products.<br />
810 (14) 765 (9)<br />
(15, 16)<br />
360<br />
Conclusion<br />
<strong>The</strong> daily intake <strong>of</strong> theobromine from <strong>cigarette</strong>s is marginal compared with the intake<br />
<strong>of</strong> theobromine from other sources, like teas, chocolate drinks and sweets. So, the<br />
plasma concentration reached after ingestion <strong>of</strong> theobromine from tea or chocolate<br />
sources is expected <strong>to</strong> be significantly higher, than after intake from <strong>cigarette</strong>s.<br />
However, the different route <strong>of</strong> application via <strong>smoking</strong> as compared <strong>to</strong> other sources<br />
should be taken in<strong>to</strong> account. <strong>The</strong>refore, local effects <strong>of</strong> theobromine on the<br />
respira<strong>to</strong>ry system might be a point <strong>of</strong> concern.<br />
.<br />
.
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