The Contribution of cocoa additive to cigarette smoking addiction

RIVM report 650270002 Page 21 of 207
Theobromine
and vasodilatory effects is limited. As an inhibitor of angiogenesis and enhancer of
antitumor activity of adriamycin it might be of more value in the future.
Conclusion
In view of cigarette smoking no relevant beneficial effects can be expected.
SUMMARY AND FINAL CONCLUSION
A source of theobromine in tobacco is cocoa powder, which is used as a flavouring
agent. There are no data available on the pyrolysis products of theobromine.
Assuming similar systemic and potential effects after oral and inhalation exposure,
the additional risk of theobromine by cigarette smoking will be low comparing the
low daily intake via cigarettes smoke (estimated to be 4.75 mg/day) with the oral
intake via tea drinks, chocolate and cocoa drinks (estimated 138 mg – 864 mg/day).
Although oral intake is significantly larger from other sources than from cigarettes,
the local effects of theobromine via inhalation on the respiratory system are not
studied and might be a point of concern.
Theobromine affects the adenosine receptor sites (A1 and A2) and antagonizes the
effect of adenosine. Theobromine exerts various pharmacological effects in the body,
but these effects are much weaker than those of other methylxanthines, like caffeine
and theophylline, and therefore its bronchodilatory capacity is questionable. As other
methylxanthines (caffeine) also occur in cigarettes, the combined effect of these
methylxanthines on the pulmonary system is not known.
After oral intake, theobromine is readily absorbed and widely distributed in tissues,
including the brain. Transplacental transport in rats and human was reported and
theobromine was identified in fetal rat brain. CYP450 is involved in the metabolism
of theobromine. The half-times in serum ranged from 6.1 to 10 h. There are no data
on pharmacokinetics in animals and humans from respiratory studies.
The acute toxicity of theobromine is low. In humans clinical signs such as sweating,
trembling and severe headache are observed at high daily doses (0.8 – 1.5 g
theobromine). Animal lethal dose (LD50) for animals range from 300 mg/kg for dogs
to 1356 mg/kg for mice. After semichronic treatment of rats with high doses of
theobromine (25 – 250 mg/kg) a reduction in body weight and testicular atrophy is
observed. Theobromine may have mutagenic properties. There is no evidence that
theobromine is carcinogenic. No data on the toxic effects of theobromine
administered through inhalation are available. Toxic effects are observed at high oral
theobromine doses. It is unlikely that exposure to theobromine through smoking leads
to systemic theobromine levels that exert toxicologically relevant effects. Since no
data on the toxicological effects of theobromine exposure through inhalation are
available, the influence of exposure to theobromine on the respiratory system through
smoking cannot be established.
Theobromine is able to form stable compounds with bases and unstable compounds
with salts. Furthermore it can form complexes. Theobromine shows interaction
effects with agonists/antagonists of the adenosine receptors, the liver enzym system
and phosphodiesterase. All these in vivo interaction effects are described for other
than inhalation route. Whether these interaction effects also occur by intake through