The Contribution of cocoa additive to cigarette smoking addiction

Page 32 of 207 RIVM report 650270002
Caffeine
Kinetic parameters
The rate of caffeine metabolism varies, with half lives ranging from 2 to 12 hours and
an average half-life of 4 to 6 hours (about 15 % metabolised per hour). Longer halflives
are seen in patients with chronic liver disease and in pregnancy. A shorter halflife
is seen in smokers (5, 9).
Critical assessment
The oral data indicate a high bioavailabilty and extensive distribution and metabolism
of caffeine.
There are no data on pharmacokinetics in animals and humans from respiratory
studies.
Conclusion
Conclusions on potential differences in kinetics between respiratory and oral
administration can neither be drawn based on the pharmacogical and toxicological
data.
TOXICOLOGY
Acute toxicity
3.2.1.1 Human
Acute toxicity due to caffeine is not very common, although some adverse effects
(e.g. gastric symptoms, insomnia, diuresis) have been observed as a result of
overdoses. In volunteers who abstained from caffeine-containing products, a bolus
dose of 250 mg led to a 5-10 % increase in both systolic and diastolic blood pressure
for 1-3 h. At low doses (up to 2 µg/ml in blood), caffeine stimulates the CNS and
many caffeine users perceived this effect as beneficial. High blood concentration (10-
30 µg/ml) of caffeine may produce restlessness, excitement, tremor, tinnitus,
headache and insomnia (1).
A one-year-old white female ingested approximately two to three grams of caffeine
(200-300 mg/kg). The patient survived the ingestion with a maximum caffeine
concentration of 385 micrograms/ml four hours postingestion. The child developed
ventricular arrhythmias, seizures, metabolic disturbances, and severe pulmonary
edema. She survived without apparent long-term sequelae despite having reached a
serum caffeine concentration that is the second highest reported level in a survivor
(25).
Only three human fatalities from caffeine have been reported and the lowest toxic
dose was 2-3 g or 57 mg/kg body weight (8).
The lethal dose is about 10 g or 170 mg/kg BW, which equivalent to 75 cups of
coffee, 125 cups of tea, or 200 cans of cola. In high doses caffeine causes
hypotension from vasodilatation (ß-adrenergic mediated) and pronounced tachycardia
with massive systemic catecholamine release (9).
Animal
Oral
LD50 rat is 200 mg/kg, mouse is127 mg/kg, hamster is 230 mg/kg, guinea pig is 246
mg/kg (1).
LD50 in mouse, hamster, rat, rabbit (mg/kg) is respectively: 127, 230, 355, 246