Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement最新文献

Twenty different heterocyclic amines have been isolated and identified from cooked foods especially beef, fish, pork and fowl. Other HCAs have also been isolated but their structure remains to be elucidated and new HCAs are likely to be identified in the future. The HCAs are highly mutagenic and all ten HCAs that have been tested for carcinogenic activity, produce tumors in mice and rats. For humans the average daily intake of HCAs is in quantities of 10-20 mg/person/day. The HCAs are procarcinogens and are activated by the cytochrome P450 system especially CYP 1A2. Rodents, monkeys and humans have the capacity to activate HCAs. Studies using hepatic microsomes demonstrated that humans have a greater capacity to activate the majority of HCAs tested than rodents or cynomolgus monkeys. Three HCAs are currently under evaluation in nonhuman primates for carcinogenic activity and one, IQ, is highly carcinogenic inducing primary hepatocellular carcinomas in the majority of cynomolgus monkeys treated. Epidemiological studies, although not definitive, are supportive of an association of HCAs intake to the etiology of human cancer. Risk assessments from animal data show a risk of HCAs to humans in the range of 10(-3) to 10(-4) which is an order of magnitude greater than compounds currently regulated by the U.S. Food and Drug Administration or the Environmental Protection Agency. Taken together evidence from mutagenicity data, activation by various species including humans, carcinogenicity in animals, human consumption data, epidemiological studies and risk assessment, supports the conclusion that HCAs are probable human carcinogens.

When comparing neurobehavioural observations from occupational lead-exposure of adults on the one hand, and environmental lead exposure of children on the other, it appears that the developing relative to the mature brain is more at risk. Neurobehavioural toxicity in occupational lead-exposure has typically not been observed at blood lead-concentrations (PbBs) below 400 micrograms/l, whereas ih environmentally exposed children such deficit has been reported to occur down to PbB of 100-150 micrograms/l and, perhaps, even below this range. Both cross-sectional and prospective studies have arrived at similar conclusions in this respect. The preferred endpoint in most such studies has been the IQ-measure, which has good psychometric qualities, is sufficiently well standardized to be comparable across studies, and exhibits attractive simplicity for the regulator in a public health context. At the same time, however, this IQ-focus has also interfered with systematic efforts to identify more specific lead-induced functional deficits by means of more detailed neurobehavioural analyses (Bellinger 1995). Metanalyses on both cross sectional and prospective studies in lead-exposed children have concluded that a typical doubling of PbB from 100 to 200 micrograms/l is associated with an average IQ-loss of 1-3 points (Pocock et al. 1994; WHO 1995), and no threshold has as yet been identified. Since, however, cause-effect contingencies necessarily remain doubtful in epidemiological studies if the observed effects are as subtle as these, experimental studies in animals have become helpful in supporting the causative role of lead to produce neurobehavioural deficit at steady-state PbB down to about 150 to 200 micrograms/l. Such deficit has been demonstrated by means of a variety of learning/memory models with positive and negative reinforcement contingencies in the rat--and in primates as well. It has also been shown in such studies that neurobehavioural deficit subsequent to early developmental exposure extends long into adulthood after cessation of exposure at weaning. It, therefore, appears that the neurobehavioural teratology of lead has more convincingly been demonstrated in animal models than in human exposure conditions, so far. A coherent theory to explain the particular vulnerability to lead of the developing brain is still lacking. Recent data do suggest, however, that Pb-induced disruption of calcium homeostasis in the immature brain might interfere with normal brain development.