Comments on the history and importance of aromatic and heterocyclic amines in public health.

The carcinogenic risk of aromatic amines in humans was first discovered when a physician related the occurrence of urinary bladder cancer to the occupation of his patients. They were employed in the dyestuff industry, chronically exposed to large amounts of intermediate arylamines. Laboratory investigations disclosed that rats and mice administered specific azo dyes arylamines or derivatives developed cancer, primarily in the liver. Also, at that time, a possible pesticide, 2-aminofluorene, was tested for chronic toxicity, revealing that it rapidly induced cancers in several organs of rodents. This led to investigations on the mode of action of this class of chemicals, including their metabolic conversion. Biochemical activation to more reactive N-hydroxy compounds was found to occur, mostly in the liver, through what is now known as the cytochrome p450 enzyme systems, and also through prostaglandin synthetases. There were species differences. Guinea pigs were resistant to carcinogenesis because of the low titer of the necessary activating enzymes. In target tissues, a second essential reaction was necessary, namely acylation or sulfate ester formation. The reactive compounds produced display attributes of genotoxicity in appropriate test systems. Interest in this class of compounds increased when of Sugimura and colleagues discovered the formation of mutagens at the surface of cooked meat or fish, that were identified as heterocyclic amines (HCAs). These compounds undergo the same type of activation reactions, as do other arylamines. Epidemiological data suggest that meat eaters may have a higher risk of breast and colon cancer. HCAs induced cancer in rats in these organs and also in the prostate and the pancreas. In addition, there is some evidence that they affect the vascular system. The formation of HCAs during cooking can be decreased by natural and synthetic antioxidants, by tryptophan or proline, or by removing the essential creatine through brief microwave cooking prior to frying or broiling. The amounts of HCAs in cooked foods are small, but other components in diet such as omega-6-polyunsaturated oils have powerful promoting effects in target organs of HCAs. On the other hand, the action of HCAs may be decreased by foods containing antioxidants, such as vegetables, soy, and tea. Some constituents in foods also induce phase II enzymes that detoxify reactive HCA metabolites. Additional mechanisms involved decreased growth of neoplasms by intake of protective foods. Possibly, the carcinogenic effect of HCAs is accompanied by the presence of reactive oxygen species (ROS), which are also inhibited by antioxidants. World-wide, there have been many contributors to knowledge in this field. Adequate information may permit now to adjust lifestyle and lower the risk of human disease stemming from this entire class of aryl and HCA.

Historical and modern epidemiological studies on populations exposed to N-substituted aryl compounds.

The historical exposures to aromatic amines of various occupational groups are briefly reviewed. Modern studies indicate that other occupational groups might have risks worth investigating; these include machinists and workers in the chemical industry. Details of a recent investigation into the exposure of dye workers are given which indicate a lowered risk in recent years since the introduction of safety measures. Nonoccupational exposures to the aromatic amines are also discussed. They include cigarette smoking and phenacetin abuse, the former being a potent causal agent in bladder cancer.