Mutagenesis and carcinogenesis: endogenous and exogenous factors.

The understanding of mutagenesis and its relation to carcinogenesis and aging is developing rapidly. A number of new findings are relevant to our understanding and are discussed: 1) The endogenous rate of oxidative DNA damage is estimated to be 10(4) hits/cell/day in humans and an order of magnitude higher in rodents. 2) The induction of cell proliferation may be a critical factor in both human cancer and the cancer caused by the maximum tolerated dose (MTD) of chemicals in rodents. 3) About half of all chemicals tested, whether synthetic or natural, are carcinogens, including the group of nature's pesticides, the main (greater than 99%) toxic chemicals in our diet. It is not clear how much, if any, of this high percentage of carcinogens is due to bias in selection of chemicals. A reasonable explanation for a very high percentage of all chemicals being carcinogenic at the MTD is that the MTD causes cell proliferation and inflammation, risk factors for cancer. 4) In the evolutionary war between plants and animals, animals have developed layers of general defenses, almost all inducible, against a world of natural toxic chemicals. This means we are well buffered against toxicity at low doses from both man-made and natural chemicals. Thus, low doses of carcinogens appear to be both much more common and less hazardous than is generally thought.