DNA in humans is a large molecule subjected to hydrolytic attack and to endogenous oxidative and other damage at 37ºC. For example, it has been estimated that 2-10 × 103 DNA purines (of a total of about 3 × 109) turn over in each human cell each day (Lindahl 1993). Over a 70-yr lifetime, depurination could affect 10% of a person's DNA. Furthermore, DNA alterations caused by the deamination (removal of an amine group) of cytosine and 5-methyl-cytosine (and to a lesser extent adenine and guanine) lead to coding changes that must be rectified.

In addition to the damage that results from its normal chemical bond breakage and reunion errors, DNA is assaulted by reactive oxygen species generated by "leakage" from mitochondria, flavin-catalyzed reactions, and many other sources, including phagocytosis and inflammation (Beckman and Ames 1997). The superoxide radical (O2-), formed by one-electron reduction of molecular oxygen, is generated in all aerobic cells. Chemical or enzymatic dismutation of (O2-) produces hydrogen peroxide, H2O2. The toxicity of these species has been attributed to the highly reactive hydroxyl radical (OH.), which can be formed by reactions of (O2-) and H2O2. Floyd (1995) has estimated that about 1% of the oxygen consumed by human cells is diverted to oxidizing cellular protein and that 0.001% of the oxygen molecules damage DNA and RNA; these numbers undoubtedly increase under conditions of oxidative stress, such as during chronic inflammation. Although protein and small molecules, such as glutathione, serve as scavengers for reactive oxygen and thus protect the nucleic acids, there is a considerable amount of oxidative DNA-base damage per cell per day (Saul and Ames 1986). However, the steady-state level of DNA damage is low, so most of the spontaneous and metabolically-generated damage is apparently repaired efficiently and correctly. Poor repair would allow the accumulation of excessive DNA damage that could interfere with DNA replication and transcription and ultimately threaten survival. Thus, although DNA in cells is frequently damaged, the damage is counteracted by DNA-repair processes.

Added to the sources of spontaneous damage and metabolically produced oxidative DNA damage is natural background radiation. The principal sources of external exposure from natural sources are cosmic radiation and naturally occurring radionuclides in the earth/soil. The primary sources of internal exposure are radionuclides, such as potassium-40, deposited within tissue. Collectively, these two sources deliver effective (whole body) close rates to members of the US public that range from 1 to 2 mSv per year. One sievert represents an amount of absorbed energy equivalent to 1 J/kg, adjusted to take into account the quality factor of the radiation. Artificial radiation sources, such as x-rays used in medical diagnosis and radiopharmaceuticals used in nuclear medicine, add an additional effective dose rate to the average member of the US public of about 0.50 mSv per year—0.40 mSv from medical x-rays, and about 0.14 mSv from nuclear medicine (NCRP 1989). The total effective dose rate from these two artificial sources is thus about half that from the natural background sources cited above. In addition, naturally occurring indoor radon and its

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement