nents followed by bond dissociation. The breaks were produced in DNA in a vacuum, so the relevance of the resonance phenomenon to DNA breaks in the intracellular aqueous environment is open to question. Hanel and colleagues (2003) have shown that electrons at energies below the threshold for electronic excitation (<3 eV) can decompose gas-phase uracil to generate a mobile hydrogen radical. The relevance of this observation to DNA damage in vivo awaits further experimentation.

Spontaneous DNA Damage Relative to Radiation-Induced DNA Damage

DNA is an unstable chemical entity under in vitro conditions because it is the target of a variety of reactive small molecules. DNA undergoes degradative reactions caused by active hydrolysis that result in depurination and deamination, and it undergoes base adduct formation by reactions with metabolites and coenzymes, damage by reactive oxygen species generated by “leakage” from mitochondria, lipid peroxidation, and many other sources of spontaneous damage (Lindahl 1993; Marnett and Burcham 1993; Beckman and Ames 1997; Lindahl and Wood 1999; see Table 1-2).

More than 90% of naturally occurring oxidation in a cell originates in the mitochondria, and oxidative nuclear damage occurs only for reactive products that can migrate far enough to enter the nucleus and react with DNA. The cell nucleus consequently is almost anoxic (Joenje 1989), and oxidative damage is quenched about fiftyfold by histones and by suppression of Fenton oxidants. However, the nucleus is not radiobiologically hypoxic (<8 μmol/L). 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. Although proteins 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

TABLE 1-2 Rates of Production and Steady-State Levels of Spontaneous DNA Damage in Mammalian Cellsa

Result of Damage

Production Rates

Steady-State Levelsb

Depurination

9000–10,000 per day

<100

Deamination

100–500 per day

<100

3-Methyladenine

600 per day

<50

8-Hydroxyguaninec

500–1000 per day

100 (15,000)

aFor comparison, background radiation of 5 mGy produces an average of about 1 electron track per cell resulting in 5–10 damaged bases, 2.5–5.0 SSBs, and 0.25 DSBs.

bValues are for repair-proficient normal cells. Value in parentheses is for repair-deficient liver cells.

cBest estimate of 8-hydroxyguanine values, disregarding reports of high values where chemical oxidation occurred during sample preparation.

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. Although DNA in cells is basically unstable, the instability is counteracted by DNA repair processes.

Strong evidence pointing to differences between X-ray damage and oxidative damage has come from studies in the yeast Saccharomyces cerevisiae. A genome-wide collection of nearly 5000 deletion mutants in all nonessential genes is now available for this species. Using this collection, all genes that were required for resistance to the lethal effects of X-rays and hydrogen peroxide were determined (Birrell and others 2001, 2002). Of those that were resistant to either agent, few genes were in common and their rankings were different. Of the top 100 genes conferring resistance to X-rays, only 35 were in the top 100 that were sensitive to hydrogen peroxide (see Annex A-1). These rankings indicate that the types of damage caused by X-rays and hydrogen peroxide were significantly different and required different mechanisms for repair. In another study using these deletion mutants, the oxidative damage caused by five different oxidants was found to differ significantly, indicating an unexpected complexity for oxidative damage (Thorpe and others 2004). Despite these differences, all of the oxidants caused predominantly protein damage, and few of the genes involved in DNA repair were involved in resistance to damage caused by any of these oxidants. These studies indicate that DNA damage is a more significant factor in resistance to X-ray damage than to oxidative damage. These studies also showed that the genes whose expression was induced by X-rays or hydrogen peroxide were not the genes required for resistance to these agents; few of the X-ray DNA repair genes in particular were inducible by damage (Birrell and others 2002).

Background Radiation

Added to the sources of spontaneous damage and metabolically produced oxidative DNA damage is background radiation, which includes radon, cosmic rays, terrestrial γ-radiation, and natural radioisotopes in the human body. Collectively, background radiation is responsible for delivering an average effective dose per person worldwide of about 2.4 mSv per year (typical range, 1–10 mSv; UNSCEAR 2000b). This background value includes radon exposure, the health effects of which are not evaluated in this report. Medical sources of radiation (diagnostic X-rays, nuclear medicine, and so on) can substantially increase a person’s yearly radiation exposure.

Ionizing radiation produces several kinds of damage in DNA, including SSBs and DSBs in DNA chains, DNA-DNA covalent cross-links, and DNA-protein covalent cross-links and a large variety of oxidative changes in the nucleotide bases (Hutchinson 1985; Ward 1988). The identified oxidative base products of ionizing radiation are chemically iden-



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