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> Myron Pollycove 1999 |
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The increased incidence of cancer observed during the fifties in atomic bomb survivors that received high-level radiation was consistent with our knowledge of radiochemistry and the newly discovered molecular structure of DNA. The damage to DNA and the risk of cancer were both proportional to radiation dose. Since some mutations of DNA initiated cellular changes that could be promoted and induce cancer, it was reasonable in the absence of low-level data, to postulate a linear, no threshold model as an upper limit to risk of cancer induction. Though epidemiologic surveys in the United States, Brazil, India, and China consistently observed less mortality and less cancer in high background populations than in low background populations, these findings were discounted because of lack of individual dosimetry, strict controls, unreliable public health data, and inadequate consideration of confounding factors. The threshold of 10 Gy (1000 rad) for development of bone cancer in the radium dial painters was simply an anomaly. Recently, however, the beneficial health effects of decreased mortality and decreased cancer in human populations exposed to low-level radiation have been observed in large populations with careful consideration of controls and high statistical power: US-Japan Atomic Radiation Effects Research Foundation (RERF) (Fig. l a), East Urals Population Study (Fig.1b), U.S. Nuclear Shipyard Worker Studies (Fig.1c), University of Pittsburgh Residential Radon Study (Fig. 2a) and the Canadian Breast Cancer Fluoroscopy Study (Fig. 2b). The UNSCEAR 1994 Report and recent studies provide extensive documentation of many cellular preventive and repair mechanisms, including the immune system, that are stimulated by low dose radiation. Nevertheless, a consequent positive health effect is still considered implausible,. "As to the biological plausibility of a radiation-induced adaptive response, it is recognized that the effectiveness of DNA repair in mammalian cells is not absolute ... An important question, therefore, is to judge the balance between stimulated cellular repair and residual damage." This reasoning focuses upon the DNA mutations produced by radiation-induced free radicals and ignores the normal presence of the very high background of free radical DNA damage unrelated to radiation. The following is an outline of the biologic system that controls the enormous burden of relentless endogenous DNA damage. This model, consistent with published data, was developed collaboratively with Ludwig E. Feinendegen, M.D. Every day endogenous human metabolism of oxygen produces an average of about 106 DNA alterations in each cell of our body. During youth and middle age these are prevented, repaired, and removed effectively so that in a lifetime, an average of only about 1 mutation/cell/d accumulates and cancer occurs infrequently (Fig. 3a).
A tenfold increase of low LET background radiation from 0.1 cGy/y to 1.0 cGy/y increases radiation-induced DNA damage from an average of 5.5 x 10-3 to 5.5 x 10-2 DNA alterations/cell/d and the ratio of daily endogenous to radiation-induced double strand breaks decreases from 103:1 to 102:1. However, this high background simultaneously stimulates the DNA damage-control system of antioxidant prevention, enzymatic repair, and apoptotic and immunologic removal of persistent DNA alterations by about 20%. The resulting decrease of mutations (residual persistent alterations) to about 0.8 mutations/cell/d is associated with the decreased cancer mortality and increased longevity seen in public, occupational, and medical cohort populations exposed to increased low-dose radiation (Fig. 3b).
High dose radiation, however, exceeds the homeostatic capacity of the DNA damage-control system and suppresses it. A single high dose of 200 cGy delivered in one minute adds only 4000 DNA alterations to the 106 DNA alterations each cell receives daily. During one minute the DNA damage-control system ordinarily copes eficiently with a numerically insignificant 2 x 10-7 background radiation-induced alterations relative to about 30 endogenous DNA alterations, a ratio of 7 x 10-9. However, during this minute the high dose of 200 cGy increases the ratio of radiation to endogenous induced alterations from 7 x 10-9 to 1.3 x 102, i.e., by a factor of 2 x l010, suppressing the efficient minimizing of mutations by the DNA damage-control system. Reduced DNA damage-control of the alterations occurring in that minute, as well as of the proximal subsequent continuous very high background of endogenous metabolic DNA damage, acutely increases mutations and the risk of developing cancer. The gradual accumulation of mutations and impairment of DNA damage-control that occurs with aging increases the risk of developing cancer with the 3rd to the 5th power of age. Genetic impairment of DNA damage-control may result in death from cancer at an early age. Similarly, high-dose radiation impairment of the cell's homeostatic damage-control functions also increases the risk of developing cancer. The health effects of radiation are not invariably negative in linear proportion to the relatively small amounts of radiation-induced DNA damage. These health effects are determined by the biphasic dose response to low- and high-dose radiation of preventive and repair cell functions that include the homeostatic DNA damage-control system. |
The
Seventh International Conference on Nuclear Engineering April 21, 1999 |
RSH > Documents > Tokyo 1999 > Myron
Pollycove 1999
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