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CAUSALITY OF A GIVEN CANCER AFTER KNOWN RADIATION EXPOSURE 30 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. does represent the successful proliferation of only one cell or at most a few cells to the point that the tumor can grow by competing with normal cell populations and tissues. In other words, the carcinogenic alteration of a cell transforms it from a cooperative unit in a population of cells (an organ) devoted to a particular function, to an alien unit capable of independent and parasitic organ like growth. Although it is assumed here that both cancer and genetic defects are of single-cell origin, it is well known that an initiated cancer cell may require an extracellular promoter (for example, a hormone or other chemical) before manifesting itself as a cancer, or that it may be prevented from expression by inhibitors such as immune mechanisms (Bond, 1984). However, most such promoters are normally present within the body, and the amount of any specific promoter is unlikely to be affected by low-level radiation exposure. The fact that such promoters may be present and may play a role in tumor expression must therefore generally be considered normal and not a phenomenon inducible by low-level radiation. Although theoretically possible, the probability of exposure to an external promoter in the workplace, for example, in conjunction with exposure to an initiator, appears small indeed (UNSCEAR, 1982). Thus, as indicated in Table 1, medical training alone provides no basis for judging whether a specific exposure to low-level radiation was or was not the cause of a specified tumor. Considering the single-cell origin of a tumor, the harm is undetectable at the time of exposure and potential initiation of a tumor, and diagnosis or prediction of malignancy is not possible. A similar situation exists for any tumor putatively associated with a radiation exposure (see Table 1). Clinical information relates only to the presence of a tumor, its type, and the prognosis with respect to a quantal effect. None of the information relates to a single-cell origin or the causes of the cellular transformation that may have initiated the process. RADIOBIOLOGICAL RESPONSE FUNCTIONS A single-cell response to low-level exposure can be initiated by a random interaction (accidental collision or event) between a single charged particle and one or more sites in the DNA of a cell. Evidence for this is the initial "linear, no- threshold" relation between the excess incidence of a quantal response seen in an exposed population of cells (animals) and the absorbed dose to the organ or other medium in which the cells are supported. Figures 1, 2, and 3 show such responses for, respectively, mutations, cancer in animals, and chromosome abnormalities. The initial proportionality is evidence that a single-hit interaction between a charged particle and an appropriate DNA target in the single cell can, to the virtual exclusion of any other
CAUSALITY OF A GIVEN CANCER AFTER KNOWN RADIATION EXPOSURE 31 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. radiation particle or increment of another transforming agent, initiate a cancer or a genetic defect. Figure 1 Radiation-induced mutations in the stamen hair cells of the plant Tradescantia. Note the double log plot, on which a slope of 45° corresponds to a linear response on arithmetic coordinates. The single-hit region extends to about 10 rads, above which the multihit region is dominant. It is in this high-dose region that the chance of cooperative interaction between two or more separate subeffective radiation events, or one such radiation and similar chemical event, may in principle occur (Underbrink and Sparrow, 1974; Emmerling-Thompson and Nawrocky, 1980). In discussing the reason why so-called dose-effect curves such as those shown in Figures 1 through 3 are initially linear, no-threshold in form, it must be recognized that the use of the word dose on the abscissa is conceptually inappropriate and misleading (Bond and Feinendegen, 1966; Kellerer, 1976; Bond, 1982a). The quantity is the average amount of energy per unit mass of organ or medium, which conveys little or no information about what happens at the cellular level as a result of a low-level exposure. The risk that any particular cell will be randomly assaulted at the appropriate site depends on the number of charged particles in the vicinity of the target cell during an exposure, whereas the chance that any cell actually hit during the exposure will then be transformed depends on the size of each physical event. That is,
CAUSALITY OF A GIVEN CANCER AFTER KNOWN RADIATION EXPOSURE 32 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. the risk of a cellular transformation or mutation depends first on the average number of charged particles traversing the environment of the cell per unit time (fluence rate), multiplied by the exposure time; this value gives the total exposure in terms of fluence (Bond, 1982a). Second, it depends on how many of these events, or hits, will be large enough to have a nonzero chance of transforming the affected cells (Bond, 1982a, 1984; Bond and Varma, 1983; Varma and Bond, 1983). Accordingly, the abscissas in Figures 1 and 2, at least in the low-exposure range, should more properly denote exposure measured by the fluence rather than the dose to either the organ or the cell. Figure 2 An initially "linear, no-threshold" response for a tumor of the Harderian gland (a retro-orbital gland of the eye) of the mouse. The initial linearity is relatively easy to demonstrate with the high linear energy transfer (LET) radiation used because such radiations are much more effective per unit dose than are low- LET radiations. The bending over of the curve at higher doses is due largely to competing effects such as killing of "induced" cells (Fry et al., 1983). The ordinate on both curves is the (excess) incidence of transformed or mutated cells, equal to the probability (risk) that the average exposed normal cell will be hit and transformed or mutated (beyond the small spontaneous rate that is always present, even without the exposure).
CAUSALITY OF A GIVEN CANCER AFTER KNOWN RADIATION EXPOSURE 33 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. Figure 3 Absorbed dose-cell quantal response curves for an induced chromosome abnormality, covering the full range of linear energy transfer (LET). Because the abnormality is detectable in moribund cells, the linear response can be observed well into the higher dose region. The curves marked "alpha He" and "alpha X" indicate that the curvilinear responses of low-LET radiation at high exposure rates, where intracellular repair is precluded because of the close temporal juxtaposition of successive hits, become linear when the exposure rate becomes very low (Skarsgard et al., 1967). From these remarks on the origins of cancer, genetic quantal responses, and their radiobiological initiation, it is evident that the "individual" to be considered under these circumstances is neither the organ nor the person, but rather the individual cell (see Table 1). Further, both mutational and transformational changes that are manifested as cancers or heritable diseases in descendants are truly rare eventsâso rare that, even with exposures well above the low-level range, only a small fraction of the exposed population of persons develops them. This means that the cell population that must be considered is much larger than that of any organ or individual. Thus, just as the public health officer must be professionally blind to the identity of individuals, so the epidemiologist must be blind to which individual is exposed and may develop a cancer. In principle, it is only the expected
