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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 14Ionizing Radiation

, MD.

The hazards of exposure to ionizing radiation were recognized shortly after Roentgen’s discovery of the x-ray in 1895. Acute skin reactions were observed in many individuals working with early x-ray generators, and by 1902 the first radiation-induced cancer was reported arising in an ulcerated area of the skin. Within a few years, a large number of such skin cancers had been observed, and the first report of leukemia in five radiation workers appeared in 1911.1 Indeed, Marie Curie and her daughter Irene are both thought to have died of radiation-induced leukemia. Since that time, many experimental and epidemiologic studies have confirmed the oncogenic effects of radiation in many tissues of many species.

There are a number of characteristics specific to ionizing radiation that differentiate it from chemical toxic agents or other physical carcinogens. Notable among these is its ability to penetrate cells and to deposit energy within them in a random fashion, unaffected by the usual cellular barriers presented to chemical agents. All cells in the body are thus susceptible to damage by ionizing radiation; the amount of damage incurred will be related to the physical parameters that determine the radiation dose received by the particular cells or tissue. Furthermore, the physical characteristics of ionizing radiation allow us to measure accurately very low levels of exposure, doses several orders of magnitude below those that produce measurable biologic effects in human cells.

This chapter will review briefly the principal cellular and tissue effects of radiation, as well as what is known about cellular and molecular mechanisms for radiation carcinogenesis. The term carcinogenesis is used in its broad sense to include the development of all types of malignant neoplasms. A more detailed description will then be presented of current knowledge concerning the induction of cancer by radiation in experimental animals and human beings. Human risk estimates are derived primarily from epidemiologic studies following relatively high-dose radiation exposures. As ionizing radiation appears in reality to be a relatively weak carcinogen and mutagen compared to many chemical agents, few reliable human data are available on its oncogenic effects in the dose range below 50 cGy.

Development of Radiation Injury

A schematic representation of the interaction of ionizing radiation with biologic tissues and the subsequent development of radiation injury is shown in Fig. 14.1. Such radiation is of two major types, electromagnetic waves or ionizing particles. In either case, interaction with orbital electrons results in ionizations and excitations. The initial deposition of energy in irradiated cells thus occurs in the form of ionized and excited atoms or molecules distributed at random throughout the cells. It is the ionizations that cause most of the chemical changes in the vicinity of the event; this energy may be subsequently transferred through a chain of chemical reactions, finally producing irreversible damage to critical molecules of biologic importance to the cell. It appears that the energy that goes into producing excited molecules produces relatively few chemical reactions and is eventually dissipated in the form of heat.

Figure 14.1. Development of radiation injury.

Figure 14.1

Development of radiation injury.

The ionizing event involves the ejection of an orbital electron from a molecule, producing a positively charged or “ionized” molecule. These molecules are highly unstable and rapidly undergo chemical change. This change results in the production of free radicals, atoms, or molecules containing unpaired electrons. These free radicals are extremely reactive and may lead to permanent damage of the affected molecule, or the energy may be transferred to another molecule. Most of the energy deposited within a cell results in the production of aqueous free radicals, since approximately 80% of the cell is water. Chemical damage may be repaired before it is irreversible by the recombination of radicals and dissipation of the associated energy, or it may be modified by agents such as molecular oxygen or sulfhydryl radioprotective compounds.

As the initial ionizing events are similar for all types of radiation, their biologic effects are also qualitatively similar. However, densely ionizing radiation such as alpha particles produce more biologic damage per unit of energy absorbed. The relative biologic effectiveness (RBE) of different types of radiation relative to x-rays is thus related to their linear energy transfer (LET), a measure of the density of the ionizations produced along the radiation track. The initial critical biologic change is thought to be damage to DNA molecules in the cell. The time required for the entire chain of physical and chemical events as shown in Figure 14.1 from the initial interaction until the production of DNA damage is of the order of a microsecond or less. The subsequent development of biochemical and physiologic changes, however, may take hours to days, whereas the induction of cancer may take many years.

Principal Cellular and Tissue Effects of Radiation

Cell Killing

Radiation can kill cells by two distinct mechanisms. The first is apoptosis, also called programmed cell death or interphase death.2, 3 Cells undergoing apoptosis as an immediate consequence of radiation damage usually die in interphase within a few hours of irradiation, irrespective of and without intervening mitosis. They share distinct morphologic changes, including loss of normal nuclear structure and degradation of DNA that can be demonstrated by a classical pattern of “laddering” on DNA blots.3 While it has long been known that apoptotic cell death occurs in a few cell types, including small lymphocytes, type A spermatogonia, and oocytes, following relatively low doses of radiation, apoptosis may also be a significant cause of death in a broader variety of cell types exposed to higher radiation doses, including those of hematopoietic or lymphoid origin, as well as some tumor cells.

Early evidence suggested that radiation-induced apoptosis was dependent upon the functional activity of the p53 gene,3 but it soon became evident that p53 independent pathways may also be involved, such as that mediated by Bcl-2/BAX.4 It has recently been proposed that p53-dependent apoptosis may involve the transcriptional induction of redox-related genes with the formation of reactive oxygen species, leading to cell death by oxidative stress.5 Although DNA damage is thought to be important in triggering the apoptotic response,6 some studies have suggested a role for membrane damage and signaling pathways outside the nucleus that involve tyrosine kinases, especially ceramide.7 In any case, apoptosis may serve as a protective mechanism for the elimination of heavily damaged and thus potentially mutated cells from an irradiated population.

The second mechanism for cell killing is radiation-induced reproductive failure. Radiation in sufficient doses can inhibit mitosis; that is, the cell’s ability to divide and proliferate indefinitely. The inhibition of cellular proliferation is the mechanism by which radiation kills most cells. The nature and kinetics of the cytotoxic effects of radiation in mammalian cells have been reviewed elsewhere.2, 8 They are discussed in detail in Chapter 34 of this text, particularly as they relate to tumor cells and radiation oncology. As radiation kills cells by inhibiting their ability to divide, its effects in human beings occur primarily in tissues with high cell turnover or renewal rates characterized by a large amount of proliferative activity. These include tissues such as the bone marrow and the mucosal lining of the stomach and small intestine. Symptoms of acute exposure to whole-body irradiation in human beings are usually observed only following doses of 150 cGy or greater, whereas significant cell killing in vitro can be detected with doses as low as 50 cGy.

Another important somatic effect related to cell killing arises from irradiation of the developing embryo and fetus.9, 10 Whereas irradiation of experimental animals with doses in the order of 200 to 400 cGy during the first trimester of pregnancy has led to a variety of congenital anomalies in the offspring, no such effects were found in large populations of mice exposed to doses below 25 cGy.9 Moreover, no increase in the frequency of congenital anomalies has been observed in human beings, even following relatively high radiation doses.

Recent epidemiologic studies on the atom bomb survivors of Hiroshima and Nagasaki have focused on mental retardation and other measures of intelligence such as test scores and school performance.10 These are presumably more sensitive indicators of radiation effects owing to cell depletion amongst the neuroblasts during development. Neuroblasts comprise by far the largest population of cells in the early fetus and continue proliferating until the fifth or sixth month of pregnancy. The number of children with such disorders in the atom bomb survivor study is small, and the mean values for all end points are not significantly different from those in controls for the dose groups below 50 to 100 cGy. The Committee on the Biologic Effects of Ionizing Radiations, of the National Research Council (BEIR V Committee)11 concluded that for mental retardation, the best documented of the developmental abnormalities, the prevalence appeared to increase with dose in a linear manner for individuals irradiated between 8 and 15 weeks, the most sensitive time period after conception. However, the data do not exclude a threshold in the range of 20 to 40 cGy and indeed best fit a threshold dose-response relationship with a lower bound of 12 to 20 cGy.11 On the assumption of a linear, nonthreshold relationship, however, the magnitude of the risk would be approximately a 4% chance of occurrence per 10 cGy for exposure at 8 to 15 weeks of gestational age, with less risk occurring for exposure at other ages.


The mutagenic effects of ionizing radiation were first described by Herman Muller in 1927 in his classic experiments with the fruit fly Drosophila. Subsequent experiments showed the dose-response relationship for such mutations to be a linear function of exposure over a wide range of radiation doses from as low as 10 to 1,000 cGy. Studies of the induction of single-gene mutations in human cells have been limited to several genetic loci. The results of most of these studies also suggest that the induction of mutations in human cells is a linear function of dose with doses as low as 10 and perhaps 1 cGy, and that the dose-rate effect appears to be relatively small.12, 13 DNA structural analyses have shown that the majority of radiation-induced mutations in human cells result from large-scale genetic events involving loss of the entire active gene and often extending to other loci on the same chromosome.14

The major potential consequence of radiation-induced mutations in human populations is heritable genetic effects resulting from mutations induced in germinal cells. Such effects have been examined in several different animal systems.11 For high dose-rate exposure, the induced mutation rate per gamete generally falls in the range of 10-4 to 10-5 per cGy. The rates per locus are in the range of 10-7 to 10-8 per cGy. Protraction of exposure appears to decrease the mutation rate in rodent systems by a factor of 2 or greater. When all of the experimental data for the various genetic end points are considered, the genetic doubling dose (radiation dose necessary to double the spontaneous mutation rate) for low dose-rate exposure appears to be in the range of 100 cGy. Although significant heritable genetic effects of radiation have not yet been demonstrated in human populations, a doubling dose of 100 cGy is not inconsistent with the absence of a statistically significant increase in hereditary disease among the children of atom bomb survivors.15 Indeed, 100 cGy represents approximately the lower 95% confidence limit for the human doubling dose calculated from the atom bomb survivor data.11

Chromosomal Aberrations

Radiation can induce two types of chromosomal aberrations in mammalian cells. The first have been termed “unstable” aberrations in that they are usually lethal to dividing cells. They include such changes as dicentrics, ring chromosomes, large deletions, and fragments. These types of aberrations do not allow the equal distribution of genetic material into daughter cells; in many cases, the frequency of such aberrations correlates well with the cytotoxic effects of radiation.

The second type has been termed “stable” aberrations. These include changes such as small deletions, reciprocal translocations, and aneuploidy—changes that do not preclude the cell from dividing and proliferating. A karyotype of a human cell showing a stable aberration is shown in Fig. 14.2. Radiation-induced reciprocal translocations such as have occurred in this cell may be passed on through many generations of cell replication and emerge in clonal cell populations.16, 17

Figure 14.2. Karyotype of normal human diploid fibroblast showing stable chromosomal rearrangement (1:16 translocation) induced by radiation.

Figure 14.2

Karyotype of normal human diploid fibroblast showing stable chromosomal rearrangement (1:16 translocation) induced by radiation. The irradiated cells were serially subcultivated for 3 months (approximately 20 cell generations) before this cell was analyzed. (more...)

It is well known that such deletions and translocations can result in gene mutations. It is tempting to speculate that they may play a more fundamental role in the process of carcinogenesis. Typically, cancer cells are aneuploid and contain multiple stable chromosomal aberrations. In a number of cases, specific chromosomal abnormalities have been associated with specific tumor types. In some instances, such as the chromosome 8:14 translocation in Burkitt’s lymphoma, the chromosomal change results in the activation of a specific oncogene. In others, such as the chromosome 13q14 deletion found in retinoblastoma (RB), tumor development has been ascribed to loss or inactivation of the RB suppressor gene. While radiation-induced cancers show multiple unbalanced chromosomal rearrangements, few show such specific translocations as would be associated with the activation of specific oncogenes or known tumor suppressor genes.18

Neoplastic Transformation

An important cellular effect of radiation is neoplastic transformation, or the conversion of a normal cell to one with the phenotype of a cancer cell, including the ability to form an invasive, malignant tumor upon re-injection into syngeneic hosts. Current knowledge concerning the transformation of cells in vitro by ionizing radiation is described in the following section.

Neoplastic Transformation in Vitro by Radiation

Most human cancers have been shown to be clonal in origin. That is, all of the cells within a tumor are descendants of a single cell that has undergone the process of neoplastic transformation. The transformation of one or more normal cells in a tissue in vivo is thought to represent the earliest step in the overall process of carcinogenesis. Whether or not such a transformed cell can successfully give rise to an invasive, malignant tumor depends upon a number of tissue and systemic factors.

Although a number of different in vitro transformation systems involving various species and cell types are under investigation, those that generate reliable quantitative data have been restricted to rodent cells, and in none of these is the entire process of malignant transformation measured. Rather, surrogate features of transformation are assayed such as changes in colony morphology, focus formation or growth under anchorage-independent conditions. No quantitative system for studying transformation of normal human diploid cells has as yet been developed.

Stages in Neoplastic Transformation

Studies of cellular and animal models for radiation carcinogenesis indicate that it is a progressive, multi-step process by which normal cells acquire the various phenotypic characteristics of cancer cells.19 There appear to be three major independent stages in the malignant transformation of cells in vitro: the development of morphologic changes, cellular immortality, and tumorigenicity.20 Morphologic changes are many and varied, including the development of abnormalities in cytology, growth pattern, and the control of cell proliferation. Immortalization occurs frequently in rodent cells but extremely rarely in human cells, either spontaneously or as a result of treatment with radiation or chemical carcinogens. It can be induced, however, by transfection of human diploid cells with certain oncogenes and/or genes associated with tumor viruses such as the SV40 T antigen or the E6/E7 genes of human papillomavirus 16 and has been associated with the production of telomerase. Immortalization may thus be an important rate-limiting step in human cell transformation and perhaps in human carcinogenesis in vivo.20 Tumorigenicity also appears to be an independent phenotype that generally occurs only in previously immortalized cells. A subpopulation of such immortal cells may undergo additional genomic rearrangements that give them a selective growth advantage in vivo perhaps related to factors present in the host animal.21

Dose-Response Relationships

Dose-response curves for the induction of transformation in two very similar mouse cell systems are shown in Fig. 14.3. Although the transformation frequencies reached a similar plateau at doses above 600 cGy, the shapes of the curves at lower doses differed significantly. Such findings, as well as the fact that transformation of individual cells represents but an early event in the overall process of carcinogenesis, suggest that it is not relevant to predict the shape of the dose-response curve for carcinogenesis in vivo at low radiation doses from studies of malignant transformation in vitro. For irradiation with densely ionizing, high LET radiation, the frequency of transformation rises much more rapidly at low doses, reaching a roughly similar plateau. RBE factors in the range of 3 to 10 have been calculated for high-LET radiations such as fast neutrons, alpha particles, and heavy charged ions. As compared with many chemical agents, ionizing radiation is not a potent inducer of transformation. Polycyclic hydrocarbons, for example, can induce much higher frequencies of transformation at doses which produce very little cell killing.

Figure 14.3. Dose-response curves for the induction of neoplastic transformation in mouse cells by x-irradiation.

Figure 14.3

Dose-response curves for the induction of neoplastic transformation in mouse cells by x-irradiation. The upper curve is for BALB/3T3 cells and the bottom curve for C3H/10T 1/2 cells.

Modifying Factors

Incubation of cells with various agents during the 4- to 6-week postirradiation expression period for transformation can markedly modify the ultimate yield of transformed cells.22 For example, the phorbol ester compound 12-0-tetradecanoyl-phorbol-13-acetate (TPA) acts as a potent promoter of x-ray transformation, if applied repeatedly, beginning either immediately after irradiation or several weeks later. Indeed, these in vitro findings offered the first evidence that the phenomenon of tumor promotion was a general one and not simply limited to mouse skin.

A number of different classes of agents applied by a similar experimental protocol can suppress transformation.23 These include selenium, retinoids, carotenoids, and ascorbic acid. Of particular interest are protease inhibitors24 and the thiol radioprotective agents,25, 26 which have also shown promise as chemopreventive agents in vivo. Transformation can also be modulated by certain hormones, growth factors, and anti-inflammatory agents.23

It has thus become evident that a number of noncarcinogenic secondary factors can markedly modulate the frequency of radiation-induced transformation. As transformation can be markedly enhanced, suppressed, or completely inhibited, such factors may become the controlling ones in the overall process of transformation of cells exposed to radiation. In most cases, the effects of such agents in vitro have been predictive of those observed in experimental animal systems. It therefore seems likely that they may be of similar importance in human radiation carcinogenesis, though very few epidemiologic data to support this contention are as yet available.

Radiation-Induced Genomic Instability

In studies of the kinetics of radiation transformation in vitro, it was observed that transformation appeared to involve two distinct events.27, 28 The first is a frequent event which involves a large fraction of the irradiated cell population and enhances the probability of the occurrence of the second event. The second is a rare event occurring at a frequency of about 10-6 and involves the actual transformation of one or more of the progeny of the original irradiated cells after many rounds of cell division. This second step occurs with a constant frequency per cell per generation and has the characteristics of a mutagenic event.28 Evidence from certain experimental animal systems also suggests that the initiating event may indeed be a frequent one,22 in contradistinction to classic theories of carcinogenesis in which the initiating event is thought to be rare and likely mutagenic in nature. These findings have led to the hypothesis that radiation may induce a type of genomic instability in cells that enhances the probability of the occurrence of malignant transformation or other genetic events in progeny cells after many generations of replication. This phenomenon is shown schematically in Fig. 14.4.

Figure 14.4. Schematic representation of radiation-induced genomic instability (Panels C and D).

Figure 14.4

Schematic representation of radiation-induced genomic instability (Panels C and D). Open circles represent normal wild-type cells, while closed circles represent mutated cells. Panel B is an example of a cell directly mutated by radiation exposure; the (more...)

This hypothesis has now been confirmed in a number of different experimental systems for end points such as mutagenesis, chromosomal aberrations, and delayed cell death.29, 30 Approximately 10% of clonal populations derived from single cells surviving radiation exposure show a persistent elevation of the rate of production of new mutations.31, 32 This increase in mutation rate lasts for 30 generations or more post irradiation; the molecular spectrum of these late arising mutants resembles that of spontaneously arising mutants in that the majority are point mutations.32, 33 In parallel experiments, an enhanced frequency of minisatellite mutations was observed in irradiated cells selected for mutations at the TK locus,34 further suggesting that a subpopulation of genetically unstable cells may arise in irradiated populations.

A higher frequency of nonclonal chromosomal aberrations was first observed in clonal descendents of mouse hematopoietic stem cells 12 to 14 generations after exposure to alpha radiation.35 Persistent chromosomal instability following irradiation has since been shown to occur in a number of other cellular systems.36– 39 Transmission of such chromosomal instability has also been demonstrated in vivo;40, 41 susceptibility to radiation-induced chromosomal instability in mice differed significantly among different strains.42, 43 Finally, a persistently increased rate of cell death has been shown to occur in cell populations many generations after radiation exposure.44, 45 Recent evidence suggests that DNA is at least one of the critical targets in the initiation of such genomic instability,46 and that oxidative stress consequent to enhanced, p53- independent apoptosis may contribute to the perpetuation of the instability phenotype in these populations.47

It is thus well established that radiation can induce a type of instability in cells that can enhance the probability of the occurrence of multiple genetic events in surviving cell populations, sometimes after many generations of replication. However, the precise mechanisms associated with this phenomenon, including how it is initiated and maintained remain to be elucidated. Various tightly regulated cellular processes may be disrupted by radiation, leading to a chaotic state that perturbs the normal regulatory and signaling pathways, thus disrupting cellular homeostasis, a state from which the cell never completely recovers.46 Though the importance of such induced instability to the early events in radiation carcinogenesis in vivo remains unknown, it is tempting to speculate that the various factors known to modulate malignant transformation in vitro may act on this process. Interestingly, this concept is consistent with the emerging findings in human populations which suggest that some types of radiation-induced cancer may follow a relative risk model (see below); that is, a given dose of radiation increases the rate of occurrence of cancer at all follow-up times rather than inducing a specific cohort of new tumors.

Bystander Effects in Irradiated Cell Populations

It has long been thought that the cell nucleus is the target for the important biologic effects of radiation; these effects occur in the irradiated cell as a direct result of DNA damage that has not been correctly restored by enzymatic repair processes. Such a direct mutational event in a critical gene has been hypothesized to represent the first step in radiation carcinogenesis. However, recent evidence has shown that targeted cytoplasmic radiation is significantly mutagenic.48 Moreover, evidence is accumulating that damage signals may be transmitted from irradiated to nonirradiated cells in the population, leading to the occurrence of biologic effects in cells that received no direct radiation exposure.49 This phenomenon has been termed the “bystander” effect of radiation; it could be of considerable importance in the carcinogenic effects of very low doses of densely ionizing radiation such as alpha particles released by radon. Only a small fraction of a person’s bronchial epithelial cells, the presumed target for lung cancer, will actually be hit by an alpha particle from residential radon exposure during an exposed person’s lifetime.

The experimental model used to study this effect has generally involved the exposure of monolayer cultures of cells to very low fluences of alpha particles, fluences whereby a very small fraction of the cell population will actually be hit by a particle. In the initial study, an enhanced frequency of sister chromatid exchanges (SCE) was observed in 30 to 50% of cells exposed to fluences by which only 1/1,000 to 1/100 cells were traversed by an alpha particle.50 This finding was later confirmed,51 and evidence presented that it involves the secretion of cytokines or other factors by irradiated cells that leads to an upregulation of oxidative metabolism in bystander cells.52, 53 There is also evidence for cytotoxic effects in bystander cells54 that may be related to the release of a factor(s) into the medium, including reactive oxygen species.55, 56 These findings are reminiscent of the reports that clastogenic activity can be isolated from the plasma of radiation-exposed people.57 Recently, evidence has been presented that gene mutations can be induced in bystander cells in populations exposed to very low levels of alpha radiation,58 a finding of potential importance in estimating risks of residential radon exposure. Finally, preliminary data indicate that chromosomal instability may be transmitted to the clonal descendants of nonirradiated bystander cells following alpha irradiation of murine bone marrow.59

It has also been shown that changes in gene expression occur in bystander cells;49 the expression levels of p53, p21, cdc2, cyclin B1, and RAD51 were significantly modulated in nonirradiated cells in confluent human diploid cell populations exposed to very low fluences of alpha particles, as determined by Western blotting and in situ immunofluorescence techniques. This phenomenon involves cell-to-cell communication via gap junctions.49 These results suggest that similar signaling pathways are induced in bystander cells that receive no direct radiation exposure as occur in irradiated cells, and that biologic effects in cell populations may not be restricted to the response of individual cells to the DNA damage they receive. It furthermore provides evidence for the involvement of the p53 damage response pathway in this phenomenon.

Molecular Mechanisms

DNA Damage and Genetic Changes

DNA damage appears to be central to the initiation phase of carcinogenesis induced by ionizing or ultraviolet light radiation, as well as by many chemical carcinogens. The cellular enzyme protein kinase C (PKC) plays a critical role in growth control and appears to be involved in the promotional phase of radiation carcinogenesis.60 PKC, activated by phorbol ester tumor promoters such as TPA, can produce a cascade of events resulting in alterations in gene expression, membrane function and ultimately cellular differentiation and proliferation. The role of these factors is described in more detail in Chapters 24 of this text. In addition, radiation can directly induce changes in gene expression via transcriptional or post-transcriptional mechanisms.8 Given the complex multistage nature of carcinogenesis, it is reasonable to speculate that clonal evolution toward neoplasia involves a sequence of changes in gene expression driven by both genetic and epigenetic changes.

From studies of radiation-induced carcinogenesis in human populations and experimental systems, it appears that radiation acts primarily as an initiating agent by its ability to damage DNA. Radiation produces both specific base damage and DNA strand breaks, and mammalian cells possess efficient enzymatic mechanisms for repairing these types of damage. Although it has long been assumed that unrejoined double-strand breaks are the critical DNA lesions responsible for cell killing by radiation, it has now become evident that incorrectly rejoined DNA double-strand breaks are important mutagenic and carcinogenic lesions.61 This DNA misrepair can lead to single base alterations as well as large-scale genetic changes, including chromosomal deletions and rearrangements, particularly when more than one double-strand break is involved. DNA structural analyses of radiation-induced mutants at specific gene loci in human cells indicate that most mutations arise as a result of such large-scale genetic and chromosomal changes.14 The p53 tumor suppressor gene appears to be involved both in sensing the DNA damage that leads to these mutational events as well as in facilitating its repair.62

It is now well established that certain chromosomal rearrangements, including translocations and deletions, are associated with a wide variety of human cancers. Although no consistent nonrandom chromosomal changes have as yet been associated with radiation carcinogenesis in vivo or in vitro, evidence has been presented implicating specific chromosomal rearrangements in preleukemic clones in ataxia telangiectasia patients and in two types of radiation-induced murine leukemia.20 Furthermore, the observation that certain radiation-induced cancers, including some types of sarcomas and leukemia, are specifically those in which a high frequency of deletions is observed has led to the hypothesis that radiation-induced cancers are likely to involve loss of heterozygosity of tumor suppressor genes.18


The involvement of various oncogenes in experimental and human carcinogenesis is well established. The role of specific oncogene activation in radiation-induced cancer is less clear.20, 63 Activation of ras oncogenes occurs, though in relatively low frequencies, in mouse thymic lymphomas induced by radiation,64 and a specific codon 146 ras mutation has been described in a small fraction of neutron-induced thymic lymphomas.65 Activation of c-Ki-ras as well as amplification of c-myc has been reported in some radiation-induced rat skin tumors,66 but not in mouse skin tumors.63 Amplification and rearrangement of c-myc has been reported in a small fraction (6–30%) of radiation-induced murine osteosarcomas.67 However, these scattered early findings have not been proven to form a consistent pattern of oncogene activation in radiation carcinogenesis. There is some evidence to suggest that radiation may induce papillary thyroid carcinomas in children as a result of activation of the RET oncogene,68, 69 and a possible relationship between murine radiation leukemogenesis and a specific chromosome 2 deletion has been described.70

If myc and ras oncogenes play a significant role in radiation carcinogenesis, activation or amplification of these genes should be found in vitro as well as in vivo. Although evidence of dominant transforming activity has been found in cells transformed by radiation in vitro,71 this activity has not been associated with a number of known oncogenes.71– 73 Specifically, no consistent evidence has been found for activation or overexpression of ras genes. Though increased expression (but no rearrangement) of c-myc has been reported in some transformed cells, this appears to be a late effect occurring during the development of the transformed phenotype after the initial transforming event.72 These findings along with those of in vivo studies have led to the conclusion that distinctive, as yet unidentified transforming genes may be involved in radiation carcinogenesis.

Finally, it is not clear from such studies whether oncogene activation arose as a consequence of a direct interaction of radiation with cellular DNA, or from a complex series of events initially triggered by DNA damage. The activation of ras oncogenes by chemical carcinogens may be either an early or a late event. In one study in which the timing of oncogene activation was studied during radiation transformation, it appeared to occur as a late event.71 As discussed above, mutations arising as a result of exposure to ionizing radiation usually involve large-scale DNA structural changes and rearrangements. As activation of proto-oncogenes such as ras usually occurs by point mutations, it seems reasonable to expect that their activation may not be an important initiating event in radiation transformation and carcinogenesis. Although the whole question of the association of oncogenes with radiation carcinogenesis needs further investigation, it is clear that the pattern of oncogene activation differs significantly for transformation and carcinogenesis induced by radiation as compared with chemical carcinogens.

Tumor Suppressor Genes

The characteristics of tumor suppressor genes and evidence for their potential importance in human carcinogenesis are also described in this book. It has been proposed that most radiation-induced cancers may be a result of mutations in tumor suppressor genes, though there are few specific examples to support this hypothesis.18 Much interest has centered about the p53 gene as it appears to play an important role in cell-cycle control, radiosensitivity, the development of genetic instability leading to cell transformation, and perhaps in the response of human tumors to radiation or chemotherapy. p53 mutations have been found in a wide spectrum of human cancers74 and in mouse skin tumors induced by ionizing radiation.75 Mutations of p53 have also been associated with lung cancer induced in underground miners by alpha radiation.76 Some strains of knockout mice, either hemizygous and homozygous for the p53 gene, are highly susceptible to radiation-induced tumors.77 However, there is increasing evidence that p53 mutations may be a late event in the development of tumors,78 and loss of heterozygosity for p53 mutation in knockout mice may also be a secondary event.79

When normal human diploid fibroblasts are exposed to radiation, a significant fraction of the population remains irreversibly arrested in the G1 phase of the cell cycle entering a senescent-like state.80 This arrest is dependent on wild-type p53 protein expression owing to activation of its downstream effector p21waf1,8, 81 and it is thought to be an alternative to apoptosis as a mechanism for the elimination of heavily damaged cells from the surviving population. No radiation-induced G1 arrest occurs in cells that lack normal p53 function. C-Abl kinase may also contribute to the G1 arrest by a p53-dependent, p21-independent mechanism;82 the ATM gene is also involved in this pathway.83, 84 The activation of the p53/p21 pathway by radiation damage in some human tumor cells also suppresses the progression of G1 cells into the DNA synthetic (S) phase of the cell cycle, as well as enhancing apoptotic cell death.85, 86 It has been hypothesized that the absence of a G1 arrest is responsible for the genetic instability that occurs in irradiated cells lacking normal p53 function; cells with extensive genetic damage will progress through the cell cycle and continue proliferation rather than becoming arrested in G1 and undergoing apoptotic cell death or becoming senescent.87 This hypothesis, however, remains controversial;88 the G1 arrest appears to be only one aspect of a complex cellular response to DNA damage.

Another area of interest has been the role of p53 in the control of cellular radiosensitivity. The absence of normal p53 function is associated with enhanced resistance of human diploid fibroblasts to radiation-induced reproductive failure.8, 89 A similar effect has been described in hematopoietic cell lineages in transgenic mice.90 For cell types that readily undergo apoptosis, such as those of hematopoietic origin, the lack of an apoptotic response in p53- deficient cells renders them more resistant to radiation. The role of p53 status in the radiosensitivity of cells derived from human solid tumors, however, remains unclear91– 93 and may depend upon tumor type. It has thus been proposed that p53 status may be a determinant in the therapeutic responsiveness of certain types of tumors.94, 95 BRCA2 mutant tumor cells also appear to be highly sensitive to both radiation and drugs that induce DNA double-strand breaks.96

RB is a tumor suppressor gene that is associated with retinoblastoma, a malignant eye tumor of children. This disorder exists in both sporadic and hereditary forms. Mutations in the RB gene have in addition been associated with several other types of tumors, especially osteosarcomas and soft tissue sarcomas, as well as small cell lung cancer and breast cancer.97 Interestingly, patients with the hereditary type of retinoblastoma appear to be at an unusually high risk for the development of radiation-induced secondary tumors, primarily osteogenic sarcomas occurring in the treatment field.98 The fact that activation of a tumor suppressor gene may result from large-scale genetic changes, such as deletions, genomic rearrangements, and recombinational events, suggests that tumors which arise as a result of the loss of suppressor gene activity may be particularly susceptible to induction by radiation. Although this is an intriguing hypothesis, there are at present insufficient data to establish suppressor gene inactivation as a general mechanism in radiation carcinogenesis. A high frequency of p53 mutations, for example, occurs in osteosarcomas, either within or distal to the irradiation field in retinoblastoma patients.

Experimental Radiation-Induced Carcinogenesis

General Characteristics of Radiation Carcinogenesis

Ionizing radiation has been called a “universal carcinogen” in that it will induce cancer in most tissues of most species at all ages, including the fetus. It is one of the few definitely established carcinogens in human beings, and perhaps the only one for which firm dose-response data in human populations are available. It is, however, a relatively weak carcinogen and mutagen when compared with certain chemical agents. The cancers induced by radiation are of the same histologic types as occur naturally, but the distribution of types may differ. For example, a higher percentage of small cell carcinomas of the lung occur as a result of exposure to alpha radiation in uranium miners; radiation generally induces follicular and papillary carcinomas of the thyroid rather than anaplastic and medullary carcinomas; and chronic lymphocytic leukemia is apparently not induced by radiation, whereas other common types of leukemia are. There is a distinct latent period between exposure to radiation and the clinical appearance of a tumor.

Dose-Response Relationships

It has been generally accepted that radiation carcinogenesis is a stochastic process. That is, the probability of the occurrence of the effect increases with dose with no threshold, but the severity of the effect is not influenced by dose. This is in contradistinction to a nonstochastic or deterministic effect for which both the probability and the severity of the effect vary with dose. There is no clear experimental evidence to suggest that the grade of malignancy, including its invasive or metastatic properties, is a function of dose; radiation-induced cancer appears to be an all-or-none effect. Stochastic effects are those that may arise from damage to a few cells or even a single cell. If this is the case, any dose, no matter how small, carries with it the finite probability of producing the effect. Studies of radiation-induced carcinogenesis in experimental animals and human populations have been designed to test this hypothesis, as most environmental exposures are in the low dose range. Unfortunately, however, it is very difficult to obtain statistically significant data in either human or animal studies at doses below 50 cGy of low LET radiation.

Many earlier studies of the effects of radiation in small animals involved its life-shortening properties. Although this effect was originally ascribed to “radiation-induced aging” in which the natural causes of death were accelerated by radiation, a critical examination of this phenomenon by use of techniques, such as serial sacrifice experiments and life table analyses, has shown that practically all of the life-shortening effect of radiation in experimental animals can be accounted for by the induction of cancer, except perhaps in the high, sublethal dose range.99, 100 Thus, the dose-response relationship for life-shortening in animals should reflect that for cancer deaths from all types of radiation-induced tumors in that species. Such a dose-response curve is shown in Fig. 14.5. A generally linear response has been observed for life-shortening in a number of different studies.

Figure 14.5. Life-shortening in mice as a function of the dose of ionizing radiation.

Figure 14.5

Life-shortening in mice as a function of the dose of ionizing radiation. The shortening of lifespan is ascribed to early death owing to induced cancers. From Lindop and Rotblat.

The dose-response relationships for the induction of cancers in specific tissues of small animals vary with site, with sex, and with species.101– 103 For low LET radiation, the frequency of induced cancers generally rises with dose in the range of 0 to 300 cGy. In some cases, tumor incidence levels off at higher doses and may even decline. This phenomenon is thought to reflect cell killing. The carcinogenic effect of low LET radiation in rodents is usually reduced with protraction of exposure. In the dose range up to 200 to 300 cGy, the dose-response curves for individual tumor types vary but generally assume a linear-quadratic to near-linear relationship.

For high LET radiation, the rise in cancer incidence with dose is much steeper. The dose-response curves are approximately linear within the range of 0 to 20 cGy, although in some cases they bend over, reaching a plateau at higher doses.101, 104 In contradistinction to low LET radiation, significant increases in cancer and life-shortening can be observed after doses as low as 10 cGy of neutrons, alpha particles, or heavy ions.101, 104, 105 RBE values in the range of 3 to15 have been estimated for the carcinogenic effects of these radiations at low doses. There is usually no dose-rate effect for high LET radiation exposure. However, an outstanding example is the induction of mouse mammary tumors by low doses of fast neutrons, in which protraction of exposure appears to increase the carcinogenic effect by a factor of 2 to 3 at doses of 2.5 to 10 cGy.104

Modifying Factors

As in the case of neoplastic transformation, radiation-induced carcinogenesis in experimental animals can also be modulated by noncarcinogenic secondary factors. Post-irradiation treatment with the tumor promoter TPA is known to enhance ultraviolet light-induced mouse skin cancer; a similar phenomenon has been shown for the induction of malignant squamous cell carcinoma of the skin of mice by ionizing radiation.63 As an illustration of the possible effects of seemingly innocuous secondary factors, eight weekly intratracheal instillations of 0.2 mL of isotonic saline given to hamsters 4 months after exposure to a relatively low dose of alpha radiation led to a 10-fold enhancement in the induction of lung cancer as compared with that occurring in animals receiving radiation alone.22 It appeared that the saline instillations, which were noncarcinogenic in themselves, had induced a transient round of cell proliferation among the target cells in the lungs of these animals, facilitating expression of the initial radiation-induced damage.

The induction of carcinogenesis in experimental animals can also be suppressed by treatment with certain agents that are known to inhibit radiation-induced transformation in vitro. These include, notably, treatment with protease inhibitors, which have been shown to suppress the induction of cancer in several different tumor systems.106 Incubation with thiol radioprotective compounds during irradiation has also been shown to protect against radiation-induced carcinogenesis and subsequent life-shortening.107 In both of these cases, clinical trials are currently underway. It is well known that the hormonal environment is important in certain radiation-induced rodent cancers, particularly ovarian and mammary tumors. These and other observations again emphasize the importance of noncarcinogenic secondary factors in the induction and expression of experimental carcinogenesis induced by radiation. However, the extent to which such factors are important in radiation-induced cancer in human populations is not clear.

Genetic Susceptibility to Radiation-Induced Cancer

The discovery of a number of specific genes associated with single or multiple cancer types has stimulated renewed interest in the potential role of genetic susceptibility in the carcinogenic effects of radiation.108, 109 Should a fraction of the population be genetically predisposed to radiation-induced cancer, this fact could be of considerable importance in the development of protection standards. Clearly, there are marked differences in the susceptibility to radiation-induced cancer among different inbred strains of mice; in general, this susceptibility correlates with the spontaneous incidence of the particular tumor.

While there is little evidence at present to suggest that such genetic factors are involved in most human cancers, they do appear to play a role in certain rare disorders which may serve as models for radiation-genetic interactions. For example, patients with hereditary retinoblastoma whose somatic cells are heterozygous for the RB gene are at markedly increased risk for the development of radiation-induced bone sarcomas,98 whereas patients with the nevoid basal cell carcinoma syndrome are at high risk for the development of basal cell cancers in irradiated areas.109 Radiation has also been associated with an enhanced incidence of early-onset breast cancer, although the hereditary nature of radiation-induced breast cancer and its relation to the breast cancer susceptibility genes BRCA1 and BRCA2 remain to be clarified. Interestingly, transgenic mice heterozygous for either the p5377 or ATM110 tumor suppressor genes also show an increased sensitivity to radiation-induced cancer; ATM and p53 heterozygosity is associated, respectively, with the human cancer–prone disorders Li-Fraumeni syndrome and ataxia telangiectasia. It is not clear the extent to which the more common, low penetrance susceptibility genes may play a role in radiationinduced cancer.

Human Epidemiologic Studies

There is now a large body of data on radiation-induced cancer derived from epidemiologic studies in irradiated human populations, and it is primarily on the basis of these data that risk estimates are derived. These data are reviewed and analyzed in detail in the latest reports from the National Research Council BEIR V Committee11 and the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR 1994).111 They are derived primarily from two sources: (1) the long-term follow-up of survivors of the nuclear bombings of Hiroshima and Nagasaki112 and (2) populations exposed to medical x-rays.113 Information is also available from certain occupational exposures, particularly from individuals with pulmonary and skeletal exposure to alpha radiation. The results of these studies have yielded significant dose-response data for the induction of cancer in at least five tissue sites. Such dose-response data are extremely important in ascribing radiation as the causal agent for the increased incidence of cancer, as well as for estimating the risks associated with a given exposure. Unfortunately, however, the epidemiologic studies yielding useful dose-response data generally involve relatively high-dose exposures ( > 10 cGy). Thus, risk estimates in the low-dose range must be derived from an extrapolation from the high-dose data. The shape of the dose-response relationship becomes of critical importance in making such extrapolations.

The observed dose-response curves from the human epidemiologic studies appear to be either linear or linear-quadratic in form (that is, a linear component at low doses with a quadratic component at higher doses). A linear curve implies a constant risk per cGy at all doses, whereas the linear-quadratic model implies a smaller risk per cGy in the low-dose range. The assumption of a linear model simplifies the extrapolation from high to low doses and the corresponding estimation of risks. Furthermore, it is a conservative technique; that is, if anything, it would overestimate rather than underestimate the potential risk. There is no evidence for a proportionally greater effect at low doses.

A final parameter of importance in determining the hazards of a given dose of radiation is the choice of risk models. For many years, risks were estimated on the basis of an absolute risk model. This model assumed that a specific number of excess cancers was induced by a given radiation dose. Radiation-induced cancers occurred in addition to the natural incidence. Thus, the increased risk could be expressed as the number of excess cancer cases (or cancer deaths) per 106 exposed people per year per cGy (the rate per year) or as the total number of excess cancers per 106 exposed people per cGy (the total risk or yield of cancers to be expected from a given radiation dose). The absolute risk model generally assumes a linear dose-response relationship, although with certain corrections it can be applied to a linear-quadratic relationship. Because the radiation exposure in Hiroshima included a small fraction of neutrons, the doses in the atom bomb–survivor studies are expressed in Sieverts (Sv) rather than Gy, a term that takes into account the RBE of neutrons. For our purposes, however, we can consider that 1 Sv equals approximately 1 Gy.

An analysis of the recent data from the atom bomb survivors suggests that some types of radiation-induced cancer more likely follow a relative-risk model.11, 112 This is also true for several different tumor types in mice.99 The relative risk model implies that radiation increases the natural incidence of cancer at all ages by a dose-dependent factor. As the excess cancer risk is proportional to the natural incidence, radiation-induced cancers would occur primarily at the times when natural tumors arose, independent of the age at irradiation. Thus, the largest cohort of radiation-induced cancers would occur in older individuals. The relative risk model appears to fit the epidemiologic data for several solid tumors, although it does not appear to be valid for leukemia or bone and lung cancers.


At one time, leukemia was thought to be the major radiation-induced cancer to arise from whole-body exposure. We now know the two reasons for this assumption: (1) the spontaneous occurrence of leukemia is low, and thus radiation-induced cases are more readily recognizable; and (2) the latent period in human beings is very short relative to other types of cancer, thus leukemias are recognized earlier. Excess leukemias begin appearing within 2 years after acute radiation exposure, reach a peak incidence within 10 years, and then fall off steadily. This is in contradistinction to other cancers for which the minimum latent period is generally 10 to 15 years, and the rate of appearance of new radiation-induced tumors increases at least up to 40 years. The major sources of data for the induction of leukemia are from the 86,500 members of the life-span study of the atom bomb survivors from whom DS86 (1986) dose estimates are available and from a study of approximately 14,000 patients in the United Kingdom treated with radiation for ankylosing spondylitis of the spine.

The dose-response relationship for the induction of leukemia in the atom bomb survivors, based on the DS86 dosimetry measurements of organ-absorbed dose, is shown in Fig. 14.6A. The data are best described by a linear-quadratic dose-response model in the dose range of 0 to 3 Sv. On the basis of the most recently available data,112 the relative risk at 1 Sv (approximately 100 cGy) is 5.62, and the absolute risk is estimated to be 2.61 excess cancer deaths/104 persons exposed/yr/Sv. This latter figure is approximately four-fold higher than that estimated from the data for the British ankylosing spondilitis patients. This may be ascribed to the younger age of the atom bomb survivors at the time of irradiation and the fact they received a single acute whole-body exposure.11 Children appear to be twice as sensitive as adults to the leukemogenic effects of radiation, whereas the unborn child may be as much as 10 times more sensitive following in utero irradiation.114, 115

Figure 14.6. Dose-response curves for the induction of cancer in human populations receiving uniform whole-body radiation exposure, derived from epidemiologic data from the atom bomb survivors of Hiroshima and Nagasaki.

Figure 14.6

Dose-response curves for the induction of cancer in human populations receiving uniform whole-body radiation exposure, derived from epidemiologic data from the atom bomb survivors of Hiroshima and Nagasaki. A. Leukemia. There is a statistically significant (more...)

Radiation-induced leukemia in human populations differs in several characteristics from solid tumors. These include the unusually short latent period, high relative risk (Table 14.1), and the fact that the epidemiologic data best fit a linear-quadratic dose-response relationship. This may be related to the nature of the hematopoietic system, which contains less stroma than do most tissues. Therefore, there may be fewer constraints on cell proliferation, in essence allowing a few transformed cells to grow rapidly and be detected earlier as a clinical cancer.

Table 14.1. Summary Measures of Radiation Dose-Response for Mortality at Statistically Significant Tissue Sites in Atom Bomb Survivors of Hiroshima and Nagasaki*.

Table 14.1

Summary Measures of Radiation Dose-Response for Mortality at Statistically Significant Tissue Sites in Atom Bomb Survivors of Hiroshima and Nagasaki*.

Other Tumors

The dose-response relationship for all cancers except leukemia is shown in Fig. 14.6B; the data are best described by a linear model in the dose range of 0 to 3 Sv. The various risk estimates for all types of cancer in which mortality was significantly increased among the atom bomb survivors are shown in Table 14.1. These data are based upon approximately 86,500 subjects, of which 50,000 were exposed to greater than 0.005 Sv (0.5 cGy). This group includes 249 leukemia deaths, of which 87 are ascribed to radiation exposure, and about 7,800 other cancer deaths, of which 334 are ascribed to radiation exposure.112 Approximately 9% of all cancer deaths in the population exposed to > 0.005 Sv are associated with radiation, though the overall mortality rate is not significantly increased. As can be seen in Table 14.1, the relative risk at 1 Sv is considerably lower for all other cancer types than it is for leukemia. The excess of cancer deaths/104 persons exposed/yr/Sv is approximately 13 for all cancers including leukemia, ranging from 0.17 to 2.11 in individual tissues.

In addition to breast and lung cancers and leukemia, dose-response data from human epidemiologic studies are available for two other sites not shown in the atom bomb survivor data in Table 14.1; these are the thyroid and bone cancers. The incidence of bone cancer was not significantly elevated in the atom bomb–survivor studies; the relative and absolute risks are low for the induction of this type of cancer by low LET radiation. The dose-response data have come from studies of persons with elevated body burdens of alpha-emitting radium isotopes as a result of occupational or medical exposures.

Thyroid cancer, on the other hand, is very efficiently induced by low LET radiation. Dose-response relationships are derived from populations receiving therapeutic irradiation, either for an enlarged thymus gland or Tinea capitis. Relative risk estimates for the development of thyroid cancer have ranged from 7 to 69 among various age groups, ethnic origins and different studies.11 However, cancer death rates are not significantly elevated in these populations, since radiation apparently induces only papillary and follicular type tumors, most of which are curable, and those that are not tend to progress slowly. Studies of populations exposed as a consequence of the Chernobyl reactor accident indicate an increase in thyroid cancers (but no other malignancy) in children, presumably from radioactive iodine.116, 117 However, there are many confounding factors in this study, which make the findings difficult to interpret.

In addition to the results from the atom bomb survivors, dose-response data are available for breast cancer from several medically exposed populations.113 The results of these studies are generally consistent in terms of risk estimates. Taken as a whole, however, several other interesting findings have arisen. Radiation-induced breast cancers are similar in histopathologic types and age distribution to those arising spontaneously. Women under 20 years of age at exposure are at a higher relative risk than adults, similar to the observations for leukemia. As in the case of thyroid cancer, the development of breast cancer is profoundly dependent on hormonal status. Finally, protraction of exposure does not appear to reduce the risk of radiation-induced breast cancer.

Additional epidemiologic studies are also available for the induction of lung cancer.11 Of particular interest among the underground uranium workers in the Colorado plateau has been an apparent multiplicative interaction with cigarette smoking. This observation is consistent with certain experimental findings on alpha radiation–induced lung cancer. However, statistically significant evidence for a more than additive effect between smoking and low LET radiation on lung cancer has not been observed in other epidemiologic studies. This important question needs further investigation.

Radiation-Induced Secondary Tumors

An increase in secondary tumors in the treatment field has now been observed in patients treated for several different types of cancer by radiation therapy, often in conjunction with chemotherapy. In some cases the incidence of radiation-associated secondary tumors appears to be proportional to dose at the treatment portal, though some epidemiologic data suggest that for leukemia in particular the tumor incidence may decline at high doses, owing to killing of the target cells.113 The extent to which genetic factors may play a general role in susceptibility to treatment-induced secondary tumors in cancer patients is unclear. Radiation alone may not be a very potent inducer of secondary tumors. This prediction arises from the localized nature of the exposure during clinical radiotherapy, in which the dose to normal tissues is minimized, and from the fact that ionizing radiation tends to be cytotoxic rather than mutagenic. The high radiation doses employed may thus kill potentially transformed cells in the treatment field. An exception may be Hodgkin’s disease, in which lower radiation doses are delivered to a relatively large volume of tissue.

Low-Dose Exposures

There have been a number of epidemiologic studies over the past two decades that purport to show a carcinogenic effect of environmental radiation exposures in the dose range below 10 cGy. The populations involved are varied but include military personnel exposed during nuclear bomb testing, workers in various nuclear and weapons facilities, and members of the general population living near nuclear facilities or exposed to fallout.

There have been several reports analyzing various of these low-dose epidemiologic studies.118, 119 On the basis of the relative and absolute risk estimates shown in Table 14.1, a significant increase in radiation-associated cancer incidence in populations of these sizes exposed to doses in the range of 10 cGy or less would imply a markedly enhanced sensitivity at low doses. That is, the dose-response curve should be concave upward with the excess cancer incidence rising rapidly at very low doses. There are no experimental data to support such a phenomenon; indeed, a careful analysis of nearly all of these low-dose studies indicates no significant increase in the incidence of all cancers or of cancers at specific sites. Recent analyses of a large number of radiation workers from the United Kingdom120 and Canada121 indicate that the risk estimates for leukemia and all cancers were consistent with an extrapolation from the atom bomb–survivor data, providing no evidence for an unexpected increase in sensitivity at low doses so as to suggest that the current radiation protection standards might be appreciably in error.

There has also been considerable concern about the risk of lung cancer from exposure to naturally occurring radon in the air of homes and the workplaces. The results of several recent epidemiologic studies, however, have been conflicting. For example, a clear association between radon exposure and lung cancer was identified in studies in Sweden and the United Kingdom, while equally rigorous investigations in Canada, China, and Missouri found no evidence of excess risk. When a meta-analysis of eight case-control studies was carried out,122 a positive trend was found consistent with projections of the high-dose data from radon-exposed underground miners. Most radon-induced cancers are expected to occur in cigarette smokers. Overall, however, the carcinogenic risks of residential radon appear to be small,123 probably of the magnitude of that attributable to passive smoking.124

Because the carcinogenic effects of radiation are apparently so small at these low doses, it appears unlikely that they will ever be defined by epidemiologic studies alone. This will likely require a better understanding of the basic mechanisms of radiation carcinogenesis, including the role of factors such as bystander effects, induced genomic instability, and the adaptive response to protracted radiation exposure. In the meantime, risk estimations must be made by extrapolation from the epidemiologic studies at high doses ( > 10–50 cGy).

Risk Assessment

The lifetime excess cancer risk estimates following exposure to 1 cGy as determined by the BEIR V Committee11 are shown in Table 14.2. These estimates were derived from a composite of the epidemiologic data from the atom bomb survivors and various medical x-ray exposures. They were derived by use of the relative risk model, on the assumption of a linear-quadratic dose-response relationship for leukemia and a straight linear relationship for other tumors. In addition, characteristics such as the latent period, age at exposure, time after exposure, and interaction effects were taken into consideration.

Table 14.2. Lifetime Excess Cancer Risk Estimates for Whole-Body Radiation Exposure to 1.0 cGy.

Table 14.2

Lifetime Excess Cancer Risk Estimates for Whole-Body Radiation Exposure to 1.0 cGy.

The risk estimates shown in Table 14.2 are for the mean of all ages at exposure. For children under 20 years, excess cancer mortality per cGy is about 50% higher than the mean for all tumors, whereas it is much lower at ages over 65 years. The leukemia risk, on the other hand, rises quite steeply in middle and old age, where the risk is nearly four times that of young adults and twice that of children.11 The lifetime excess yield of death from all cancers including leukemia for acute radiation exposure as shown in Table 14.2 is approximately 800 per 106 exposed people per cGy; the UNSCEAR Committee111 estimates that the yield may be 20 to 40% higher. On an individual basis, this is approximately a 1:1,250 (0.8 × 10-3) effect per cGy. For example, a person receiving 10 cGy acute whole-body exposure would have a 0.8% chance of developing cancer as a result of this radiation exposure, whereas his chances of dying of cancer unrelated to radiation exposure are approximately 18%. This risk would be lower for protracted exposure (see Table 14.2). It should be emphasized, however, that these risks are for uniform whole-body irradiation. For localized radiation exposures, the risks will be much lower and related to the critical tissues, including the bone marrow included within the radiation field. For localized exposures, estimates are based on data such as those shown in Table 14.1 and the utilization of models developed for specific tissue sites as described by the BEIR Committee.11

It is often the perception of risk rather than the actual risk itself which is particularly important in the promotion and regulation of health and safety.125 For example, members of the League of Women Voters and a group of college students were asked to order their perception of the risk of fatality for 30 activities and technologies. Both placed nuclear power in first position ahead of smoking, ingestion of alcoholic beverages, and riding in motor vehicles. The risk experts ranked smoking and motor vehicle accidents first (there are about 50,000 motor vehicle deaths in the United States each year, at least 50% of them involving alcohol or drug use), whereas they ranked nuclear power 20th in the same range as the ingestion of food coloring and the use of home appliances.

It is thus of interest to compare the risk of death from various activities associated with everyday living.126, 127 Such a comparison is shown in Table 14.3. In general, it turns out that the risk from radiation exposure is relatively small compared with other risks associated with everyday living. Similarly, a comparison of occupational hazards shows that the risks to radiation workers are much lower than those associated with many other occupations. In this context, it is of interest to note the estimation that over 430,000 excess deaths each year are associated with cigarette smoking in the United States.126 On the assumption that 40% of the population smokes, such an excess death rate would be comparable with that resulting from approximately 350 cGy of uniform whole-body radiation exposure.

Table 14.3. Risk of Death from Various Activities*.

Table 14.3

Risk of Death from Various Activities*.

Of concern to the clinical oncologist, however, is the risk of inducing a secondary malignant tumor as a result of exposure to high doses of radiation often in conjunction with chemotherapy. This will, of course, depend upon the particular tissue sites included in the radiation field. One could then derive risk estimates on the basis of the type of information shown in Table 14.1. The information in Table 14.1, however, was derived from presumably normal people in the general population exposed to tens to hundreds rather than thousands of cGy. As discussed earlier, a number of factors might determine susceptibility to secondary tumors in cancer patients treated with high doses of radiation. One risk factor is the irradiation of large tissue volumes as in the treatment of disorders such as Hodgkins’ disease. Genetic factors would be another. It is well known, for example, that retinoblastoma patients are at very high risk for developing secondary tumors in the irradiated field. The extent to which genetic hypersusceptibility may be important in some of the more common cancers remains to be determined.

In most cases, it would seem that a benefit-risk estimation would be positive; that is, the benefit of treatment would outweigh the risk of developing secondary tumors. However, information concerning the relative carcinogenicity of various combinations of radiation and chemotherapeutic agents is now becoming available, and it appears that certain combinations may be more carcinogenic than others. Clearly, additional knowledge is needed concerning treatment regimens which might minimize their carcinogenic effects, and thus the risk of developing secondary treatment-induced tumors, while producing an optimal therapeutic gain.


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