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.

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

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. 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 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. The upper curve is for BALB/3T3 cells and the bottom curve for C3H/10T 1/2 cells.

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). 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.

Molecular Mechanisms

Experimental Radiation-Induced Carcinogenesis

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. 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

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.

Leukemia

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. 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*.

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.

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*.

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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