13
Summary and Research Needs

The research needs stated here relate to the committee’s primary task: “To develop the best possible risk estimate for exposure to low-dose, low-LET [linear energy transfer] radiation in human subjects.”

EVIDENCE FROM BIOLOGY

Molecular and Cellular Responses to Ionizing Radiation

This chapter discusses the biological effects of the ranges of radiation dose that are most relevant for the committee’s deliberations on the shapes of dose-response relationships. Considering the levels of background radiation, the maximal permissible levels of exposure of radiation workers now in effect, and the fact that much of the epidemiology of low-dose exposures includes people who in the past have received up to 500 mGy, the committee has focused on evaluating radiation effects in the low-dose range of <100 mGy, with emphasis on the lowest doses when relevant data are available. Effects that may occur as the radiation is delivered chronically over several months to a lifetime are thought to be most relevant.

At low doses, damage is caused by the passage of single particles that can produce multiple, locally damaged sites leading to DNA double-strand breaks (DSBs). DNA DSBs in the low-dose range can be quantified by a number of novel techniques, including immunofluorescence, comet assay, chromosome aberrations, translocation, premature chromosome condensation, and others. Some of these indicators of DSBs show linearity down to doses of 5 to 10 mGy.

In vitro data on the introduction of gene mutations by low-LET ionizing radiation are consistent with knowledge of DNA damage response mechanisms and imply a nonthreshold low-dose response for mutations involved in cancer development. Experiments that quantified DNA breakage, chromosomal aberrations, or gene mutations induced by low total doses or low doses per fraction suggest that the dose-response over the range of 20 to 100 mGy is linear. Limited data indicate that the dose-response for DNA breakage is linear down to 1 mGy, and biophysical arguments suggest that the response should be linear between zero and 5 mGy.

In vitro studies of gene mutation induction provide evidence for a dose and dose rate effectiveness factor (DDREF) in the range of 2–4. The DDREF has been used in past estimates of risk to adjust data obtained from acute exposures at Hiroshima and Nagasaki to the expected lower risk posed by chronic low-dose exposures that the general population might experience.

Research Need 1. Determination of the level of various molecular markers of DNA damage as a function of low-dose ionizing radiation

Currently identified molecular markers of DNA damage and other biomarkers that can be identified in the future should be used to quantify low levels of DNA damage and to identify the chemical nature and repair characteristics of the damage to the DNA molecule. These biomarkers have to be evaluated fully to understand their biological significance for radiation damage and repair and for radiation carcinogenesis.

Most studies suggest that the repair of ionizing radiation damage occurs through nonhomologous end joining and related pathways that are constitutive in nature, occur in excess, and are not induced to higher levels by low radiation doses.

Data from animal models of radiation tumorigenesis were evaluated with respect to the cellular mechanisms involved. For animal models of radiation carcinogenesis that are dependent on cell killing, there tend to be threshold-like dose-responses and high values of DDREF; therefore, less weight was placed on these data. Once cell-killing dependence is excluded, animal data are not inconsistent with a linear nonthreshold (LNT) dose response, and DDREF values are in the range 2–3 for solid cancers and somewhat higher for acute myeloid leukemia.



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13 Summary and Research Needs The research needs stated here relate to the committee’s linear. Limited data indicate that the dose-response for DNA primary task: “To develop the best possible risk estimate for breakage is linear down to 1 mGy, and biophysical argu- exposure to low-dose, low-LET [linear energy transfer] ra- ments suggest that the response should be linear between diation in human subjects.” zero and 5 mGy. In vitro studies of gene mutation induction provide evi- dence for a dose and dose rate effectiveness factor (DDREF) EVIDENCE FROM BIOLOGY in the range of 2–4. The DDREF has been used in past esti- mates of risk to adjust data obtained from acute exposures at Molecular and Cellular Responses to Ionizing Radiation Hiroshima and Nagasaki to the expected lower risk posed by This chapter discusses the biological effects of the ranges chronic low-dose exposures that the general population of radiation dose that are most relevant for the committee’s might experience. deliberations on the shapes of dose-response relationships. Considering the levels of background radiation, the maximal Research Need 1. Determination of the level of permissible levels of exposure of radiation workers now in various molecular markers of DNA damage as a func- effect, and the fact that much of the epidemiology of low- tion of low-dose ionizing radiation dose exposures includes people who in the past have received Currently identified molecular markers of DNA up to 500 mGy, the committee has focused on evaluating damage and other biomarkers that can be identified in radiation effects in the low-dose range of <100 mGy, with the future should be used to quantify low levels of emphasis on the lowest doses when relevant data are avail- DNA damage and to identify the chemical nature and able. Effects that may occur as the radiation is delivered repair characteristics of the damage to the DNA mol- chronically over several months to a lifetime are thought to ecule. These biomarkers have to be evaluated fully to be most relevant. understand their biological significance for radiation At low doses, damage is caused by the passage of single damage and repair and for radiation carcinogenesis. particles that can produce multiple, locally damaged sites leading to DNA double-strand breaks (DSBs). DNA DSBs Most studies suggest that the repair of ionizing radiation in the low-dose range can be quantified by a number of novel damage occurs through nonhomologous end joining and techniques, including immunofluorescence, comet assay, related pathways that are constitutive in nature, occur in excess, chromosome aberrations, translocation, premature chromo- and are not induced to higher levels by low radiation doses. some condensation, and others. Some of these indicators of Data from animal models of radiation tumorigenesis were DSBs show linearity down to doses of 5 to 10 mGy. evaluated with respect to the cellular mechanisms involved. In vitro data on the introduction of gene mutations by low- For animal models of radiation carcinogenesis that are de- LET ionizing radiation are consistent with knowledge of pendent on cell killing, there tend to be threshold-like dose- DNA damage response mechanisms and imply a non- responses and high values of DDREF; therefore, less weight threshold low-dose response for mutations involved in was placed on these data. Once cell-killing dependence is cancer development. Experiments that quantified DNA excluded, animal data are not inconsistent with a linear breakage, chromosomal aberrations, or gene mutations nonthreshold (LNT) dose response, and DDREF values are induced by low total doses or low doses per fraction suggest in the range 2–3 for solid cancers and somewhat higher for that the dose-response over the range of 20 to 100 mGy is acute myeloid leukemia. 313

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314 BEIR VII Research Need 2. Determination of DNA repair fidelity, greater than ~200 mGy generally give very little, if any, ad- especially as regards double- and multiple-strand aptation, and adaptation has not been reported for challenge breaks at low doses, and determination of whether doses of less than about 1000 mGy. To have relevance for repair capacity is independent of dose risk assessment, the adaptive response has to be demon- Repair capacity at low levels of damage must be strated for both priming and challenging doses of 1–50 mGy. investigated, especially in light of conflicting evidence Furthermore, the induction and magnitude of the adap- for stimulation of repair at low doses. In such studies tive response in human lymphocytes are highly variable, with the accuracy of DNA sequences rejoined by these path- much heterogeneity demonstrated among different individu- ways has to be determined, and the mechanisms of als. The adaptive response could not be induced when error-prone repair of radiation lesions must be eluci- noncycling lymphocytes were given the priming dose. Al- dated. Identification of critical genetic alterations that though inhibitor and electrophoretic studies suggest that al- can be characteristic of radiation exposure would be terations in messenger RNA transcription and protein syn- important. thesis are involved in the adaptive response in lymphocytes, no specific signal transduction or repair pathways have been identified. At this time, the assumption that any stimulating Consideration of Phenomena That Might Affect Risk effects from low doses of ionizing radiation will have a sig- Estimates for Carcinogenesis at Very Low Doses nificant effect in reducing long-term deleterious effects of A number of biological phenomena that could conceiv- radiation on humans is unwarranted. ably affect risk estimates at very low radiation doses have been reported. These phenomena include the existence of Bystander Effects radiation-sensitive human subpopulations, hormetic or adap- tive effects, bystander effects, low-dose hyperradiosensi- The bystander effect that results from irradiated cells’ re- tivity, and genomic instability. acting with nearby nonirradiated cells could influence dose- response relationships. Such an effect might come into play at low-LET doses below 1–5 mGy, where some cells of the Radiation-Sensitive Subpopulations body would not be irradiated. Current limitations of low- Epidemiologic, clinical, and experimental data provide LET bystander studies include the lack of demonstrated by- clear evidence that genetic factors can influence radiation stander effects below 50 mGy and uncertainties about cancer risk. Strongly expressing human mutations of this whether the effect occurs in vivo. Another complication is type are rare and are not expected to influence significantly that both beneficial and detrimental effects have been postu- the development of estimates of population-based, low-dose lated for bystander effects by different investigators. Until risks. They are, however, potentially important in the con- molecular mechanisms are elucidated, especially as they re- text of high-dose medical exposures. Evidence for the com- late to an intact organism, and until reproducible bystander plex interaction of weakly expressing genetic factors in can- effects are observed for low-dose low-LET radiation in the cer risk is growing, but current understanding is insufficient dose range of 1–5 mGy, where an average of less than 1 for a detailed consideration of the potential impact on popu- electron tracks traverse the nucleus, the assumption should lation risk. be made that bystander effects will not influence the shape of the low-dose, low-LET dose-response relationship. Adaptive Response Hyperradiosensitivity for Low Doses Adaptive responses have been well documented in bacte- In some cell lines, hyperradiosensitivity (HRS) has been ria, where exposures to radiation or chemicals induce subse- reported for cell lethality induced by low-LET radiation at quent resistance to these agents by inducing expression of doses less than 100–200 mGy. In this dose range, survival DNA damage repair genes. This induced expression of re- decreases to 85–90%, which is significantly lower that pro- pair genes does not occur to a significant extent in human jected from data obtained above 1–2 Gy. It is not known cells, although changes in signal transduction do take place. whether HRS for cell lethality would cause an increase in A type of apparent adaptive response, however, has been deleterious effects in surviving cells or would actually de- documented for the induction of chromosomal aberrations in crease deleterious effects by increased killing of damaged human lymphocytes stimulated to divide. cells. Until molecular mechanisms responsible for HRS that In most studies, a priming or adaptive dose of about may or may not play a role in carcinogenesis are understood, 10 mGy significantly reduces the frequency of chromosomal the extrapolation of data for HRS for cell lethality to the aberrations and mutations induced a few hours later by 1000– dose-response for carcinogenesis in the 0–100 mGy range is 3000 mGy. Similar effects are sometimes seen with other not warranted. end points. However, priming doses less than 5 mGy or

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SUMMARY AND RESEARCH NEEDS 315 Genomic Instability hormetic effects exist for radiation-induced carcino- genesis. During the last decade, evidence has accumulated that under certain experimental conditions, the progeny of cells Radiation-Induced Cancer: Mechanism, Quantitative surviving radiation appear to express new chromosomal ab- Experimental Studies, and the Role of Molecular Genetics errations and gene mutations over many postirradiation cell generations. This feature is termed radiation-induced persis- A critical conclusion on mechanisms of radiation tumori- tent genomic instability. Some inconsistencies were identi- genesis is that the data reviewed greatly strengthen the view fied in the data that describe the diverse manifestation of that there are intimate links between the dose-dependent in- induced genomic instability, and clear evidence of its gen- duction of DNA damage in cells, the appearance of gene or eral involvement in radiation-induced cancer is lacking. Al- chromosomal mutations through DNA damage misrepair, though developing data on the various phenomena classified and the development of cancer. Although less well estab- as genomic instability may eventually provide useful insights lished, the data available point toward a single-cell (mono- into the mechanisms of carcinogenesis, it is not possible to clonal) origin for induced tumors and suggest that low-dose predict whether induced genomic instability will influence radiation acts predominantly as a tumor-initiating agent. low-dose, low-LET response relationships. These data also provide some evidence on candidate, radia- tion-associated mutations in tumors. These mutations are Research Need 3. Evaluation of the relevance of predominantly loss-of-function DNA deletions, some of adaptation, low-dose hypersensitivity, bystander effects, which are represented as segmental loss of chromosomal and genomic instability for radiation carcinogenesis material (i.e., multigene deletions). Mechanistic data are needed to establish the rel- This form of tumorigenic mechanism is broadly consis- evance of these processes to low-dose radiation expo- tent with the more firmly established in vitro processes of sure (i.e., <100 mGy). Relevant end points should in- DNA damage response and mutagenesis considered in Chap- clude not only chromosomal aberrations and mutations ters 1 and 2. Thus, if as judged in Chapters 1 and 2, error- but also genomic instability and induction of cancer. prone repair of chemically complex DNA double-strand In vitro and in vivo data are needed for delivery of low damage is the predominant mechanism for radiation-induced doses over several weeks or months at very low dose gene or chromosomal mutation, there can be no expectation rates or with fractionated exposures. The cumulative of a low-dose threshold for the mutagenic component of ra- effect of multiple low doses of less than 10 mGy diation cancer risk. delivered over extended periods has to be explored One mechanistic caveat explored was that novel forms of further. The development of in vitro transformation cellular damage response, collectively termed induced ge- assays utilizing nontransformed human diploid cells is nomic instability, might contribute significantly to radiation judged to be of special importance. cancer risk. The cellular data reviewed in Chapter 2 identi- fied uncertainties and some inconsistencies in the expres- Hormesis sion of this multifaceted phenomenon. However, telomere- The possibility that low doses of radiation may have ben- associated mechanisms did provide a coherent explanation eficial effects (a phenomenon often referred to as “horm- for some in vitro manifestations of induced genomic insta- esis”) has been the subject of considerable debate. Evidence bility. The data considered did not reveal consistent evidence for hormetic effects was reviewed, with emphasis on mate- for the involvement of induced genomic instability in radia- rial published since the 1990 BEIR V study on the health tion tumorigenesis, although telomere-associated processes effects of exposure to low levels of ionizing radiation. Al- may account for some tumorigenic phenotypes. A further though examples of apparent stimulatory or protective ef- conclusion was that there is little evidence of specific tumori- fects can be found in cellular and animal biology, the pre- genic signatures of radiation causation, but rather that radia- ponderance of available experimental information does not tion-induced tumors develop in a tumor-specific multistage support the contention that low levels of ionizing radiation manner that parallels that of tumors arising spontaneously. have a beneficial effect. The mechanism of any such pos- Quantitative animal data on dose-response relationships sible effect remains obscure. At this time, the assumption provide a complex picture for low-LET radiation, with some that any stimulatory hormetic effects from low doses of ion- tumor types showing linear or linear-quadratic relationships izing radiation will have a significant health benefit to hu- while other studies are suggestive of a low-dose threshold, mans that exceeds potential detrimental effects from radia- particularly for thymic lymphoma and ovarian cancer. Since, tion exposure at the same dose is unwarranted. however, the induction or development of these two cancer types is believed to proceed via atypical mechanisms involv- Research Need 4. Identification of molecular mecha- ing cell killing, it was judged that the threshold-like re- nisms for postulated hormetic effects at low doses sponses observed should not be generalized. Definitive experiments that identify molecular mechanisms are necessary to establish whether

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316 BEIR VII Radiation-induced life shortening in mice is largely a re- Given that functional gene polymorphisms associated flection of cancer mortality, and the data reviewed generally with cancer risk may be relatively common, the potential for support the concept of a linear dose-response at low doses and significant distortion of population-based risk was explored low dose rates. Other dose-response data for animal tumori- with emphasis on the organ specificity of the genes of inter- genesis, together with cellular data, contributed to the judg- est. An interim conclusion was that common polymorphisms ments developed and the choice of a DDREF for use in the of DNA damage response genes associated with organ-wide interpretation of epidemiologic information on cancer risk. radiation cancer risk would be the most likely source of ma- Adaptive responses for radiation tumorigenesis have been jor interindividual differences in radiation response. investigated in quantitative animal studies, and recent infor- Research Need 6. Genetic factors in radiation cancer mation is suggestive of adaptive processes that increase tu- risk mor latency but not lifetime risk. However, these data are Further work is needed in humans and mice on gene difficult to interpret, and the implications for radiological mutations and functional polymorphisms that influ- protection remain most uncertain. ence the risk of radiation-induced cancers. Where Research Need 5. Tumorigenic mechanisms possible, human molecular genetic studies should be Further cytogenetic and molecular genetic studies coupled with epidemiologic investigations. are needed to reduce current uncertainties about the specific role of radiation in multistage radiation GENETIC EFFECTS OF RADIATION ON HUMAN tumorigenesis; such investigations would include POPULATIONS studies with radiation-associated tumors of humans and experimental animals. As noted in BEIR V, heritable effects of radiation are The review of cellular, animal, and epidemiologic or clini- estimated using what is referred to as the “doubling dose cal studies on the role of genetic factors in radiation tumori- method” and expressed in terms of increases in the frequen- genesis suggests that many of the known strongly express- cies of genetic diseases in the population over and above ing cancer-prone human genetic disorders are likely to show those that occur as a result of spontaneous mutations. The an elevated risk of radiation-induced cancer, probably with a doubling dose (DD) is the amount of radiation required to high degree of organ specificity. Cellular and animal studies produce as many mutations as those that occur spontane- suggest that the molecular mechanisms underlying these ge- ously in a generation and is calculated as a ratio of the aver- netically determined radiation effects largely mirror those age rates of spontaneous and induced mutations in defined that apply to spontaneous tumorigenesis and are consistent genes. If the DD is small, the relative mutation risk per unit with knowledge of somatic mechanisms of tumorigenesis. dose (i.e., 1/DD) is high, and if DD is large, the relative In particular, evidence was obtained that major deficiencies mutation risk is low. The DD, therefore, provides a conve- in DNA damage response and tumor-suppressor-type genes nient yardstick to express risks and a perspective of whether can serve to elevate radiation cancer risk. the predicted increases are trivial, small, or substantial rela- Limited epidemiologic data from follow-up of second tive to the baseline. cancers in gene carriers receiving radiotherapy were sup- portive of the above conclusions, but quantitative judgments Revision of the Conceptual Basis for Calculating the DD about the degree of increased cancer risk remain uncertain. In the BEIR V report, mouse data on both spontaneous However, since major germline deficiencies in the genes of and induced mutation rates were used for DD calculations. interest are known to be rare, it has been possible to con- A reassessment of the assumptions underlying this proce- clude from published analyses that they are most unlikely to dure revealed that the use of mouse data for spontaneous create a significant distortion of population-based estimates mutation rates can no longer be considered appropriate and of cancer risk. The major practical issue associated with these that reverting to the use of human data on spontaneous muta- strongly expressing cancer genes is judged to be the risk of tion rates for DD calculations, as was first done in the 1972 radiotherapy-related cancer. BEIR report, is correct. The DD calculated is 1 Gy and is the A major theme developing in cancer genetics is the inter- same as the one based entirely on mouse data. action and potential impact of more weakly expressing vari- ant cancer genes that may be relatively common in human populations. The animal genetic data provide proof-of-prin- Revision of the Baseline Frequencies of Mendelian ciple evidence of how such variant genes with functional Diseases in Humans polymorphisms can influence cancer risk, including limited The baseline frequencies of genetic diseases constitute an data on radiation tumorigenesis. Attention was also given to important quantity in risk estimation. While there is no rea- human molecular epidemiology data on associations be- son to consider revision of the baseline frequencies of con- tween functional polymorphisms and cancer risk, particu- genital abnormalities (6%) and chronic diseases (65%), these larly with respect to DNA damage response genes. two classes together constitute what are referred to as “mul-

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SUMMARY AND RESEARCH NEEDS 317 tifactorial diseases” because of the multiple factors involved also subject to the action of natural selection. The prediction in their etiology. Advances in human genetics now suggest is that a new equilibrium between mutation and selection that the frequencies of Mendelian diseases (i.e., those that will be reached. The time it takes in terms of generations to are due to mutations in single genes and show simple and attain the new equilibrium, the rate of approach to it, and the predictable patterns of inheritance) have to be revised up- magnitude of increase in mutant (and disease) frequencies wards from the 1.25% used previously (based on estimates are dependent on the induced mutation rate, the intensity of made in the mid-1970s) to 2.40% at this time. selection, and the type of disease. Research Need 7. Heritable genetic effects of radiation Delineation of a New Concept—The Concept of Potential Further work is necessary to establish (1) the poten- Recoverability Correction Factor tial roles of DNA DSB repair processes in the origin of Mouse data on rates of radiation-induced mutations con- deletions in irradiated stem cell spermatogonia and stitute the primary basis for estimating the risk of radiation- oocytes (the germ cell stages of importance in risk es- inducible genetic diseases in humans. Advances in the mo- timation) in mice and humans and (2) the extent to lecular biology of human genetic diseases and in studies of which large, radiation-induced deletions in mice are radiation-induced mutations in experimental systems show associated with multisystem development defects. In that mouse mutation rates cannot readily be converted into humans, the problem can be explored using genomic rates of genetic disease in human live births and that a cor- databases and knowledge of mechanisms of the origin rection factor, the potential recoverability correction factor of radiation-induced deletions to predict regions that (PRCF), is required to make the transition from induced may be particularly prone to such deletions. These pre- mutations in mice to inducible genetic disease in humans. A dictions can subsequently be tested in the mouse, these framework and methods have been developed to estimate tests can also provide insights into the potential PRCFs for Mendelian and chronic multifactorial diseases. phenotypes associated with such deletions in humans. With respect to epidemiology, studies on the ge- netic effects of radiotherapy for childhood cancer, of Introduction of the Concept That Adverse Hereditary the type that have been under way in the United States Effects of Radiation Are Likely to Be Manifest as and Denmark since the mid-1990s, should be encour- Multisystem Developmental Abnormalities aged, especially when they can be coupled with The adverse hereditary effects of radiation are more likely modern molecular techniques (such as array-based to be manifest as multisystem developmental abnormalities comparative genomic hybridization. These techniques than as Mendelian diseases. This concept incorporates ele- enable one to screen the whole genome for copy num- ments of current knowledge of the mechanisms of radiation- ber abnormalities (i.e., deletions and duplications of induced genetic damage, the molecular nature of radiation- genomic segments) with a resolution beyond the level induced mutations, the phenotypic manifestations of of a light microscope. naturally occurring multigene deletions in humans, empiri- cal observations in mice on the phenotypic effects of radia- tion-induced multigene deletions, and the enormous number EPIDEMIOLOGIC STUDIES OF POPULATIONS and distribution of genes involved in development in nearly EXPOSED TO IONIZING RADIATION all the human chromosomes. Appropriate mouse data that can serve as a basis for a preliminary estimate of radiation- Atomic Bomb Survivor Studies induced adverse developmental effects have been identified The Life Span Study (LSS) cohort of survivors of the and used. atomic bombings in Hiroshima and Nagasaki continues to Risk estimates have been made only for the first two post- serve as a major source of information for evaluating health irradiation generations. The population genetic theory of risks from exposure to ionizing radiation, and particularly equilibrium between mutation and selection (i.e., the equi- for developing quantitative estimates of risk. Its advantages librium theory) underlies the DD method that is used to esti- include its large size, the inclusion of both sexes and all ages, mate genetic risks of radiation. This theory postulates that a wide range of doses that have been estimated for individual the stability of mutant gene frequencies (and therefore of subjects, and high-quality mortality and cancer incidence disease frequencies) in a population is a reflection of the data. In addition, the whole-body exposure received by this existence of a balance between the rates at which spontane- cohort offers the opportunity to assess risks for cancers of a ous mutations arise in every generation and enter the gene large number of specific sites and to evaluate the compara- pool and the rates at which they are eliminated by natural bility of site-specific risks. selection. When such an “equilibrium population” sustains As an illustration, Figure 13-1 shows estimated ERRs of radiation exposure generation after generation, additional solid cancer versus dose (averaged over sex and standard- mutations are introduced into the gene pool, and these are ized to represent individuals exposed at age 30 at attained

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318 BEIR VII 1.5 Low Dose Range 5 Leukemia (for comparison) 2 Excess Relative Risk of Solid Cancer 1.0 0.1 1.2 0.5 Linear fit, 0 - 1.5 Sv Linear-quadratic fit, 0 - 1.5 Sv 0.0 0.0 0.5 1.0 1.5 2.0 Radiation Dose (Sv) FIGURE 13-1 Excess relative risks of solid cancer for Japanese atomic bomb survivors. The insert shows the fit of a linear-quadratic model for leukemia, to illustrate the greater degree of curvature observed for that cancer. age 60) for atomic bomb survivors with doses in each of 10 lines are approximate 95% confidence intervals. Solid and dose intervals less than 2.0 Sv. This plot helps convey the dotted lines are estimated linear and linear-quadratic models overall dose-response relationship from the LSS cohort and for ERR, estimated from all subjects with doses in the range its role in low-dose risk estimation. Specific models are de- 0 to 1.5 Sv. (These are not estimated from the points, but tailed in Chapter 6. It is important to note that the difference from the lifetimes and doses of individual survivors, using between the linear and linear-quadratic models in the low- statistical methods discussed in Chapter 6.) A linear-qua- dose ranges is small relative to the error bars; therefore, the dratic model will always fit the data better than a linear difference between these models is small relative to the un- model, since the linear model is a restricted special case with certainty in the risk estimates produced from them. For solid quadratic coefficient equal to zero. For solid cancer inci- cancer incidence the linear-quadratic model did not offer sta- dence, however, there is no statistically significant improve- tistically significant improvement in the fit, so the linear ment in fit due to the quadratic term. It should also be noted model was used. For leukemia, a linear-quadratic model (in- that in the low-dose range of interest the difference between sert in Figure 13-1) was used because it fitted the data sig- the estimated linear and linear-quadratic models is small rela- nificantly better than the linear model. tive to the 95% CIs. Plotted points are the estimated ERRs of solid cancer The full LSS cohort consists of approximately 120,000 incidence (averaged over sex and standardized to represent persons who were identified at the time of the 1950 census. individuals exposed at age 30 attained age 60) for atomic However, most recent analyses have been restricted to ap- bomb survivors with doses in each of 10 dose intervals, proximately 87,000 survivors who were in the city at the plotted above the midpoints of the dose intervals. If R(d) time of the bombings and for whom it is possible to estimate represents the age-specific instantaneous risk at some dose doses. Special studies of subgroups of the LSS have pro- d, then the excess relative risk at dose d is [R(d) – R(0)] / vided clinical data, biological measurements, and informa- R(0) (which is necessarily zero when dose is zero). Vertical tion on potential confounders or modifiers.

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SUMMARY AND RESEARCH NEEDS 319 The availability of high-quality cancer incidence data has sible reduction of risks following protracted low-dose-rate resulted in several analyses and publications addressing spe- exposures. cific cancer sites. These analyses often include special patho- For thyroid cancer, all of the studies providing quantita- logical review of the cases and sometimes include data on tive information about risks are studies of children who re- additional variables (such as smoking for the evaluation of ceived radiotherapy for benign conditions. A combined lung cancer risks). Papers focusing on the following cancer analysis of data from some of these cohorts and data from sites have been published in the last decade: female breast atomic bomb survivors and from two case-control studies of cancer, thyroid cancer, salivary gland cancer, liver cancer, thyroid cancer nested within the International Cervical Can- lung cancer, skin cancer, and central nervous system tumors. cer Survivor Study and the International Childhood Cancer Special analyses have also been conducted of cancer mortal- Survivor Study provides the most comprehensive informa- ity in survivors who were exposed either in utero or during tion about thyroid cancer risks. For subjects exposed below the first 5 years of life. the age of 15, a linear dose-response was seen, with a level- Health end points other than cancer have been linked with ing or decrease in risk at the higher doses used for cancer radiation exposure in the LSS cohort. Of particular note, a therapy. The pooled ERR was 7.7 Gy–1, and the EAR was dose-response relationship with mortality from nonneoplas- 4.4 per 104 PY-Gy. Both estimates were significantly af- tic disease was demonstrated in 1992, and subsequent analy- fected by age at exposure, with a strong decrease in risk with ses in 1999 and 2003 have strengthened the evidence for this increasing age at exposure and little apparent risk for expo- association. Statistically significant associations were seen sures after age 20. The ERR appeared to decline over time for the categories of heart disease, stroke, and diseases of the about 30 years after exposure but was still elevated at digestive, respiratory, and hematopoietic systems. The data 40 years. were inadequate to distinguish between a linear dose-re- Little information on thyroid cancer risk in relation to sponse, a pure quadratic response, or a dose-response with a exposure in childhood to iodine-131 was available. Studies threshold as high as 0.5 Sv. of the effects of 131I exposure later in life provide little evi- dence of an increased risk of thyroid cancer following 131I exposure after childhood. Medical Radiation Studies For leukemia, ERR estimates from studies with average Published studies on the health effects of medical expo- doses ranging from 0.1 to 2 Gy are relatively close, in the sures were reviewed to identify those that provide informa- range 1.9 to 5 Gy–1, and are statistically compatible. Esti- tion for quantitative risk estimation. Particular attention was mates of EAR are also similar across studies, ranging from 1 focused on estimating risks of leukemia and of lung, breast, to 2.6 per 104 PY-Gy. Little information is available on the thyroid, and stomach cancer in relation to radiation dose for effects of age at exposure or of exposure protraction. comparison with estimates derived from other exposed popu- For stomach cancer, the estimates of ERR range from lations, particularly the atomic bomb survivors. The possible negative to 1.3 Gy–1. The confidence intervals are wide, association between radiation exposure and cardiovascular however, and they all overlap, indicating that these estimates mortality and morbidity was also reviewed. are statistically compatible. For lung cancer, the ERRs per Gy (ERRs/Gy) from the Finally, studies of patients having undergone radiotherapy studies of acute high-dose-rate exposures are statistically for Hodgkin’s disease or breast cancer suggest that there may compatible and in the range 0.1–0.4. It is difficult to evaluate be some risk of cardiovascular morbidity and mortality for the effects of age at exposure or of exposure protraction based very high doses and high-dose-rate exposures. The magni- on these studies because only one study (the hemangioma tude of the radiation risk and the shape of the dose-response cohort) is available in which exposure occurred at very curve for these outcomes are uncertain. young ages and protracted low-dose-rate exposures were received. The study of tuberculosis patients, however, Research Need 8. Future medical radiation studies appears to indicate that substantial fractionation of exposure Most studies of medical radiation should rely on leads to a reduction of risk. exposure information collected prospectively, includ- For breast cancer, excess absolute risks (EARs) appear to ing cohort studies as well as nested case-control be similar—of the order of 9.9 per 104 person-years (PY) per studies. Future studies should continue to include indi- gray at age 50—following acute and fractionated moderate- vidual dose estimation to the site of interest, as well as to high-dose-rate exposure. Effects of attained age and age an evaluation of the uncertainty in dose estimation. at exposure are important modifiers of risk. The excess risks Ideally, where population-based cancer registries do appear to be higher in populations of women treated for not exist to establish cohorts of cancer survivors, benign breast conditions, suggesting that these women may hospital-based registries can be established to identify be at an elevated risk of radiation-induced breast cancer. The cohorts of exposed patients whose mortality and mor- hemangioma cohorts showed lower risks, suggesting a pos- bidity can be followed. If these registries can be linked

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320 BEIR VII to appropriate radiation therapy or diagnostic records, tive studies at present are those of nuclear industry workers they can be used as a basis for nested case-control (including the workers at Mayak in the former USSR), for studies of specific outcomes, and detailed exposure whom individual real-time estimates of doses have been col- estimation for the site of interest can be undertaken. lected over time with the use of personal dosimeters. More Studies of populations with high- and moderate- than 1 million workers have been employed in this industry dose medical exposures are particularly important for since its beginning in the early 1950s. However, studies of the study of modifiers of radiation risks. Because of individual worker cohorts are limited in their ability to esti- the high level of radiation exposure in these popula- mate precisely the potentially small risks associated with low tions, they are also ideally suited to study the effects of levels of exposure. Risk estimates from these studies are gene-radiation interactions that may render particular variable, ranging from no risk to risks an order of magnitude subsets of the population more sensitive to radiation- or more than those seen in atomic bomb survivors. induced cancer. Genes of particular interest include Combined analyses of data from multiple cohorts offer an BRCA1, BRCA2, ATM, CHEK2, NBS1, XRCC1, and opportunity to increase the sensitivity of such studies and XRCC3. These are among the most important genes provide direct estimates of the effects of long-term, low- known to be involved in detection and repair of dose, low-LET radiation. The most comprehensive and pre- radiation-induced DNA damage. cise estimates to date are those derived from the U.K. Of concern for radiological protection is the in- National Registry of Radiation Workers and the three- creasing use of computed tomography (CT) scans and country study (Canada-U.K.-U.S.), which have provided diagnostic X-rays. Epidemiologic studies of these estimates of leukemia and all cancer risks. Although the exposures would be particularly useful if they are fea- estimates are lower than the linear estimates obtained from sible, particularly the following: (1) follow-up studies studies of atomic bomb survivors, they are compatible with of cohorts of persons receiving CT scans, especially a range of possibilities, from a reduction of risk at low doses children; and (2) studies of infants who experience to risks twice those on which current radiation protection diagnostic exposures related to cardiac catheterization, recommendations are based. Overall, there is no suggestion those who have recurrent exposures to follow their that the current radiation risk estimates for cancer at low clinical status, and premature babies monitored for pul- levels of exposure are appreciably in error. Uncertainty monary development with repeated X-rays. regarding the size of this risk remains as indicated by the width of the confidence intervals. The widespread use of interventional radiological Because of the absence of individual dose estimates in procedures in the heart, lungs, abdomen, and many most of the cohorts, studies of occupational exposures in vascular beds, with extended fluoroscopic exposure medicine and aviation provide minimal information useful times of patients and operators, emphasizes the need for the quantification of these risks. for recording of dose and later follow-up studies of Because of the uncertainty in occupational risk estimates potential radiation effects among these populations. and the fact that errors in doses have not formally been taken There is a need to organize worldwide consortia that into account in these studies, the committee concluded that would use similar methods in data collection and the occupational studies were not suitable for the projection follow-up. These consortia should record delivered of population-based risks. These studies, however, provide a doses and technical data from all X-ray or isotope- comparison to the risk estimates derived from atomic bomb based imaging approaches including CT, positron survivors. emission tomography, and single photon emission computed tomography. Research Need 9. Future occupational radiation studies Studies of occupational radiation exposures, par- Occupational Radiation Studies ticularly among nuclear industry workers, including nuclear power plant workers, are well suited for direct The risk of cancer among physicians and other persons assessment of the carcinogenic effects of long-term, exposed to ionizing radiation in the workplace has been a low-level radiation exposure in humans. Ideally, subject of study since the 1940s, when increased mortality studies of occupational radiation should be prospec- from leukemia was reported among radiologists in compari- tive in nature and rely on individual real-time estimates son to mortality among other medical specialists. Since then, of radiation doses. Where possible, national registries numerous studies have considered the mortality and cancer of radiation exposure of workers should be established incidence of various occupationally exposed groups in medi- and updated as additional radiation exposure is accu- cine, industry, defense, research, and aviation industries. mulated and as workers change employers. These Studies of occupationally exposed groups are, in principle, registries should include at least annual estimates of well suited for direct estimation of the effects of low doses whole-body radiation dose from external photon ex- and low dose rates of ionizing radiation. The most informa- posure. These exposure registries should be linked

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SUMMARY AND RESEARCH NEEDS 321 with mortality registries and, where they exist, with may be due to the underlying thyroid condition and not ra- national tumor (and other disease) registries. Where diation exposure. national dose registries cannot be set up, cohort studies Results from external environmental exposures to 131I based on records of nuclear installations are a useful have been inconsistent. The most informative findings are alternative. It is noted that the power of individual from studies of individuals exposed to radiation after the cohort studies at the local and even national levels is Chernobyl accident. Recent evidence indicates that expo- limited. To maximize the information about the effects sure to radiation from Chernobyl is associated with an in- of low-dose, protracted exposures from these studies, creased risk of thyroid cancer and that the relationship is it is therefore necessary to combine data across co- dose dependent. The quantitative estimate of excess thyroid horts and countries. Most studies published to date cancer risk is generally consistent with estimates from other have been based on relatively short follow-up periods, radiation-exposed populations and is observed in both males and the majority of workers were still young at the end and females. Iodine deficiency appears to be an important of follow-up. Extended mortality follow-up over the modifier of risk, enhancing the risk of thyroid cancer follow- next decades—and, where possible, cancer morbidity ing radiation exposure. follow-up—of these workers, as they enter an age Ecologic studies of persons exposed to environmental range when cancer incidence and mortality rates in- sources of ionizing radiation have not been useful in devel- crease, will provide useful improvements of the direct oping risk estimates. Exposure levels are low, the studies cancer risk estimates drawn from these studies of relate to exposure of populations rather than individuals, and exposure to low-dose, low-LET radiation. It is also im- there is minimal possibility of follow-up of exposed indi- portant to continue follow-up of workers exposed to viduals. The few exceptions to these circumstances are popu- relatively high doses, that is, workers at the Mayak lations where there is unusual exposure because of accidents nuclear facility and workers involved in the Chernobyl involving radiation exposure or long-term releases of rela- cleanup. tively high levels of ionizing radiation (e.g., Chernobyl, Hanford). Environmental Radiation Studies Research Need 10. Future environmental radiation Ecologic studies of populations living around nuclear fa- studies cilities and of other environmentally exposed populations do In general, additional ecologic studies of persons not contain individual estimates of radiation dose or provide exposed to low levels of radiation from environmental a direct quantitative estimate of risk in relation to radiation sources are not recommended. However, if disasters dose. This limits the interpretation of these data. occur in which a local population is exposed to unusu- Several cohort studies have reported health outcomes ally high levels of radiation, it is important that there among persons exposed to environmental radiation. No con- be a rapid response not only for the prevention of fur- sistent or generalizable information is contained in these ther exposure but also for the establishment of scien- studies. Four ecologic studies of populations exposed to tific evaluation of the possible effects of exposure. The natural background did not find any association between dis- data collected should include basic demographic ease rates and indicators of high background levels of radia- information on individuals, estimates of acute and pos- tion exposure. Ecologic studies of children of adults exposed sible continuing exposure, the nature of the ionizing to radiation while working at the Sellafield nuclear facility radiation, and the means of following these individuals in Great Britain have suggested some increased risk of leu- for many years. The possibility of enrolling a compa- kemia and lymphoma associated with individual dose, but rable nonexposure population should be considered. the findings are based on small numbers of cases and the Studies of persons exposed environmentally as a re- results across studies are not consistent. sult of the Chernobyl disaster or as a result of releases Evidence from ecologic studies does not indicate an in- from the Mayak nuclear facility should continue. creased risk of leukemia among persons exposed in utero to radiation from Chernobyl or an increase in rates of childhood INTEGRATION OF BIOLOGY AND EPIDEMIOLOGY leukemia. In contrast to a considerable body of evidence re- garding the risk of thyroid cancer in persons exposed to ex- This chapter highlights the ways in which cellular, mo- ternal radiation, there is relatively little information regard- lecular, and animal data can be integrated with epidemio- ing the risk of thyroid cancer in humans exposed internally logic findings in order to develop coherent judgments on the to 131I. There is some evidence of a small increase in thyroid health effects of low-LET radiation. Emphasis is placed on cancer associated with exposure to 131I from therapeutic and data integration for the purposes of modeling these health diagnostic uses, but the findings are inconsistent and the risks. The principal conclusions from this work are the fol- small increases in thyroid cancer observed in some studies lowing:

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322 BEIR VII • Current knowledge on the cellular and molecular Although the committee did not conduct its own analyses mechanisms of radiation tumorigenesis tends to support the of data from studies other than the LSS, for most studies application of models that incorporate the excess relative risk with suitable data, results of analyses based on models simi- projection over time. lar to those used by the committee were available and were • The choice of models for the transport of cancer risk evaluated. For cancers of the breast and thyroid, several from Japanese A-bomb survivors to the U.S. population is medically exposed groups offer quantitative data suitable for influenced by mechanistic knowledge and information on risk assessment, and the recommended models for these sites the etiology of different cancer types. are those developed in published combined analyses of data • A combined Bayesian analysis of A-bomb epidemio- from the relevant studies. logic information and experimental data has been employed To use models developed primarily from the LSS cohort to provide an estimate of the DDREF for cancer risk. for the estimation of lifetime risks for the U.S. population, it • Knowledge of adaptive responses, genomic instability, was necessary to make several assumptions. Because of in- and bystander signaling between cells that may act to alter herent limitations in epidemiologic data and in our under- radiation cancer risk was judged to be insufficient to be in- standing of radiation carcinogenesis, these assumptions in- corporated in a meaningful way into the modeling of epide- volve uncertainty. Two important sources of uncertainty are miologic data. The same judgment is made with respect to (1) the possible reduction in risk for exposure at low doses the possible contribution to cancer risk of postirradiation and low-dose rates (i.e., the DDREF), and (2) the “transport” genomic instability and bystander signaling between cells. of risk estimates based on Japanese atomic bomb survivors • Genetic variation in the population is a potentially im- to use in estimating risks for the U.S. population. With re- portant factor in the estimation of radiation cancer risk. gard to the DDREF, the committee concluded that linear risk Strongly expressing cancer-predisposing mutations are estimates obtained from the LSS cohort should be reduced judged from modeling studies to be too rare to distort popu- by a factor of 1.1 to 2.3 for estimating risks at low doses and lation-based estimates of risk appreciably, but they are a sig- low dose rates, and the BEIR VII committee used a value of nificant issue in some medical radiation settings. The posi- 1.5 to estimate solid cancer risks. To estimate the risk of tion regarding potentially more common variant genes that leukemia, the BEIR VII model is linear-quadratic, since this express only weakly remains uncertain. model fitted the data substantially better than the linear • Estimation of the heritable effects of radiation takes model. The use of data on Japanese A-bomb survivors to advantage of new information on human genetic disease and estimate risks for the U.S. population (transport) is problem- on mechanisms of radiation-induced germline mutation. The atic for sites where baseline risks differ greatly between the application of a new approach to genetic risk estimation leads two countries. For cancer sites other than breast and thyroid the committee to conclude that low-dose induced genetic (where data on Caucasian subjects are available), the com- risks are very small compared to baseline risks in the popu- mittee presents estimates based on the assumption that the lation. excess risk due to radiation is proportional to baseline risks • The committee judges that the balance of evidence from (relative risk transport) and also presents estimates based on epidemiologic, animal, and mechanistic studies tends to fa- the assumption the excess risk is independent of baseline vor a simple proportionate relationship at low doses between risks. As a central estimate, the committee recommends a radiation dose and cancer risk. Uncertainties in this judg- weighted estimate of these two results, with the ratio of the ment are recognized and noted. two used to reflect the uncertainty in transporting risks. For most sites, a weight of 0.7 is used for relative transport and a weight of 0.3 is used for absolute transport; the weighting is MODELS FOR ESTIMATING THE LIFETIME RISK OF reversed for lung cancer. CANCER The committee provides estimates of lifetime risks of both As in past risk assessments, the LSS cohort of survivors cancer incidence and mortality for leukemia, all solid can- of the atomic bombings of Hiroshima and Nagasaki plays a cers, and cancers of several specific sites: stomach, colon, principal role in developing the committee’s recommended liver, lung, female breast, prostate, uterus, ovary, bladder, cancer risk estimates. In contrast to previous BEIR reports, and all other solid cancers. The committee’s models provide data on both cancer mortality and cancer incidence (from the the basis for sex-specific estimates for exposure scenarios Hiroshima and Nagasaki tumor registries) were available to including single exposures at various ages, chronic exposure the committee. The cancer incidence data analyzed by the throughout life, or occupational exposure from age 18 to 65. committee included nearly 13,000 cases occurring in the These models are based primarily on the LSS study, with period 1958–1998. In addition, the committee evaluated data additional use of medical data for breast and thyroid. on approximately 10,000 cancer deaths occurring in the As an example, Table 13-1 shows the estimated number period 1950–2000, in contrast to fewer than 6000 cancer of incident cancer cases and deaths expected to result if a deaths available to the BEIR V committee. population of 100,000 persons with an age distribution simi-

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SUMMARY AND RESEARCH NEEDS 323 TABLE 13-1 Committee’s Preferred Estimates of the Lifetime Attributable Risk of Incidence and Mortality for All Solid Cancers and for Leukemia All Solid Cancer Leukemia Males Females Males Females Excess cases (including nonfatal cases) from exposure to 0.1 Gy 800 (400, 1600) 1300 (690, 2500) 100 (30, 300) 70 (20, 250) Number of cases in the absence of exposure 45,500 36,900 830 590 Excess deaths from exposure to 0.1 Gy 410 (200, 830) 610 (300, 1200) 70 (20, 220) 50 (10, 190) Number of deaths in the absence of exposure 22,100 17,500 710 530 NOTE: Number of cases or deaths per 100,000 exposed persons. lar to that of the entire U.S. population were each exposed to Development and application of analytic methods 0.1 Gy; also shown are the numbers that would be expected that allow more reliable site-specific estimates are also in the absence of exposure. Results are shown for all solid needed. Specifically, methods that draw on both data cancers and for leukemia. The estimates are accompanied by for the specific site and data on broader cancer catego- 95% subjective confidence intervals that reflect the most ries could be useful. important uncertainty sources—namely, statistical variation, Research Need 12. Epidemiologic studies in general uncertainty in the factor used to adjust risk estimates for ex- Data from the LSS should be supplemented with posure at low doses and low dose rates, and uncertainty in data on populations exposed to low doses and/or low the method of transport. Additional sources of uncertainty dose rates, especially those with large enough doses to would increase the width of these intervals. Mortality esti- allow risks to be estimated with reasonable precision. mates are reasonably compatible with those in previous risk Studies of nuclear industry workers and careful studies assessments, particularly if uncertainties are considered. of persons exposed in countries of the former Soviet The committee also presents estimates for each of several Union are particularly important in this regard. specific cancer sites and for other exposure scenarios, al- Studies in non-Japanese populations are also im- though they are not shown here. For many cancer sites, un- portant, especially for estimating risks of cancers in certainty is very large, with subjective 95% confidence in- organs where baseline risks vary widely. Studies that tervals covering more than an order of magnitude. elucidate the relationship of radiation and other risk In general the magnitude of estimated risks for total factors (for example, smoking) are needed, possibly cancer mortality or leukemia has not changed greatly from by conducting nested case-control studies within co- estimates provided in past reports such as BEIR V, those of horts currently under study. the United Nations Scientific Committee on the Effects of Combined analyses of data from several cohorts Atomic Radiation, and those of the International Commis- have been used successfully in the past and are en- sion on Radiological Protection. New data and analyses have couraged to provide a unified treatment of data from reduced sampling uncertainty, but uncertainties related to the LSS and other studies. estimating risk for exposure at low doses and low dose rates Development and application of analytic methods and to transporting risks from Japanese A-bomb survivors to that take account of dosimetry uncertainties are en- the U.S. population remain large. Uncertainties in estimat- couraged for all studies. For the LSS, analyses that ing risks of site-specific cancers are especially large. make use of the uncertainty evaluation of the DS02 Research Need 11. Japanese atomic-bomb survivor dosimetry system, which is expected to become avail- studies able in the near future, are needed. The LSS cohort of Japanese A-bomb survivors has played a central role in BEIR VII and past risk assess- CONCLUSION ments. It is thus important that follow-up for mortality and cancer incidence continue for the 45% of the co- The committee concludes that the current scientific evi- hort who remained alive at the end of 2000. dence is consistent with the hypothesis that there is a linear, In the near future, an uncertainty evaluation of the no-threshold dose-response relationship between exposure DS02 dosimetry system is expected to become avail- to ionizing radiation and the development of cancer in able. Dose-response analyses that make use of this humans. evaluation should thus be conducted to account for dosimetry uncertainties.

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