A study conducted by The National Research Council of the National Academies found that there is no level of radiation that could be considered "safe". As we watch government agencies 'raising' the acceptable level of radiation that humans can be exposed to, understand that they do this while blatantly lying about the health risks. There is NO SAFE level of radiation: radiation will do damage to your cells. Period.The study that follows concludes with this: CONCLUSIONhttp://www.nap.edu/openbook.php?record_id=11340&page=323
The committee concludes that the current scientific evidence is consistent with the hypothesis that there is a linear, no-threshold dose-response relationship
between exposure to ionizing radiation and the development of cancer in humans.Here are Excepts from the original study, available at this link:
HEALTH RISKS FROM
EXPOSURE TO LOW LEVELS OF IONIZING RADIATION
BEIR VII PHASE 2
Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation
Board on Radiation Effects Research
Division on Earth and Life Studies
NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
This report focuses on the health effects of low-dose, low-LET (low linear energy transfer) radiation. In this chapter the committee provides background information relating to the physical and chemical aspects of radiation and the interaction of radiation with the target molecule DNA. The committee discusses contributions of normal oxidative DNA damage relative to radiation-induced DNA damage and describes the DNA repair mechanisms that mammalian cells have developed to cope with such damage. Finally, this chapter introduces a special subject, the physical characteristics that determine the relative biological effectiveness (RBE) of neutrons, estimates of which are required in the derivation of low-LET radiation risk estimates from atomic bomb survivors.PHYSICAL ASPECTS OF RADIATION
The central question that must be resolved when considering the physical and biological effects of low-dose ionizing radiation is whether the effects of ionizing radiation and the effects of the free radicals and oxidative reaction products generated in normal cellular metabolism are the same or different. Is ionizing radiation a unique insult to cells, or are its effects lost in the ocean of naturally occurring metabolic reaction products? Can cells detect and respond to low doses of ionizing radiation because of detectable qualitative and quantitative differences from endogenous reaction products?Molecular and Cellular Responses to Ionizing Radiationhttp://www.nap.edu/openbook.php?record_id=11340&page=43
Since the early years of radiobiology the cellular effects of ionizing radiation have been studied in the context of induced chromosomal aberrations, and early models of radiation action were largely based upon such studies (Savage 1996). In the 1970s, somatic cell genetic techniques were developed to allow the quantification and characterization of specific gene mutations arising in irradiated cultures of somatic cells. In more recent years, findings of persistent postirradiation genomic instability, bystander effects, and other types of cellular response have posed additional questions regarding the mechanisms underlying the cytogenetic and mutagenic effects of radiation and their potential to contribute to radiation tumorigenesis.
This chapter considers the general aspects of dose-response relationships for radiobiological effects and subsequently reviews the largely cellular data on a range of radiobiological end points. The main focus of the review is the issue of cellular effects at low doses of low-LET (linear energy transfer) radiation. Many of the conclusions reached from this review, when aggregated with those of Chapters 1 and 3, contribute to the judgments made in this report about human cancer risk at low doses and low dose rates.Heritable Genetic Effects of Radiation in Human Populationshttp://www.nap.edu/openbook.php?record_id=11340&page=91INTRODUCTION AND BRIEF HISTORY
Naturally occurring mutations in somatic and germ cells contribute respectively to cancers and heritable genetic diseases (i.e., hereditary diseases). The discoveries by Muller (1927) of the mutagenic effects of X-rays in fruit flies (Drosophila) and by Stadler (1928a, 1928b) of similar effects in barley and maize, and the subsequent extension of these findings to other types of ionizing radiation (and also to ultraviolet) and other organisms, conclusively established the genetic damage-inducing effects of radiation. However, widespread and serious concern over the possible adverse genetic effects of exposure of large numbers of people to low levels of radiation first arose in the aftermath of the detonation of atomic bombs over Hiroshima and Nagasaki in World War II, some 20 years after the discoveries of the mutagenic effects of X-rays. In June 1947, at the meeting of the Conference on Genetics convened by the Committee on Atomic Casualties of the U.S. National Research Council to assess the program of research on the heritable effects of radiation to be undertaken in Japan, the leading geneticists voted unanimously to record the following expression of their attitude toward the program: “Although there is every reason to infer that genetic effects can be produced and have been produced in man by atomic radiation, nevertheless the conference wishes to make it clear that it cannot guarantee significant results from this or any other study on the Japanese material. In contrast to laboratory data, this material is too much influenced by extraneous variables and too little adapted to disclosing genetic effects. In spite of these facts, the conference feels that this unique possibility for demonstrating genetic effects caused by atomic radiation should not be lost …” (NRC 1947). Thus came into existence the genetics program in Hiroshima and Nagasaki under the auspices of the Atomic Bomb Casualty Commission (ABCC), the newly formed joint agency of the Japanese Ministry of Health and Welfare and the U.S. National Academy of Sciences. The ABCC was renamed the Radiation Effects Research Foundation in 1976. In the late 1940s, the mouse was chosen as the primary surrogate for assessing the genetic radiosensitivity of humans, and extensive studies were initiated in different research centers in the United States, England, and Japan.
In the mid-1950s, one major international and several national scientific bodies came into existence, including the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), the Committee on the Biological Effects of Atomic Radiation (the BEAR committee; renamed the Committee on the Biological Effects of Ionizing Radiation [BEIR] in 1972) set up by the U.S. National Academy of Sciences, and the Committee of the British Medical Research Council. The UNSCEAR and the BEIR committees have continued their work up to the present, periodically reviewing the levels of radiation to which human populations are exposed and improving assessment of the somatic and genetic risks of radiation exposure (NRC 1972, 1980, 1988, 1990, 1999; UNSCEAR 1993, 2000b, 2001).
From the beginning of these efforts, it was obvious that in the absence of direct human data on radiation-induced germ cell mutations, quantitative estimates of genetic risk could be derived only through a knowledge of the prevalence of naturally occurring hereditary ill health in the population, the role of spontaneous mutations in supporting this burden, and plausible assumptions on the rates of induced germ cell mutations in humans. The methods developed and used by the above committees for risk estimation, therefore, were necessarily indirect. All were geared toward using human data on genetic diseases as a frame of reference, together with mouse data on radiation-induced mutations, to predict the radiation risk of genetic disease in humans. Both the UNSCEAR and the BEIR committees are cognizant of the need to make assumptions given the consequent uncertainties in extrapolating from mouse data on induced mutation rates to the risk of genetic disease in humans.
Details of the genetics program that evolved in Japan and the vast body of data that emerged from these studies have been published in a series of articles. The most relevant ones have now been compiled in a single volume (Neel and Schull 1991). The most important finding of these studies is that there are no statistically demonstrable adverse genetic effects attributable to radiation exposures sustained by the survivors. Although cited and discussed in the UNSCEAR and BEIR reports over the years, these results did not constitute part of the “mainstream thinking” of genetic risk estimators and therefore were not used in risk estimation.
During the past few years, estimates of the baseline frequencies of Mendelian diseases have been revised and mathematical methods have been developed to estimate the impact of an increase in mutation rate (as a result of radiation exposures) on the frequencies of different classes of genetic diseases in the population. Additionally, there have been several advances in our understanding of the molecular basis and mechanisms of origin of human genetic diseases and of radiation-induced mutations in experimental systems. As a result of these developments, it now is possible to reexamine the conceptual basis of risk estimation, reformulate some of the critical questions in the field, and address some of the problems that could not be addressed earlier.
This chapter summarizes the general framework and the methods and assumptions used in risk estimation until the publication of BEIR V (NRC 1990). This is followed by a discussion of the advances in knowledge since that time, their impact on the concepts used in risk estimation, and how they can be employed to revise the risk estimates. Throughout this chapter, the terms “genetic diseases,” “genetic effects,” and “genetic risks” are used exclusively to mean “heritable genetic diseases,” “heritable genetic effects,” and “heritable genetic risks,” respectively.GENERAL FRAMEWORKGoal of Genetic Risk Estimation
The goal of genetic risk estimation, at least as envisioned and pursued by UNSCEAR and the BEIR committees, remains prediction of the additional risk of genetic diseases in human populations exposed to ionizing radiation, over and above that which occurs naturally as a result of spontaneous mutations. The concept of “radiation-inducible genetic diseases,” which emerged early on in the field, is based on two established facts and an inference. The facts are that (1) hereditary diseases result from mutations that occur in germ cells and (2) ionizing radiation is capable of inducing similar changes in all experimental systems adequately investigated. The inference, therefore, has been that radiation exposure of human germ cells can result in an increase in the frequency of genetic diseases in the population. Worth noting is the fact that although there is a vast amount of evidence for radiation-induced mutations in diverse biological systems, there is no evidence for radiation-induced germ cell mutations that cause genetic disease in humans.
Germ Cell Stages and Radiation Conditions of Relevance
From the standpoint of genetic risks, the effects of radiation on two germ cell stages are particularly important. In the male, these are the stem cell spermatogonia, which constitute a permanent germ cell population in the testes and continue to multiply throughout the reproductive life span of the individual. In the female, the corresponding cell stages are the oocytes, primarily the immature ones. The latter constitute the predominant germ cell population in the female. Female mammals are born with a finite number of oocytes formed during fetal development. These primordial oocytes, as they are called, grow, and a sequence of nuclear changes comprising meiosis takes place in them. The latter however are arrested at a particular stage until just before ovulation. Because oocytes are not replenished by mitosis during adult life and immature oocytes are the predominant germ cell population in the female, these are clearly the cell stages whose irradiation has great significance for genetic risks.
The radiation exposures sustained by germ cells in human populations are generally in the form of low-LET (linear energy transfer) irradiation (e.g., X-rays and γ-rays) delivered as small doses at high dose rates (e.g., in diagnostic radiology) or are greatly protracted (e.g., continuous exposures from natural and man-made sources). In estimating genetic risks to the population therefore, the relevant radiation conditions are low or chronic doses of low-LET irradiation. As discussed later, most mouse data used for estimating the rates of induced mutations have been collected at high doses and high dose rates. Consequently, assumptions have to be made to convert the rates of induced mutations at high doses and dose rates into mutation rates for radiation conditions applicable for risk estimation in humans.GENETIC DISEASEShttp://www.nap.edu/openbook.php?record_id=11340&page=91
Since the aim of genetic risk estimation is to predict the additional risk of genetic diseases relative to the baseline frequency of such diseases in the population, the concept of genetic diseases and their classification and attributes are considered in this section. The term genetic diseases refers to those that arise as a result of spontaneous mutations in germ cells and are transmitted to the progeny.Mendelian Diseases
Diseases caused by mutations in single genes are known as Mendelian diseases and are further divided into autosomal dominant, autosomal recessive, and X-linked, depending on the chromosomal location (autosomes or the X chromosome) and transmission patterns of the mutant genes. In an autosomal dominant disease, a single mutant gene (i.e., in the heterozygous state) is sufficient to cause disease. Examples include achondroplasia, neurofibromatosis, Marfan syndrome, and myotonic dystrophy. Autosomal recessive diseases require homozygosity (i.e., two mutant genes at the same locus, one from each parent) for disease manifestation. Examples include cystic fibrosis, phenylketonuria, hemochromatosis, Bloom’s syndrome, and ataxia-telangietasia.
The X-linked recessive diseases are due to mutations in genes located on the X chromosome and include Duchenne’s muscular dystrophy, Fabry’s disease, steroid sulfatase deficiency, and ocular albinism. Some X-linked dominant diseases are known, but for most of them, no data on incidence estimates are currently available. Therefore, these diseases are not considered further in this report. The general point with respect to Mendelian diseases is that the relationship between mutation and disease is simple and predictable.Multifactorial Diseases
The major burden of naturally occurring genetic diseases in human populations, however, is not constituted by Mendelian diseases, which are rare, but by those that have a complex etiology. The term “multifactorial” is used to designate these diseases to emphasize the fact that there are multiple genetic and environmental determinants in their etiology. Their transmission patterns do not fit Mendelian expectations. Examples of multifactorial diseases include the common congenital abnormalities such as neural tube defects, cleft lip with or without cleft palate, and congenital heart defects that are present at birth, and chronic diseases of adults (i.e., with onset in middle and later years of life) such as coronary heart disease, essential hypertension, and diabetes mellitus.
Evidence for a genetic component in their etiology comes from family and twin studies. For example, first-degree relatives of patients affected with coronary heart disease have a two- to sixfold higher risk of the disease than those of matched controls, and the concordance rates of disease for monozygotic twins are higher (but never 100%) than those for dizygotic twins (Motulsky and Brunzell 1992; Sankaranarayanan and others 1999).
As mentioned earlier, multifactorial diseases are presumed to originate from the joint action of multiple genetic and environmental factors; consequently, the presence of a mutant allele is not equivalent to having the disease. For these diseases, the interrelated concepts of genetic susceptibility and risk factors are more appropriate. The genetic basis of a common multifactorial disease is the presence of a genetically susceptible individual, who may or may not develop the disease depending on the interaction with other genetic and environmental factors. These concepts are discussed further in Annex 4A. The important general point is that unlike the situation with Mendelian diseases, the relationships between mutations and disease are complex in the case of multifactorial diseases. For most of them, knowledge of the genes involved, the types of mutational alterations, and the nature of environmental factors remains limited. Among the models used to explain the inheritance patterns of multifactorial diseases and to estimate the recurrence risks in relatives is the multifactorial threshold model (MTM) of disease liability. The MTM, its properties, and its predictions are discussed in Annex 4A.Chromosomal Diseases
Historically, both UNSCEAR and the BEIR committees have always had an additional class of genetic diseases—“chromosomal diseases”—in their lists that included those that had long been known to arise as a result of gross (i.e., microscopically detectable), numerical (e.g., Down’s syndrome, which is due to trisomy of chromosome 21), or structural abnormalities of chromosomes (e.g., cri du chat syndrome, due to deletion of part or the whole short arm of chromosome 5 [5p-]). As discussed later, this is really not an etiological category, and deletions (microscopically detectable or not) are now known to contribute to a number of constitutional genetic diseases grouped under autosomal dominant, autosomal recessive, and X-linked diseases.Atomic Bomb Survivor Studieshttp://www.nap.edu/openbook.php?record_id=11340&page=141INTRODUCTION
The Life Span Study (LSS) cohort consists of about 120,000 survivors of the atomic bombings in Hiroshima and Nagasaki, Japan, in 1945 who have been studied by the Radiation Effects Research Foundation (RERF) and its predecessor, the Atomic Bomb Casualty Commission. The cohort includes both a large proportion of survivors who were within 2.5 km of the hypocenters at the time of the bombings and a similar-sized sample of survivors who were between 3 and 10 km from the hypocenters and whose radiation doses were negligible. The LSS cohort has several features that make it uniquely important as a source of data for developing quantitative estimates of risk from exposure to ionizing radiation. The population is large, not selected because of disease or occupation, has a long follow-up period (1950–2000), and includes both sexes and all ages at exposure, allowing a direct comparison of risks by these factors.
Doses are reasonably well characterized and cover a useful range. Doses are lower than those usually involved in medical therapeutic exposures, but many survivors were exposed at doses that are sufficiently large to estimate risks with reasonable statistical precision. In addition, the cohort includes a large number of survivors exposed at low doses, allowing some direct assessment of effects at these levels. The exposure is a whole-body exposure, which makes it possible to assess risks for specific cancer sites and to compare risks among sites. Because of the use of the Japanese family registration system, mortality data are virtually complete for survivors who remained in Japan. High-quality tumor registries in both Hiroshima and Nagasaki allow the study of site-specific cancer incidence with reasonably reliable diagnostic data. In addition, the LSS cohort is probably less subject to potential bias from confounding than many other exposed cohorts because a primary determinant of dose is distance from the hypocenter, with a steep gradient of dose as a function of distance. Finally, special studies involving subgroups of the LSS have provided clinical data, biological measurements, and information on potential confounders or effect modifiers.
The LSS also has limitations, which are important to consider in using and interpreting results based on this cohort. The subjects were Japanese and exposed under wartime conditions and, in this sense, differ from various populations for which risk estimates are desired. To be included in the study, subjects had to survive the initial effects of the bombings, including the acute effects of radiation exposure, and it is possible that this might have biased the findings. Dose estimates are subject to uncertainty, especially that due to survivor location and shielding. The cohort provides no information on dose-rate effects since all exposure is at high dose rates. Estimates of linear risk coefficients tend to be driven by doses that exceed 0.5 Gy; although estimates based only on survivors with lower doses can be made, their statistical uncertainty is considerably greater than those that include survivors with higher doses. Even at higher doses, data are often inadequate for evaluating risks of cancers at specific sites, especially those that are not common (although, for many site-specific cancers, the LSS provides more information than any other study).
Because of its many advantages, the LSS cohort of A-bomb survivors serves as the single most important source of data for evaluating risks of low-linear energy transfer radiation at low and moderate doses. This chapter describes the LSS cohort and presents findings for leukemia and for solid cancers as a group. The most recent major publications on cancer mortality (Preston and others 2003) and incidence (Preston and others 1994; Thompson and others 1994) are emphasized, but papers addressing special issues such as the shape of the dose-response function are also considered. Results for cancers of specific sites, including results from the three publications just noted, are discussed along with material from various special studies. Risks from in utero exposure are discussed separately. Although cancer is the main late effect that has been demonstrated in the
A-bomb survivor studies, several studies have addressed the effects of radiation exposure on other health outcomes including benign tumors and mortality from causes of death other than cancer. These are discussed at the end of the chapter. In general, the committee has summarized papers on cancer incidence, cancer mortality, and noncancer mortality in the LSS cohort that have been published since BEIR V (NRC 1990).
This chapter is based on published material and does not include results of analyses conducted by the committee, which are described in Chapter 12. At the time of this writing, detailed analyses of mortality data covering the period 1950–1997 and of incidence data covering the period 1958–1987 had been published. The committee’s analyses were based on the most recent DS02 dosimetry system, whereas most of the published analyses described in this chapter were based on the earlier DS86 dosimetry system (see discussion of dosimetry below for further comment). Preston and colleagues (2004) recently evaluated the impact of changes in dosimetry on cancer mortality risk estimates using mortality data through 2000; these results are summarized in the discussion of dosimetry.DESCRIPTION OF THE COHORT
The full LSS cohort consists of approximately 120,000 persons who were identified at the time of the 1950 census. It includes 93,000 persons who were in Hiroshima or Nagasaki at the time of the bombings and 27,000 subjects who were in the cities at the time of the census but not at the time of the bombings. This latter group has been excluded from most analyses since the early 1970s because of inconsistencies between their mortality rates and those for the remainder of the cohort.Health End Point Data
Data on health end points are obtained from several sources. Vital status is updated in 3-year cycles through the legally mandated Japanese family registration system in which deaths, births, marriages, and divorces are routinely recorded. This ensures virtually complete ascertainment of death regardless of where individual subjects reside in Japan. Death certificates provide data on the cause of death. The Leukemia Registry has served as a resource for leukemia and related hematological disease (Brill and others 1962; Ichimaru and others 1978). In the 1990s, it became possible to link data from both the Hiroshima and the Nagasaki tumor registries to the LSS cohort, which allows the evaluation of cancer incidence (Mabuchi and others 1994). An advantage of the registry data, in addition to the inclusion of nonfatal cancers, is that diagnostic information is of higher quality than that based on death certificates. Both tumor registries employ active approaches for case ascertainment and provide high-quality data from 1958 onward. Published analyses based on these data cover the period 1958–1987 (Thompson and others 1994). Limitations of the incidence data are that they are not available before 1958 and do not include subjects who have migrated from Hiroshima or Nagasaki.1
The Adult Health Study (AHS) is a resource for data on health end points that require clinical data. The AHS cohort is a 20% subsample of the LSS, oversampled to provide greater representation of subjects in high-dose categories. Since 1958, AHS subjects have been invited to participate in biennial comprehensive health examinations at RERF. The level of participation has been between 70 and 85% for those living in the Hiroshima and Nagasaki areas (Ron and others 1995a).Leukemia
This section reviews analyses of mortality data for the period 1950–1990 (Pierce and others 1996) and of incidence data for the period 1958–1987 (Preston and others 1994). Leukemia mortality data for the period 1950–2000 were analyzed by Preston and colleagues (2004) and used to develop the committee’s models for estimating leukemia risks; these analyses are described in Chapter 12.Leukemia was the first cancer to be linked with radiation exposure in A-bomb survivors (Folley and others 1952) and has the highest relative risk of any cancer.
Pierce and colleagues estimated that 78 of 176 (44%) leukemia deaths among survivors with doses exceeding 0.005 Sv were due to radiation exposure.
Leukemia risks increased with dose up to about 3 Sv, with evidence of upward curvature; that is, a linear-quadratic function fitted the data significantly better than a linear function. With this linear-quadratic function, the excess risk per unit of dose at 1 Sv was about three times that at 0.1 Sv.
For those exposed under about age 30, nearly all of the excess deaths occurred before 1975, but for those exposed at older ages, the excess risk appeared to persist throughout the follow-up period. The temporal trends also differed by sex, with evidence of a steeper decline in risk for males than for females. Both the nonlinear dose-response and the complex patterns by age and time since exposure mean that simple models cannot adequately summarize leukemia risks.
Preston and colleagues (1994) analyzed data from the leukemia registry. An important recent development in studies of leukemia is the reclassification of leukemia cases by new systems and criteria (Matsuo and others 1988; Tomonaga and others 1991), which allows meaningful analyses of specific types of leukemia. Preston and colleagues evaluated patterns of risk by sex, age at exposure, and time since exposure for four major subtypes of leukemia: acute lymphocytic leukemia (32 cases), acute myelogenous leukemia (103 cases), chronic myelogenous leukemia (57 cases), and adult T-cell leukemia (39 cases). Dose-response relationships were seen for the first three but not for adult T-cell leukemia. The estimated numbers of cases in excess of background were 17.1 for acute lymphocytic leukemia, 29.9 for acute myelogenous leukemia, and 25.9 for chronic myelogenous leukemia. The other major type of leukemia, chronic lymphocytic leukemia, showed no excess, but it is infrequent in Japan.
Results of analyses of all types of leukemia showed dependencies on sex, age at exposure, and time since exposure similar to those for the mortality data and led to a model similar to that based on mortality data. Preston and colleagues note that allowing overall modification by sex and age at exposure in an EAR model did not significantly improve the fit once time since exposure was included in the model, but that these factors significantly modified the time since exposure effects. Specifically, risks for those exposed early in life decreased more rapidly than for those exposed later, and the decrease was less rapid for women than for men. Analyses of specific leukemia types indicated that there were significant differences in the effects of age at exposure and sex and in the temporal pattern of risks. The shape of the dose-response did not show statistically significant differences among the subtypes.ALL SOLID CANCERS
Analyses of cancers in this category, which excludes leukemia and other hematopoietic cancers, are useful for providing summary information and models based on larger numbers than are available for cancers of specific sites (discussed below). The discussion in this section is based on both mortality (Preston and others 2003) and incidence data (Thompson and others 1994). Mortality analyses were based on 9335 solid cancer deaths that occurred during 1950–1997, whereas incidence analyses included 8613 incidence cases occurring during 1958–1987.6
The incidence data do not include cases of subjects who migrated and were diagnosed with cancer outside of Hiroshima and Nagasaki; as noted above, analyses were adjusted for migration.
Preston and collegues estimate that 8% of the 5502 solid cancer deaths among those with doses exceeding 0.005 Sv were due to radiation, much lower than the corresponding percentage of 44% for leukemia. This percentage was slightly higher for the incidence data, where 11% of 4327 cancers in the exposed were estimated to result from radiation exposure (Thompson and others 1994).
6 These numbers contrast with 10,127 solid cancer deaths occurring in 1950–2000 and 12,778 incident cases of solid cancer excluding thyroid and nonmelanoma skin cancer occurring in 1958–1998, the periods covered by analyses conducted by the committee and described in Chapter 12.
=======================Estimating Cancer Riskhttp://www.nap.edu/openbook.php?record_id=11340&page=267INTRODUCTION
This chapter presents models that allow one to estimate the lifetime risk of cancer resulting from any specified dose of ionizing radiation and applies these models to example exposure scenarios for the U.S. population. Models are developed for estimating lifetime risks of cancer incidence and mortality and take account of sex, age at exposure, dose rate, and other factors. Estimates are given for all solid cancers, leukemia, and cancers of several specific sites. Like previous BEIR reports addressing low-LET (linear energy transfer) radiation, risk models are based primarily from data on Japanese atomic bomb survivors. However, the vast literature on both medically exposed persons and nuclear workers exposed at relatively low doses has been reviewed to evaluate whether findings from these studies are compatible with A-bomb survivor-based models. In many cases, results of fitting models similar to those in this chapter have been published.
Risk estimates are subject to several sources of uncertainty due to inherent limitations in epidemiologic data and in our understanding of exactly how radiation exposure increases the risk of cancer. In addition to statistical uncertainty, the populations and exposures for which risk estimates are needed nearly always differ from those for whom epidemiologic data are available. This means that assumptions are required, many of which involve considerable uncertainty. Risk may depend on the type of cancer, the magnitude of the dose, the quality of the radiation, the dose-rate, the age and sex of the person exposed, exposure to other carcinogens such as tobacco, and other characteristics of the exposed individual. Despite the abundance of epidemiologic and experimental data on the health effects of exposure to radiation, data are not adequate to quantify these dependencies precisely. Uncertainties in the BEIR VII risk models are discussed, and a quantitative assessment of selected sources of uncertainty is made.
In recent years, several national and international organizations have developed models for estimating cancer risk from exposure to low levels of low-LET ionizing radiation. These include the work of the BEIR V committee (NRC 1990), the International Commission on Radiological Protection (ICRP 1991), the National Council on Radiation Protection and Measurements (NCRP 1993), the Environmental Protection Agency (EPA 1994, 1999), the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR 2000b), and the National Institutes of Health (NIH 2003). The approaches used in these past assessments are described in Annex 12A.DATA EVALUATED FOR BEIR VII MODELS
As in earlier BEIR reports addressing health effects from exposure to low-LET radiation, the committee’s models for risk estimation are based primarily on the Life Span Study (LSS) cohort of survivors of the atomic bombings in Hiroshima and Nagasaki. As discussed in Chapter 6, the LSS cohort offers several advantages for developing quantitative estimates of risk from exposure to ionizing radiation. These include its large size, the inclusion of both sexes and all ages, a wide range of doses that have been estimated for individual subjects, and high-quality mortality and cancer incidence data. In addition, because the exposure was to the whole body, the LSS cohort offers the opportunity to assess risks for cancers of a large number of specific sites and to evaluate the comparability of site-specific risks.
Another consideration in the choice of data was that it was considered essential that the data used by the committee eventually be available to other investigators. The Radiation Effects Research Foundation (RERF) has developed a policy of making summarized data available to those who request it, thus enabling other investigators to analyze data used by the BEIR VII committee. This is not the case for data sets on most other radiation-exposed cohorts.
Although the committee’s models have been developed from A-bomb survivor data, attention has been given to their compatibility with data from other cohorts. Fortunately, for most cohorts with suitable data for developing quantitative risk models, analyses based on models similar to those used by the committee have been conducted and published. This facilitated the committee’s evaluation of data from other studies. Pooled analyses of thyroid cancer risks (Ron and others 1995a) and of breast cancer risks (Preston and others 2002a) were especially helpful in this regard, as were several meta-analyses by Little and colleagues. In addition, the many published analyses based on A-bomb survivor data have guided and facilitated the committee’s efforts in its choice of models. The committee notes particularly the main publications on mortality (Preston and others 2003) and incidence data (Thompson and others 1994) and the models developed by UNSCEAR (2000b) and NIH (2003).
The use of data on persons exposed at low doses and low dose rates merits special mention. Of these studies, the most promising for quantitative risk assessment are the studies of nuclear workers who have been monitored for radiation exposure through the use of personal dosimeters. These studies, which are reviewed in Chapter 8, were not used as the primary source of data for risk modeling principally because of the imprecision of the risk estimates obtained. For example, in a large combined study of nuclear workers in three countries, the estimated relative risk per gray (ERR/Gy) for all cancers other than leukemia was negative, and the confidence interval included negative values and values larger than estimates based on A-bomb survivors (Cardis and others 1995).
Since the publication of BEIR V, data on cancer incidence in the LSS cohort from the Hiroshima Tumor Registry have become available, whereas previously only data from the Nagasaki Tumor Registry were available. Thus, the committee could use both incidence and mortality data to develop its models. The incidence data offer the advantages of including nonfatal cancers and of better diagnostic accuracy. However, the mortality data offer the advantages of covering a longer period (1950–2000) than the incidence data (1958–1998) and of including deaths of LSS members who migrated from Hiroshima and Nagasaki to other parts of Japan.Summary and Research Needshttp://www.nap.edu/openbook.php?record_id=11340&page=313
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 BIOLOGYMolecular 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.Research Need 2. Determination of DNA repair fidelity, especially as regards double- and multiple-strand breaks at low doses, and determination of whether repair capacity is independent of dose
Repair capacity at low levels of damage must be investigated, especially in light of conflicting evidence for stimulation of repair at low doses.
In such studies the accuracy of DNA sequences rejoined by these pathways has to be determined, and the mechanisms of error-prone repair of radiation lesions must be elucidated. Identification of critical genetic alterations that can be characteristic of radiation exposure would be important.Consideration of Phenomena That Might Affect
Risk Estimates for Carcinogenesis at Very Low Doses
A number of biological phenomena that could conceivably affect risk estimates at very low radiation doses have been reported. These phenomena include the existence of radiation-sensitive human subpopulations, hormetic or adaptive effects, bystander effects, low-dose hyperradiosensitivity, and genomic instability.Radiation-Sensitive Subpopulations
Epidemiologic, clinical, and experimental data provide clear evidence that genetic factors can influence radiation cancer risk. Strongly expressing human mutations of this type are rare and are not expected to influence significantly the development of estimates of population-based, low-dose risks. They are, however, potentially important in the context of high-dose medical exposures. Evidence for the complex interaction of weakly expressing genetic factors in cancer risk is growing, but current understanding is insufficient for a detailed consideration of the potential impact on population risk.Adaptive Response
Adaptive responses have been well documented in bacteria, where exposures to radiation or chemicals induce subsequent resistance to these agents by inducing expression of DNA damage repair genes. This induced expression of repair genes does not occur to a significant extent in human cells, although changes in signal transduction do take place. A type of apparent adaptive response, however, has been documented for the induction of chromosomal aberrations in human lymphocytes stimulated to divide.
In most studies, a priming or adaptive dose of about 10 mGy significantly reduces the frequency of chromosomal aberrations and mutations induced a few hours later by 1000–3000 mGy. Similar effects are sometimes seen with other end points. However, priming doses less than 5 mGy or greater than ~200 mGy generally give very little, if any, adaptation, and adaptation has not been reported for challenge doses of less than about 1000 mGy. To have relevance for risk assessment, the adaptive response has to be demonstrated for both priming and challenging doses of 1–50 mGy.
Furthermore, the induction and magnitude of the adaptive response in human lymphocytes are highly variable, with much heterogeneity demonstrated among different individuals. The adaptive response could not be induced when noncycling lymphocytes were given the priming dose. Although inhibitor and electrophoretic studies suggest that alterations in messenger RNA transcription and protein synthesis 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 effects from low doses of ionizing radiation will have a significant effect in reducing long-term deleterious effects of radiation on humans is unwarranted.Bystander Effects
The bystander effect that results from irradiated cells’ reacting 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 body would not be irradiated. Current limitations of low-LET bystander studies include the lack of demonstrated bystander effects below 50 mGy and uncertainties about whether the effect occurs in vivo. Another complication is that both beneficial and detrimental effects have been postulated for bystander effects by different investigators. Until molecular mechanisms are elucidated, especially as they relate to an intact organism, and until reproducible bystander effects are observed for low-dose low-LET radiation in the dose range of 1–5 mGy, where an average of less than 1 electron tracks traverse the nucleus, the assumption should be made that bystander effects will not influence the shape of the low-dose, low-LET dose-response relationship.Hyperradiosensitivity for Low Doses
In some cell lines, hyperradiosensitivity (HRS) has been reported for cell lethality induced by low-LET radiation at doses less than 100–200 mGy. In this dose range, survival decreases to 85–90%, which is significantly lower that projected from data obtained above 1–2 Gy. It is not known whether HRS for cell lethality would cause an increase in deleterious effects in surviving cells or would actually decrease deleterious effects by increased killing of damaged cells. Until molecular mechanisms responsible for HRS that may or may not play a role in carcinogenesis are understood, the extrapolation of data for HRS for cell lethality to the dose-response for carcinogenesis in the 0–100 mGy range is not warranted.Genomic Instability
During the last decade, evidence has accumulated that under certain experimental conditions, the progeny of cells surviving radiation appear to express new chromosomal aberrations and gene mutations over many postirradiation cell generations. This feature is termed radiation-induced persistent genomic instability. Some inconsistencies were identified in the data that describe the diverse manifestation of induced genomic instability, and clear evidence of its general involvement in radiation-induced cancer is lacking. Although developing data on the various phenomena classified as genomic instability may eventually provide useful insights into the mechanisms of carcinogenesis, it is not possible to predict whether induced genomic instability will influence low-dose, low-LET response relationships.Research Need 3
. Evaluation of the relevance of adaptation, low-dose hypersensitivity, bystander effects, and genomic instability for radiation carcinogenesis
Mechanistic data are needed to establish the relevance of these processes to low-dose radiation exposure (i.e., <100 mGy). Relevant end points should include not only chromosomal aberrations and mutations but also genomic instability and induction of cancer. In vitro and in vivo data are needed for delivery of low doses over several weeks or months at very low dose rates or with fractionated exposures. The cumulative effect of multiple low doses of less than 10 mGy delivered over extended periods has to be explored further. The development of in vitro transformation assays utilizing nontransformed human diploid cells is judged to be of special importance.Hormesis
The possibility that low doses of radiation may have beneficial effects (a phenomenon often referred to as “hormesis”) has been the subject of considerable debate. Evidence for hormetic effects was reviewed, with emphasis on material published since the 1990 BEIR V study on the health effects of exposure to low levels of ionizing radiation. Although examples of apparent stimulatory or protective effects can be found in cellular and animal biology, the preponderance of available experimental information does not support the contention that low levels of ionizing radiation have a beneficial effect. The mechanism of any such possible effect remains obscure. At this time, the assumption that any stimulatory hormetic effects from low doses of ionizing radiation will have a significant health benefit to humans that exceeds potential detrimental effects from radiation exposure at the same dose is unwarranted.Research Need 4. Identification of molecular mechanisms for postulated hormetic effects at low doses
Definitive experiments that identify molecular mechanisms are necessary to establish whether hormetic effects exist for radiation-induced carcinogenesis.Radiation-Induced Cancer:
Mechanism, Quantitative Experimental Studies,
and the Role of Molecular Genetics
A critical conclusion on mechanisms of radiation tumorigenesis is that the data reviewed greatly strengthen the view that there are intimate links between the dose-dependent induction of DNA damage in cells, the appearance of gene or chromosomal mutations through DNA damage misrepair, and the development of cancer. Although less well established, the data available point toward a single-cell (monoclonal) origin for induced tumors and suggest that low-dose radiation acts predominantly as a tumor-initiating agent
These data also provide some evidence on candidate, radiation-associated mutations in tumors. These mutations are predominantly loss-of-function DNA deletions, some of which are represented as segmental loss of chromosomal material (i.e., multigene deletions).
This form of tumorigenic mechanism is broadly consistent with the more firmly established in vitro processes of DNA damage response and mutagenesis considered in Chapters 1 and 2. Thus, if as judged in Chapters 1 and 2, error-prone repair of chemically complex DNA double-strand damage is the predominant mechanism for radiation-induced gene or chromosomal mutation, there can be no expectation of a low-dose threshold for the mutagenic component of radiation cancer risk.
One mechanistic caveat explored was that novel forms of cellular damage response, collectively termed induced genomic instability, might contribute significantly to radiation cancer risk. The cellular data reviewed in Chapter 2 identified uncertainties and some inconsistencies in the expression of this multifaceted phenomenon.
However, telomere-associated mechanisms did provide a coherent explanation for some in vitro manifestations of induced genomic instability. The data considered did not reveal consistent evidence for the involvement of induced genomic instability in radiation tumorigenesis, although telomere-associated processes may account for some tumorigenic phenotypes. A further conclusion was that there is little evidence of specific tumorigenic signatures of radiation causation, but rather that radiation-induced tumors develop in a tumor-specific multistage manner that parallels that of tumors arising spontaneously.Quantitative animal data on dose-response relationships provide a complex picture for low-LET radiation, with some tumor types showing linear or linear-quadratic relationships while other studies are suggestive of a low-dose threshold, particularly for thymic lymphoma and ovarian cancer
. Since, however, the induction or development of these two cancer types is believed to proceed via atypical mechanisms involving cell killing, it was judged that the threshold-like responses observed should not be generalized.
Radiation-induced life shortening in mice is largely a reflection of cancer mortality, and the data reviewed generally support the concept of a linear dose-response at low doses and low dose rates. Other dose-response data for animal tumorigenesis, together with cellular data, contributed to the judgments developed and the choice of a DDREF for use in the interpretation of epidemiologic information on cancer risk.
Adaptive responses for radiation tumorigenesis have been investigated in quantitative animal studies, and recent information is suggestive of adaptive processes that increase tumor latency but not lifetime risk. However, these data are difficult to interpret, and the implications for radiological protection remain most uncertain.Research Need 5. Tumorigenic mechanisms
Further cytogenetic and molecular genetic studies are needed to reduce current uncertainties about the specific role of radiation in multistage radiation tumorigenesis; such investigations would include studies with radiation-associated tumors of humans and experimental animals.
The review of cellular, animal, and epidemiologic or clinical studies on the role of genetic factors in radiation tumorigenesis suggests that many of the known strongly expressing cancer-prone human genetic disorders are likely to show an elevated risk of radiation-induced cancer, probably with a high degree of organ specificity. Cellular and animal studies suggest that the molecular mechanisms underlying these genetically determined radiation effects largely mirror those that apply to spontaneous tumorigenesis and are consistent with knowledge of somatic mechanisms of tumorigenesis. In particular, evidence was obtained that major deficiencies in DNA damage response and tumor-suppressor-type genes can serve to elevate radiation cancer risk.
Limited epidemiologic data from follow-up of second cancers in gene carriers receiving radiotherapy were supportive of the above conclusions, but quantitative judgments about the degree of increased cancer risk remain uncertain. However, since major germline deficiencies in the genes of interest are known to be rare, it has been possible to conclude from published analyses that they are most unlikely to create a significant distortion of population-based estimates of cancer risk. The major practical issue associated with these strongly expressing cancer genes is judged to be the risk of radiotherapy-related cancer.
A major theme developing in cancer genetics is the interaction and potential impact of more weakly expressing variant cancer genes that may be relatively common in human populations. The animal genetic data provide proof-of-principle evidence of how such variant genes with functional polymorphisms can influence cancer risk, including limited data on radiation tumorigenesis. Attention was also given to human molecular epidemiology data on associations between functional polymorphisms and cancer risk, particularly with respect to DNA damage response genes.
Given that functional gene polymorphisms associated with cancer risk may be relatively common, the potential for significant distortion of population-based risk was explored with emphasis on the organ specificity of the genes of interest. An interim conclusion was that common polymorphisms of DNA damage response genes associated with organ-wide radiation cancer risk would be the most likely source of major interindividual differences in radiation response.Research Need 6. Genetic factors in radiation cancer risk
Further work is needed in humans and mice on gene mutations and functional polymorphisms that influence the risk of radiation-induced cancers. Where possible, human molecular genetic studies should be coupled with epidemiologic investigations.GENETIC EFFECTS OF RADIATION ON HUMAN POPULATIONS
As noted in BEIR V, heritable effects of radiation
are estimated using what is referred to as the “doubling dose method” and expressed in terms of increases in the frequencies of genetic diseases in the population over and above those that occur as a result of spontaneous mutations. The doubling dose (DD) is the amount of radiation required to produce as many mutations as those that occur spontaneously in a generation and is calculated as a ratio of the average rates of spontaneous and induced mutations in defined genes. If the DD is small, the relative mutation risk per unit dose (i.e., 1/DD) is high, and if DD is large, the relative mutation risk is low. The DD, therefore, provides a convenient yardstick to express risks and a perspective of whether the predicted increases are trivial, small, or substantial relative to the baseline.
The committee concludes that the current scientific evidence is consistent with the hypothesis that there is a linear, no-threshold dose-response relationship
between exposure to ionizing radiation and the development of cancer in humans.