The G2 chromosomal radiosensitivity assay (also known as G2 assay) is a method that illustrates the existence of enhanced radiosensitivity and cancer predisposition based on the chromatid aberrations after G2-phase irradiation. For the evaluation of the individual radiosensitivity with this technique, peripheral blood lymphocytes are irradiated in vitro in their G2-phase of the cell cycle, incubated to allow repair of DNA damage, and blocked in mitosis by the use of colcemid, so that the chromatid aberrations can be observed and quantified. A high yield of chromatid breaks can indicate high radiosensitivity. This methodology has a major advantage as it enables a time-efficient individual radiosensitivity assessment.


The original G2 assay was developed by Sanford et al. [126]. However, a significant problem of this method was the high variability in radiation-induced damage observed in different samples even from the same donor. In addition, there was often an overlap between the G2 chromatid aberration yield in lymphocytes from healthy donors and cancer patients. Following further development, Terzoudi et al. [127, 128] proposed the use of caffeine in order to induce G2/M checkpoint abrogation, simulating this way the high radiosensitivity of AT patients. AT cells are known to have a defective G2/M checkpoint arrest and therefore AT patients are highly radiosensitive. With the use of caffeine, it was feasible to express the individual radiosensitivity in relation to the high radiosensitivity level observed in AT patients (Figs. 7.8 and 7.9). This protocol has a great advantage that it minimizes the effects of laboratory specific parameters and makes the inter-laboratory comparison feasible by enabling an ameliorated intra-experimental and inter-laboratory reproducibility. More recently, efforts have been realized for further optimization of the G2 assay by using other DNA Damage Response (DDR) and G2-checkpoint inhibitors—than caffeine—such as ATR- or ATM/ATR inhibitors (e.g., VE-821 and UCN-1). Of these inhibitors, VE-821 has been proven effective in a rapid radiosensitivity assessment of different cell lines as well as normal tissue and primary tumor cells [129].

An illustration of a cluster of chromosomes. Some have broken chromatids, while arrows point from one pair of chromosomes to the other.

Fig. 7.8
G2 chromosomal radiosensitivity assay. Chromatid breaks after 1 Gy of γ-irradiation as visualized at a metaphase peripheral blood lymphocyte from a healthy donor where four chromatid breaks are observed. (Reproduced with permission from [128])

An illustration of a cluster of chromosomes, some with broken chromatids.

Fig. 7.9
G2 chromosomal radiosensitivity assay. Chromatid breaks after 1 Gy of γ-irradiation as visualized at a metaphase peripheral blood lymphocyte after applying G2-checkpoint abrogation by means of caffeine where 13 chromatid breaks are visualized. (Reproduced with permission from [128])


An illustration of a cluster of chromosomes. Some have broken chromatids, while arrows point from one pair of chromosomes to the other.


An illustration of a cluster of chromosomes, some with broken chromatids.


Age at the time of radiation exposure is a key factor contributing for radiation-induced health effects, namely cancer. In a general way, it is accepted that individuals exposed at early ages are the most radiosensitive, whereas the latency period from primary damage to outbreak into cancer is longer. Then, radiation sensitivity decreases until maturity and increases again at older ages [130, 131]. In addition, considering that both cancer incidence and mortality rates increase with age, a model of radiation-induced cancer must also include the attained age. Attained age is defined as the sum of the age of the person at the time of radiation exposure and the period elapsed since the radiation exposure (“attained age” = “age-at-exposure” + “time since exposure”) [132].


Age-time patterns may also be represented as the “time since exposure,” corresponding to the “attained age” subtracting the “age-at-exposure.” For example, the cancer risk for someone with an age at exposure of 15 years and observed at an attained age of 40 years (time since exposure of 25 years) will be different from the risk for someone exposed at the same age but observed at an attained age of 79 years (time since exposure of 64 years) [132].


The understanding of the age-related alterations that may compromise individuals’ health after exposure to IR is increasingly relevant, along with the elucidation of the biological mechanisms underlying the aging-radiation exposure association. The fact that life expectancy of the worldwide population is steadily rising emphasizes the urgent need for a better understanding of the relationship between aging and sensitivity to radiation, which impacts radiation protection in clinical practice [130].


Epidemiological studies developed in the Life Span Study (LSS) cohort of the Japanese atomic bomb survivors have provided valuable data on the relationship between the age at the time of exposure and oncogenic risks. The most standard models for radiation sensitivity, based on the measure of carcinogenic events, predict that the relative risks decrease monotonically with the increase of age at exposure, at all ages. However, new epidemiological data suggest that risks differ by age at the time of radiation exposure and by type of cancer (Fig. 7.10) [130].

A line graph of relative susceptibility of cancers over time. Leukemia and cancer of brain, skin, and thyroid peaks at birth and reduces by childhood. Breast and uterine cancers peak at puberty. Most solid cancers reduce over time. Lung cancer increases. Cancer of colon, liver, and bladder reduce.

Fig. 7.10
Schematic representation of the relationship between the relative susceptibility and the age at exposure. (Reproduced with permission from [133])


A line graph of relative susceptibility of cancers over time. Leukemia and cancer of brain, skin, and thyroid peaks at birth and reduces by childhood. Breast and uterine cancers peak at puberty. Most solid cancers reduce over time. Lung cancer increases. Cancer of colon, liver, and bladder reduce.


Data from the LSS cohort of the Japanese atomic bomb survivors showed that the excess relative risks (ERRs) of developing cancer following radiation exposure were higher during childhood and progressively decreased as a function of age until ages of 30–40 years old. However, for ages of exposure higher than 40, the ERR of developing solid cancer increased again. Thus, a bimodal distribution of radiation-induced cancer risks is associated with different biological processes. The greater susceptibility of children to radiation carcinogenesis is thought to be associated with three mechanisms: (1) long latency period between the primary injury and the cancer onset, that make children more likely to experience the long-term consequences, such as cancer; (2) faster radionuclides accumulation in growing bones compared to bones of an adult; (3) high frequency of cell division (as the one occurring in a growing organism) may allow an impairment of the radiation-induced DNA damage repair mechanisms. At a cellular level, this high radiosensitivity of children may be also related with the initiation of malignant processes due to the larger number of stem cells that can derive into cancer cells in younger people compared with aged ones. On the other hand, the radiation risks for individuals exposed at later ages are related to the age-related deterioration of cell functions, which can be responsible for an augmented susceptibility for oncogenic transformation [130, 131, 134].


The results of surveys targeting atomic bomb survivors also showed that the periods that relate to high radiation sensitivity vary according to the type of cancer. For individuals exposed while they were young, the risks of thyroid and stomach cancers and solid cancer as a whole are higher, while individuals exposed during puberty have an increased risk of breast cancer and people with 40 years old or older have increased risk of lung cancer [135, 136].


The higher radiosensitivity of individuals exposed at early ages is likely to have a long-term biological counterpart in their organisms. The mechanistic interplay between age and radiosensitivity is thought to be influenced by age-related cellular changes, such as impaired DNA damage repair, telomere erosion and accelerated cellular senescence, augmented susceptibility of cells to oxidative stress and inflammation, and radiation-induced epigenetic alterations (Fig. 7.11) [130, 131].

An illustration of the mechanistic interplay between age and radiosensitivity for impaired D N A damage repair, telomeres attrition, oxidative stress, and epigenetic alterations in young and aged cells.

Fig. 7.11
Age-related cellular changes that may influence radiosensitivity and their mechanistic interplay. Compared to young cells, aged cells present increased impaired DNA damage repair, telomeres attrition, increased oxidative stress, and additional epigenetic alterations


An illustration of the mechanistic interplay between age and radiosensitivity for impaired D N A damage repair, telomeres attrition, oxidative stress, and epigenetic alterations in young and aged cells.


Aged cells show a decline in the efficiency of the DNA damage response (DD) after radiation-induced DNA DSBs. The DDR should begin with the recruitment of proteins involved in both nonhomologous end joining (NHEJ) and homologous recombination (HR) repair pathways (see Chap. 3). Aged cells present several defects in these repair pathways such as delayed DDR kinetics, poor repair efficiency, and compromised repair due to chromatin reorganization as a result of aging. Thus, the aging process entails a disturbed nuclear organization that may compromise the recruitment of DDR proteins to the site, where they are needed, the nucleus. Irradiating aged cells will increase the damages in an already dysfunctional repair system, leading to irreversible damages. These damages are usually persistent and appear in a chronic mode increasing the damage burden in cells and tissues. Such accumulated damages can trigger enhanced inflammatory and immune system responses often leading to pathophysiological conditions like autoimmune disease and sensitivity to radiation and other types of environmental stresses [130, 137, 138].


Previous studies showed that telomere shortening relates to increased radiosensitivity. When aged cells escape from replicative senescence (a state of permanent growth arrest induced when shortened telomere length is attained), telomeres keep getting shorter, originating a greater number of uncapped chromosomes available to rearrangements. This loss of telomere integrity leads to an increase of genomic instability, which can initiate a carcinogenic process [130, 131].


Although there is some controversy about the causal relation between oxidative stress and an aged phenotype, it is known that aged cells have higher ROS levels production and a compromised antioxidant machinery compared with younger cells. This progressive loss of the pro-oxidant/antioxidant equilibrium compromises both cellular structures and homeostasis of aged cells. Exposing these aged cells to IR will unequivocally overload the antioxidant system, making them more susceptible to the IR-induced cell damages [139].


Radiation-induced oxidative stress can drive epigenetic alterations, such as (1) DNA hypomethylation through 8-OHdG methylation inhibition or DNA demethylation processes, (2) DNA hypermethylation through DNA methyltransferase up-regulation or DNA methylation catalysis, (3) histone modifications, and (4) miRNA expression. On the other hand, cumulative epigenetic alterations can also occur upon aging. Although this topic must be further explored, it seems to be a relation between epigenetic alterations and age-dependent radiosensitivity [131].


In children/adolescents/young adults, RT remains essential for the curative treatment of brain tumors, Hodgkin lymphomas (HL), acute leukemias, Ewing and soft tissue sarcomas, neuroblastomas, nephroblastomas, or high-risk retinoblastomas. Life expectancy is long for the 80% of children/adolescents who are likely to be cured. The incidence of acute post-radiation complications, especially late, and proportional to the dose delivered may exceed that in adults. In fact, the cumulative incidence of overall iatrogenic sequelae 30 years after the end of treatment reaches more than 70% in this population compared to 15% maximum in the adult population after a median 3–5 years of follow-up. This late toxicity can lead to sometimes lethal sequelae with a major socio-economic impact (e.g., educational problems, parental mobilization, difficulties in entering the workforce, hospitalizations and costly symptomatic treatments and impoverishment, etc.). Along with high cure rates in this population, radiation-induced cancers appear with a probabilistic distribution (20-year cumulative incidence of secondary malignancies 3%)—but the incidence of which increases with the dose delivered and the duration of follow-up. Also note, however, that risk of secondary cancers increases in cancer patients who have not had prior radiation treatment as well as those who had chemotherapy [140, 141]. Differences are observed in the long-term, site-specific patterns of excess radiation inducing second malignancies between survivors of childhood cancer and adult-onset cancer, in terms of second malignancies histologic distribution, magnitude of risk, latency period, associated risk factors (genetic predisposition, environmental exposures, hormonal factors, and immune function) [142, 143].


On the other hand, RT is essential in the multidisciplinary management of the majority of cancer types in elderly patients, where it sometimes is considered as the first treatment option, often hypofractionated, and in others, as an alternative to surgery and/or chemotherapy.


In adults and the elderly, self-sustaining inflammation, fibrosis/atrophy, microcirculatory abnormalities are more readily associated with radiation-induced sequelae. In addition, in children, the manifestation of radiation-induced sequelae involves abnormalities in tissue maturation, delays (or even cessation) of growth of irradiated tissues—resulting in additional hypoplasia and/or hypofunction [144].


In adults, the distribution of individual radiosensitivity follows a Gaussian curve, and the toxicity observed in 5% of the most radiosensitive individuals is at the origin of dose recommendations to be applied to organs at risk in any patient in daily RT practice. There are many reasons to believe that this is not the case with children and seniors, with likely great variability with age. This is especially true if one consider all the changes in metabolic functions throughout growth and/or due to additional comorbidities, variations in tumor death, and tissue healing pathways with age and tumor predispositions associated with childhood cancer involving DNA repair pathways (assuming that this trait correlates with individual radiosensitivity).


Differences in organ development and tissue repair in children and adults have a significant effect on the expression of radiation injury. In many tissues, organ development is supported by cell proliferation from the prenatal period. During the development of each tissue, pluripotent embryonic stem cells differentiate into different unipotent lineages that will participate in mature tissue homeostasis. Some stem cells remain—ensuring self-renewal within the tissue. Thus, these two mechanisms are involved in growth as well as in tissue repair and regeneration. As the tissue matures, each organ thus contains a mosaic of dividing cells that are at rest either transiently or permanently. During childhood and adolescence, body tissues follow different growth patterns with their own kinetics. Not surprisingly, the rapid growth of normal tissues also seems to coincide with increased tissue radiosensitivity and, consequently, with a higher susceptibility to radiation-induced neoplasia. Overall, neurocognitive effects, development of muscles, and growth of bones are all sensitive to the age at treatment. For example, the intelligence quotient (IQ) deteriorates more in children irradiated on the brain before the age of 5 years compared to older children [145].


In contrast, in the elderly, the cells of the proliferative compartment move toward a permanent state of rest or senescence. This aging process becomes critical after injury because, although senescent cells are capable of metabolic functions, they lose their proliferative capacity after stress such as radiation. Therefore, late effects in the elderly population can be seen as the result of an interaction between their diminishing ability of cells to repair themselves after injury and their natural tendency to progress to a state of senescence, which itself can be accelerated by irradiation.


Only very rare cases of children have been studied for their individual radiosensitivity. Three genetic syndromes have formally been associated with RT-induced fatal non-cancer adverse tissue events:  AT (homozygous ATM mutations), LIG4 syndrome (homozygous LIG4 mutations), Nijmegen’s syndrome (homozygous NBS1 mutations)—all characterized by the impairment in DSB repair and signaling pathways (see detailed information in Sect. 7.8). Noticeably, some syndromes also confer an increased individual cancer predisposition. Some cases of significant radiosensitivity with mutations of genes whose function was not expected in the radiation response have to be stressed—involving cytoplasmic functions or cell scaffold and membrane organization (for example, Huntingdon disease, Usher syndrome; [146]).


The individual radiosensitivity in children/adolescents and elderly is thus so far mainly unknown, and clinical trials are pending using individual radiosensitivity assays and very long-term observational studies (Box 7.5).


Age at time of radiation exposure is a key factor contributing to radiation-induced health effects.

New epidemiological data suggest that risk of developing cancer differs by age at the time of radiation exposure as well as by type of cancer.

Cellular and molecular changes related to aging influence radiosensitivity.

Differences in organ development and tissue repair in children and adults have a significant effect on the expression of radiation injury.


Age at time of radiation exposure is a key factor contributing to radiation-induced health effects.


New epidemiological data suggest that risk of developing cancer differs by age at the time of radiation exposure as well as by type of cancer.


Differences in organ development and tissue repair in children and adults have a significant effect on the expression of radiation injury.


The different individual radiosensitivity may be affected by genetic and individual factors as well as by lifestyle factors. One of the individual factors that have been associated with radiation sensitivity is biological sex.


The different radiosensitivity and radiosusceptibility for each sex could be due to biological factors. The human sex is determined by the sex chromosomes, namely by Y and X chromosomes. Whereas females have two X chromosomes, males have one Y and one X chromosome. These two sex chromosomes differ in terms of length, structures, and in the number and types of genes. Thus the X chromosome is approximately 160 Mb with more than 1000 genes while the Y chromosome is approximately 65 Mb with only 100 genes. The Y-specific genes are expressed mostly in testicular tissue with the SRY gene being the most important for determining male sex [147, 148].


Gene mutations or defects in gene expression of sex chromosomes dominantly affect the X chromosome and could be responsible for the death of the zygote and, consequently, decrease female birth. It also is hypothesized that differences in biological sex-related radiation responses could be due to immunological and hormonal differences apart from epigenetic and genetic factors. The mechanism underlying biological sex-related radiation sensitivity is still not clear and needs to be studied in more detail. Until now, it is known that the cellular response to radiation is highly complex and involves several processes like alterations in gene expression, signal transduction, repair process, and cell proliferation and death which could vary with sex.


Most of the data used for improving the knowledge on radiation-induced health effects and radioprotection was gained from the atomic bomb survivors in Hiroshima and Nagasaki (in Japan) and Chernobyl (in Ukraine). Also, the development of other epidemiological and cohort studies to evaluate the effects of radiation on the population exposed to high-dose levels due to medical reasons, radiation accidents, or from natural sources, contributed to the effects documented till now, as summarized in Figs. 7.12 and 7.13. The use of cancer risk models allows to predict the excess relative risk (ERR), i.e., the proportional increase in risk over the background absolute risk, and the excess absolute risk (EAR) of cancer, i.e., the additional risk above the background absolute risk, of cancer as a consequence of radiation exposure [134].

An illustration of the health risks to different radiation exposures in males and females. The different exposures in increasing order of risk are occupational exposure, A-bomb survivors, and Chernobyl disaster. The health risks are listed under each exposure for males and females.

Fig. 7.12
Summary of biological sex-dependent health risks induced by radiation exposure. (Reproduced with permission from [149])

An illustration of the most common radiation-exposure associated morbidities in males and females, along with their details.

Fig. 7.13
Summary of most common morbidities induced by radiation exposure for each biological sex. (Reproduced with permission from [149])


An illustration of the health risks to different radiation exposures in males and females. The different exposures in increasing order of risk are occupational exposure, A-bomb survivors, and Chernobyl disaster. The health risks are listed under each exposure for males and females.


An illustration of the most common radiation-exposure associated morbidities in males and females, along with their details.


The analyses of the several investigations done since 1945, based on data from Hiroshima and Nagasaki A-bomb survivors, revealed a higher incidence of cancer with elevated rated of leukemia, breast cancer, thyroid carcinoma, stomach and lung cancers, with risk for solid cancers varying with sex (Table 7.7). Related to radiation-induced lung cancer (LC), an increased radiation risk was evidenced and it is nearly four times greater for females than males [150]. Furthermore, a report on mortality from a follow-up from 1950 to 1997 showed that only ERR of cancer is far higher for females than males, without significance for EAR [134] (UNSCEAR 2000).Table 7.7
Values for excessive relative risk per Sv (ERR/Sv) obtained from A-bomb survivors data for age at exposure of 30 years (UNSCEAR 2000)

Cancer type

Males

Females

Female/male ratio

All solid cancer

0.38

0.79

2.1

Lung

0.50

2.18

4.3

Esophagus

0.41

0.84

2.1

Stomach

0.29

0.60

2.1

Colon

0.46

0.95

2.1

Liver

0.58

0.58

1.0

Bladder

1.18

0.98

0.8

Breast

0

1.55

–

Other cancer

0.47

0.28

0.6


Reports and studies based on the nuclear catastrophe in Chernobyl in 1986, where the population was exposed mostly to iodineIodine-131, showed an increased incidence of a range of cancers. Apart from the incidence of the same types of cancers report from A-bomb survivors (Table 7.7), there was also an increase in the incidence of bladder cancer and renal-cell carcinoma. There are still new cases of non-hematological cancers detected every year, so it is too early to present the final reports. The development of various radiation-related health problems in people living in the contaminated territories of Ukraine, Russia, and Belarus were more evident in women, inclusively by affecting their reproductive abilities and leading to an increase in the number of spontaneous miscarriages, mostly of the female fetus. Moreover, in Ukraine, the development of thyroid cancer was seen 2.5 times more often in females than in males who lived in contaminated territories [149, 151].


Data from the most recent nuclear accident in Fukushima is not yet enough to reach conclusions. Although the residing population was immediately evacuated from the most contaminated area, in the most affected areas that were not evacuated, average doses to adults in the first year were estimated to be <4 mSv, so discernable increases in related cancers are not expected (UNSCEAR 2021).


Studies from health care workers exposed to IR strongly indicate that occupational exposure leads to increased rates of IR-related cancers. Although these outcomes are associated with dose and also are age dependent, little attention has been given to biological sex [149].


A study carried out in Mayak workers about LC mortality revealed that ERR is four times higher for females than males, but the EAR is 0.43 less in the same comparison. Related to other cancers, the ERRs per Gy is also higher in females than males for lung, liver, and bone cancers. Moreover, a cohort study from Sweden, Denmark, and the USA about the carcinogenic effects of long-term internal exposure to alpha-particles radionuclides showed no significant differences between sex for solid cancer. The reduction of the female birth rate was also reported for the population living close to nuclear power plants or affected by nuclear testing [147, 149].


Thus, the epidemiological studies presenting separated risk coefficients for females and males do not present a consensus about sex-related radiation sensitivity. Although the studies from A-bomb survivors demonstrated higher ERR values for women than for men for all solid cancers, the corresponding EAR values are similar for males and females when sex-specific organs are not considered. The data collected from the radiation-induced occurrence of the same cancer type in different cohorts is also inconsistent. Although all these differences, the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) concludes that the EAR and ERR for total solid tumors are around two times higher in women than men, varying with site and organs, but for leukemia, no sex differences were observed [147, 149].


Several experiments were carried out in animal models to provide clear information about the relationship between biological sex and radiation sensitivity as well as to confirm and expand the evidence obtained from epidemiological studies. Also, cell models were created from peripheral blood samples from healthy donors, cell lines, or primary cultures from organs of interest. These studies made it possible to study in depth the molecular mechanism inherent to sex differences in radiation sensitivity, namely to access cellular responses to IR, whole-genome screening for gene expression, and analyses of epigenetic regulatory mechanisms [147].


The data obtained through the analyses of gene expression as well as from epidemiological studies showed no correlations among the sex-specific expressed genes and corresponding cellular phenotypes. Nevertheless, a much higher incidence of thymic lymphoma and osteosarcoma have been found in female mice after treatment with 227Th than in male mice. Most recently, it was reported bystander effects in the non-radiated spleen of mice and rats varying according to the sex-specific differences. A sex-specific activation of distinct pathways was also suggested in mice, in response to whole-body irradiation as well as different tissues and organs irradiations with acute and chronic low doses [147, 149].


The differences in radiosensitivity of males and females could be due to biological factors.

UNSCEAR concludes that the EAR and ERR for solid tumors are around two times higher in females than in males.

The identification of biological sex-related radiosensitivity will contribute to personalized dose and fractionation for RT as well as for radiation protection.

Currently, the annual dose limits for occupational exposures recommended by ICRP do not recognize sex.


The differences in radiosensitivity of males and females could be due to biological factors.


UNSCEAR concludes that the EAR and ERR for solid tumors are around two times higher in females than in males.


The identification of biological sex-related radiosensitivity will contribute to personalized dose and fractionation for RT as well as for radiation protection.


Currently, the annual dose limits for occupational exposures recommended by ICRP do not recognize sex.


The severity of tissue reactions observed in cancer patients exposed to the same dose of IR during RT is assigned to differences in individual radiosensitivity [152]. It is generally believed that individual radiosensitivity is genetically determined based on the existence of certain hereditary diseases that we detailed more in Chap. 3. Moreover, the response to RT could also be influenced by other facts than the biological and physiological differences between males and females in organs and tissues, such as lifestyle, i.e., be sex related (Box 7.6).


There was evidence that females when exposed to the same whole-body exposure dose of IR have a greater risk of cancer than males [153]. Moreover, radiogenomic research has brought evidence that individual polymorphisms are correlated with treatment response with significant differences between females and males. However, the few available findings do not allow any conclusions to be drawn about sex-specific differences in radiation sensitivity, mostly because there are no studies that present enough data to support these hypotheses, without other confounding factors, or whose focus is specifically on sex [154]. So, the inclusion of biological sex or even gender as a variable in future randomized control trials or cohort studies will be crucial. The identification of the individual radiosensitivity of each patient will allow a personalized dose adjustment for RT as well as to use the values to improve the protection of occupationally exposed persons.


Regarding fractionation, high total doses delivered at a high-dose rate, in fractions, at appropriate intervals showed a lesser genetic effect in both males and females than the same dose delivered in a single fraction. It was also reported that the magnitude of its reduction is the same as the low dose rate effect.


Since its foundation, the International Commission on Radiological Protection (ICRP) has issued recommendations and guidelines related to the use of IR, based on the most recent scientific evidence and experience obtained through the years of implementation of the system of radiation protection. Until now, the annual dose limit for occupational exposure recommended by ICRP is not based on individual characteristics, such as biological sex or gender. Although the inclusion of these characteristics will increase the complexity of the model, it would be a critical step to overcome the actual generalized system used for determining the proper radiation protection for each specific case [134].


Two radiation research projects, Multidisciplinary European Low Dose Initiative (MELODI, https://melodi-online.eu/) and European Alliance Medical Radiation Protection Research (EURAMED, https://www.euramed.eu/), have been working on this topic defining the individual differences in radiation sensitivity as a key research priority.


Ataxia Telangiectasia (AT) is an autosomal recessive neurodegenerative disease that is caused by mutations in AT mutated (ATM) gene. A-T was first described by Sillaba and Henner in 1926, however, its phenotypic spectrum was only expanded after the description of the ATM gene in 1995. A-T has a worldwide estimated prevalence of 1:40,000 to 1:100,000 and is related with a poor prognosis and a short life span, being chronic pulmonary diseases and malignancy the A-T-related most common causes of death [155, 156].

An illustration of four D N A lesions, their treatment pathways, and their syndromes. The lesions are as follows: Single-strand break, single-base damage, bully lesions and crosslinks, base mismatch, and double-strand break, or D S B.

Fig. 7.14
Overview of DNA damage and repair pathways and most common genetic disorders


An illustration of four D N A lesions, their treatment pathways, and their syndromes. The lesions are as follows: Single-strand break, single-base damage, bully lesions and crosslinks, base mismatch, and double-strand break, or D S B.


As the main known gene related to A-T clinical phenotype, ATM gene contains 66 exons and encodes the ATM protein, one of the three members of the PI3K-like family. ATM protein plays a pivotal role in the activation of cellular signaling pathways upon DSBs, apoptosis, and genotoxic stresses, such as IR. It functions essentially in the nuclear compartment; however, it is known that ATM is also present as a soluble protein in the cytoplasm [157]. In the nucleus, as part of DNA damage response upon DNA DSBs or oxidative stress, ATM is activated leading to a phosphorylation cascade of several target substrates involved in DNA repair, chromatin remodeling, cell cycle checkpoint, and transcription, namely P53 (S15), CHK2 (T68), and MDM2 (S395). In the cytoplasm, it is thought to be responsible for the functions of peroxisomes and mitochondria upon oxidative stress stimuli, as well as regulating angiogenesis, glucose metabolism, and telomere processing [155, 158].


A-T is a complex multisystem disorder characterized by a phenotypic heterogeneity, since patients show a broad range of clinical manifestations, including progressive cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasia, increased metabolic diseases, radiosensitivity, and cancer predisposition. Other abnormalities can also be manifestations of A-T, such as dystonia, chorea, athetosis, tremor, and parkinsonism. Clinical heterogeneity of A-T can be assigned to different types of mutations that cause an impaired ATM protein expression or affect its function in different ways. Clinical and preclinical studies revealed that the presence of inactive ATM is more cancer prone and lethal than null ATM [156, 157]. A-T patients show potentially a 10–25% increased risk of developing cancer, due to their immunodeficiency. In childhood, the most common types of malignancy are leukemia and lymphoma, while adults may also develop different solid tumors, namely breast, gastric, liver, parotid gland, and esophageal carcinomas. It is described that heterozygous ATM mutations lead to an increased risk of 5.1 for the development of breast cancer, compared to the general population; while ATM monoallelic defects are associated with an estimated relative risk of ~3%. Although there are some controversy on the association between ATM mutations and breast cancer susceptibility, cancer screening guidelines are being developed for ATM-mutated carriers [155].


The first association between the A-T caused by ATM homozygous mutations and its higher human radiosensitivity was made in 1975. This hypothesis has been clearly strengthened over the years by the fact that several studies reported lower SF2 (survival fraction at 2 Gy) in ATM-mutated cells compared to other radiosensitive cases, reinforcing its higher radiosensitivity. These cells are inclusively characterized as hyper-radiosensitive (SF2 ranging from 1% to 10%). In a mechanistic point of view, it is proposed that ATM protein may act upstream of the molecular process of radiation response, namely upstream of the predominant DSB repair pathway, NHEJ. Although it is not yet fully understood which of the ATM functions has the biggest influence on radiosensitivity, the hyper-radiosensitivity of ATM-mutated cells is mainly explained by the deficient recognition of DSBs by NHEJ, as a consequence of the absence of an ATM kinase activity in the nucleus [158].


DNA ligase IV deficiency or Ligase 4 (or LIG4) syndrome is an extremely rare autosomal recessive disease caused by mutations in DNA ligase IV. LIG4 was the first radiosensitive-severe combined immunodeficiency (RS-SCID) disorder to be described and belongs to the group of hereditary disorders associated with impaired DNA damage response mechanisms. Only few cases were recognized with LIG4 worldwide, the reason why its prevalence is difficult to estimate [159].


The LIG4 gene encodes a key component of the major DSB repair machinery, the NHEJ pathway. This pathway constitutes a multistep process that involves several proteins, such as Ku 70/80, DNA-PKcs, XRCC4, and DNA ligase IV, among others ([160]; see also Chap. 3). DNA ligase IV is an ATP-dependent ligase IV involved in the final step of NHEJ. It forms a complex with XRCC4 and then interacts with DNA-PKcs and XLF to rejoin a pair of DNA ends. DNA ligase IV also develops an important role in the production of T and B lymphocytes receptors, being recruited to repair programmed DNA DSB induced during lymphocyte receptor development [160].


All mutations of LIG4 gene identified in patients are located near its active site and are typically hypomorphic. This means they are not fully inactivating, since they do not affect ligase expression and maintain a residual but impaired activity of the enzyme (5–10% compared to the wild-type) [159, 160].


Clinically and morphologically, LIG4 syndrome is characterized by microcephaly, unusual facial features, growth retardation, and skin anomalies. Patients also manifest acute radiosensitivity, immunodeficiency, and bone marrow abnormalities. Some clinical phenotypes of LIG4 syndrome overlap with other genetic syndromes, like Seckel syndrome, NBS, and FA. Although the incidence of this disorder is very low, some patients were reported with malignancy, mainly lymphoma [7, 160].


The LIG4 syndrome is also considered a hyper-radiosensitive condition, which is caused by the loss of DNA ligase IV function and consequent impaired NHEJ activity, with a gross DSB repair defect. The first patient described with LIG4 syndrome developed acute lymphoblastic leukemia at age 14. The patient dramatically over-responded to cranial RT and died from radiation morbidity. Subsequent studies revealed a homozygous mutation in DNA ligase IV, which is located near the ATP binding site and is thought to hamper the formation of DNA ligase IV-adenylate complex, reducing its activity to ~10%. This post-RT fatal reaction made this genetic syndrome to be associated with hyper-radiosensitivity [7, 159].


Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease mainly characterized by presenting microcephaly at birth, stunted growth, immunodeficiency, and high predisposition to cancer, without the manifestation of ataxia. NBS was first described in 1979 in a 10-year-old Dutch boy and, then, was formally reported in 1981 when a brother of the boy presented similar clinical features. NBS is estimated to have a prevalence at 1:100,000 live births worldwide, being most common in Eastern Europe [161]. NBS is a consequence of mutations in the NBS1 gene, also named NBN, on chromosome 8q21. It was determined a Slavic founder mutation, considering that most of the individuals with this syndrome are from Slavic regions and carry the same deleterious deletion, c.657del5. Eleven NBS-causing mutations have been identified, all of them in exons 6–10 of the NBS gene [162].


The NBN gene encodes a 754 amino acid protein named Nibrin (NBN), p95 or nbs1. Nibrin is part of the MRN (Mre11/Rad50/Nibrin) complex involved in the repair of DNA DSB, as well as in immune gene rearrangements, maintenance of telomeres, and meiotic recombination. When exposed to DNA damaging agents, the MRN complex is activated by ATM phosphorylation and localized to DNA damage sites forming protein foci at DNA breaks. Consequently, mutations in this NBN gene lead to impaired translocation of the Nibrin protein into the MRN complex impairing subsequent repair of the DNA DSB lesion [162].


The diagnosis of this syndrome is based on the identification of the main clinical manifestations and posterior confirmation by genetic analysis. The previous knowledge of disease-causing mutation in both alleles of the NBN gene allows the realization of prenatal molecular genetic diagnosis. NBS patients have a high predisposition to develop malignancies, being the syndrome with highest cancer incidence among all chromosomal instability syndromes. Till now, no specific therapies are defined, and the prognosis for NBN patients with malignancies is still poor [162].


The first documented case of radiation sensitivity observed in an NBS patient involved a 3-year-old microcephalic boy with medulloblastoma. Also, several in vitro studies have shown that NBS cells present high sensitivity to IR and radioresistant DNA synthesis. Thus, the NBS patients face several challenges in treating their presented malignancies, such as cancer, due to the limitation of using RT. In fact, considering the defective DNA repair system, the exposure of these individuals to radiation should be minimized and avoided when possible [161].


Xeroderma Pigmentosum (XP) is a rare hereditary autosomal recessive disorder with an incident rate of 1:250,000 in North America, and 1:1,000,000 in Europe, affecting both sexes equally [163]. XP is clinically characterized by the presence of pain induced by UV exposure, skin dryness, progressive pigmentary alterations, xerosis, several types of skin lesions and damage, and high incidence of malignant tumors affecting skin, head, and neck. In fact, acute severe sunburns are present in 50% of XP patients as a consequence of the hypersensitivity to sunlight. Some patients also showed neurological disorders and ophthalmologic degeneration [164, 165]. XP is caused by defects in seven complementation groups (XPA to XPG) which play a role in  NER systems. XPC and XPA are the most prevalent in Southern Europe and North Africa. XPC is caused by mutation in the gene XPC, which contains 16 exons and is located in chromosome 3 (3p25), encoding for xeroderma pigmentosum group C (XPC) protein. The most frequent mutation in the XPC gene is a 2 bp deletion, c.1643_1644delTG, p.Val548AlafsX25 [164].


XPC is a protein with several functions in the NER system to repair DNA damage by recognizing the damaged bases and forming a stable complex with UV excision repair protein RAD23 (“HR23B”) protein needed for the recruitment of other actors involved in the removal of bulky DNA adducts. Mutation in these genes leads to an irreparable DNA damage that confers hypersensitivity to radiation to these patients, including UV exposure, and predisposition to develop malignancies [163, 164].


XP patients have 10,000-fold more probability in developing skin cancer than the general population. No cure is yet available for XP patients, so they need to be completely protected and isolated from any source of UV radiation. Although there is a correlation between XP syndrome and hypersensitivity to UV radiation, there are only few reports presenting the effects of using radiation therapy in XP patients with malignancies. Most of those reports did not show acute or chronic complication after treatment, probably due to the action of other repair pathways, such as NHEJ or HR instead of NER. However, there have been reported preclinical studies showing that some variants of XP could be more susceptible to IR and it is recommended that all XP patients should be classified before starting radiation therapy [166].


Fanconi anemia (FA) was firstly described by Guido Fanconi in 1927, a pediatrician who reported three children, brothers, with specific features: short stature, physical abnormalities, and anemia [167]. Defined as a rare genetic disease, FA is caused by pathogenic variants in at least 23 genes: FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP, FANC, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCU/XRCC2, FANCV/REV7, FANCW/RFWD3, and FANCY/FAP100. All these genes play a critical role in DNA repair and genomic instability and can be organized in different complexes [168]. Classified as an inherited bone marrow failure syndrome, FA is the most common genetic cause of aplastic anemia and, besides that related to hematologic malignancies, is one of the most common genetic causes with a ratio of males to females 1.2:1 [169]. Concerning heritability, FA can be inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA) [170].


This syndrome of impaired DNA repair and genomic instability, defined as complex and heterogeneous, is based on different mutations. FA patient cells are unable to perform different functions, namely repair DNA interstrand crosslinks, NER, translesion synthesis, and HR, inhibiting DNA replication and transcription, important cellular processes [171]. Related to IR, DNA damage and in particular DSB are the main alterations caused, with it reported that hypersensitivity to IR on FA mutation carriers translated not only into deterministic effects but also into stochastic effects [169].


FA is diagnosed at the median age of 7 years although symptomatic and asymptomatic family members have been described from birth to >50 years of age [172]. This syndrome is classified as multisystem disease, characterized by clinical features such as congenital malformations (short stature, skeletal malformations of the lower and/or upper limbs, abnormal skin pigmentation, microcephaly, and genitourinary tract and ophthalmic alterations), progressive bone marrow failure with pancytopenia presentation, typically presents in the first decade, often initiated with thrombocytopenia or leukopenia, and increased probability of hematologic (myelodysplastic syndrome or acute myeloid leukemia) and solid malignancies (head and neck, skin, and genitourinary tract; [170]).


Hereditary Breast and Ovarian Cancer (HBOC) syndrome was first reported by the French physician Pierre Paul Broca, in 1866, when observed a greater predisposition to cancer in his wife’s family. This syndrome is an autosomal dominant disease, mostly caused by germline deleterious mutations in Breast Cancer gene 1 (BRCA1) and Breast Cancer gene 2 (BRCA2). The exact cancer risks depend on the type of pathogenic variant, being this syndrome mainly characterized by an increased predisposition to different types of cancer. These mutations affect all ethnic groups and races: in the general population, mutations in BRCA1 and BRCA2 genes are estimated to have a frequency between 1:400 and 1:500. However, in Ashkenazy Jewish people, the frequency of causal variants is higher: 1:40 [173, 174].


HBOC is mostly a consequence of mutations in BRCA1 gene, located in chromosome 17, and BRCA2 gene, located in chromosome 13. However, only 25% of cases are associated with these two genes. Therefore, other genes are associated with this syndrome and, currently, more than 25 genes have been associated, such as Checkpoint Kinase 2 (CHEK2) gene, AT Mutated (ATM) gene, and Partner And Localizer Of BRCA2 (PALB2) gene. Most of them encode proteins that, in conjunction with BRCA1 and BRCA2 genes, act on genome maintenance pathways. More than 1600 mutations in BRCA1 gene and more than 1800 in BRCA2 gene associated with tumor susceptibility have been described [173, 175].


BRCA1 and BRCA2 genes are tumor suppressor genes with a crucial role in the cell, since they encode proteins that repair DNA DSB through HR recombination, allowing the maintenance of genomic stability and tumor suppression. When exposed to IR, these proteins are activated, localize DNA damage, and repair it. In this way, mutations in these genes lead to an inefficient repair mechanism and to an increase in genomic instability, increasing the probability of cancer development [176].


The diagnosis of HBOC associated with mutations in BRCA genes is based on the identification of pathogenic variants in these genes through molecular genetic tests. HBOC patients have a high predisposition to develop different types of cancers, some of which at an earlier stage, such as breast cancer (in both sex) and ovarian cancer. Additionally, HBOC is also associated with an increased risk of developing prostate cancer, melanoma, and pancreatic cancer although to a lesser degree. Until the moment, there are no specific therapies defined, so early diagnosis in carriers of pathogenic variants in the BRCA1 and BRCA2 genes is crucial to apply effective surveillance and prophylaxis measures [173].


Since the twentieth century, several studies have been carried out to understand whether individuals with mutations in the BRCA genes are more sensitive to IR, trying to understand the role of exposure to IR in patients with HBOC and whether there are differences in the ability to repair of DNA damage between carriers and non-carriers of mutations in these genes. Although some studies show an association between the exposure of individuals with the syndrome to diagnostic doses and the development of cancer [177, 178], other studies fail to show any association [91, 179]. Thus, it is crucial to carry out more specific studies to obtain clear and objective conclusions in relation to this subject.


Biological markers of changes in the body in response to radiation have long been used to assess radiation dose and exposure circumstances (see Chaps. 3 and 8). In recent years, with advances in technology and the sophistication of the markers, the potential to use biomarkers of the body’s response to radiation and other stressors to help predict treatment outcome and indeed to tailor treatments has begun to be explored [180].


Development, validation, and implementation of biomarkers are not a simple process (see Chap. 3). Firstly because our bodies are hugely complex systems relying on hundreds of thousands of changing and interacting processes at any one moment, many of which have associated measurable changes, there are a huge number of potential biomarkers based on the body’s complex response to IR confounded by a large number of other internal and external factors. Secondly, and just as importantly, there is huge variation in interindividual responses for most biomarkers. One recent study, for example, identified 40 blood-based biomarkers which could provide informative data on carbon metabolism, vitamin status, inflammation, and endothelial and renal function in cancer-free older adults alone [181]. Harlid et al. [182] also outlined the large number of potential biomarkers for risk predictive and diagnostic biomarkers for colorectal cancers, in a recent systematic review. In terms of molecular radiation epidemiology, a very large number of potential biomarkers have been identified, but despite a very large amount of work in this area, only one biomarker (based on transcriptional changes) has been identified as suitable to pursue now [14]. Furthermore, the practicalities of development of protocols and standard operating procedures for clinical use are also a barrier to implementation [183].


However, in wider clinical practice as well as for radiation medicine, biomarkers to support personalized intervention are in development and in some cases, already in use. For example, Karschnia et al. [184] reported improved survival in patients with advanced cancers of the central nervous system, following application of systemic targeted immunotherapeutic agents. Connor et al. [185] showed how implementation of novel image-based biomarkers to support RT has improved patient-specific therapy outcomes for glioma patients.


Going forward, despite the fact that the mechanisms of radiation resistance are still not well understood, use of miRNA in prostate cancer has shown promise. For example, Soares et al. [186] found 23 miRNAs which were involved in genetic regulation of prostate cancer cell response to RT. In the lung, Leiser et al. [187] recently demonstrated the potential utility of caveolin-1 (a membrane protein highly expressed in radiation resistant lung cancer cells) as a prognostic biomarker for response to treatment with radiation as well as for tumor progression, in support of precision medicine. And for cancers of the liver, De la Pinta [188] recently identified a number of candidate biomarkers of radiation response and toxicity and highlighted how close this field in particular is to use of such techniques to support personalized radiation medicine.


Indeed, use of large scale “omics” data together with machine learning or other artificial intelligence approaches has opened up a number of avenues of research. For example, Manem [189] compared five different machine learning based approaches in two existing radiogenomics datasets and found a large number of biomarkers associated with statistically significant pathways of response associated with surviving fractions of cells. New techniques in cellular barcoding are also proving incredibly interesting, with Wursthorn et al. [190], for example, recently demonstrating the use of this technique for assessing clonogenic survival in response to radiation and quantification of radiosensitivity as well as the contribution of stochastic and deterministic processes. Major bioinformatics studies can help in the identification of gene signatures as biomarkers for predicting normal tissue radiosensitivity. A key challenge is still the need for large scale, independent, validation of biomarkers in prediagnostic studies [182] as well as biomarker-driven randomized controlled trials [191]. Nevertheless, given the recent advances, use of radiation biomarkers to support precision radiation medicine is an exciting field in which large leaps forward are expected in a relatively short timescale.


Q1.
Cite a genetic syndrome associated with both radiosensitivity and radiosusceptibility.
 Q2.
Cite a genetic syndrome associated with radiosusceptibility, but not radiosensitivity.
 Q3.
What is described as the attained age in relation to radiosensitivity?(a)
The age from birth to death
 (b)
The sum of the age at exposure and time since exposure
 (c)
The age between onset of cancer diagnosis and end of treatment
 (d)
The sum of the age at exposure and time of exposure

 Q4.
What are the three mechanisms associated with the greater susceptibility of children to radiation carcinogenesis?
 Q5.
Which of the following sentences are true or false?(a)
Aged cells may have a compromised repair due to chromatin reorganization.
 (b)
Senescence in older cells can be accelerated by irradiation.
 (c)
Abnormalities in tissue maturation is often seen as radiation-induced sequelae in adults.

 Q6.
Is the radiation sensitivity higher for males or females?
 Q7.
Why is sex important to consider in context of radiation therapy?
 Q8.
Why is sex not yet included in the ICRP recommendations?
 Q9.
Why is it necessary to identify biomarkers to predict the response of the tumor to radiation therapy?
 Q10.
What circulatory biomarkers are of current interest in the field of radiation oncology?
 Q11.
Why are liquid biopsies rapidly being adopted into translational research?
 Q12.
What is the current gold standard for assessing radiosensitivity?
 Q13.
What advantages do vibrational spectroscopic techniques have over conventional radiobiological assays?
 Q14.
If normal tissue toxicity determines the total dose to be delivered to a patient, what outcome will this have on their treatment?


What is described as the attained age in relation to radiosensitivity?(a)
The age from birth to death
 (b)
The sum of the age at exposure and time since exposure
 (c)
The age between onset of cancer diagnosis and end of treatment
 (d)
The sum of the age at exposure and time of exposure


The sum of the age at exposure and time since exposure


The age between onset of cancer diagnosis and end of treatment


The sum of the age at exposure and time of exposure


What are the three mechanisms associated with the greater susceptibility of children to radiation carcinogenesis?


Which of the following sentences are true or false?(a)
Aged cells may have a compromised repair due to chromatin reorganization.
 (b)
Senescence in older cells can be accelerated by irradiation.
 (c)
Abnormalities in tissue maturation is often seen as radiation-induced sequelae in adults.


Aged cells may have a compromised repair due to chromatin reorganization.


Abnormalities in tissue maturation is often seen as radiation-induced sequelae in adults.


Why is sex important to consider in context of radiation therapy?


Why is it necessary to identify biomarkers to predict the response of the tumor to radiation therapy?


What circulatory biomarkers are of current interest in the field of radiation oncology?


What advantages do vibrational spectroscopic techniques have over conventional radiobiological assays?


If normal tissue toxicity determines the total dose to be delivered to a patient, what outcome will this have on their treatment?


SQ1.
Ataxia telangiectasia (AT) caused by homozygous ATM mutations is associated with fatal tissue reactions post-RT and high cancer proneness after exposure to radiation.
 SQ2.
Li-Fraumeni’s syndrome (LFS) caused by heterozygous p53 mutations is associated with high cancer proneness after an exposure to radiation but LFS patients do not show adverse tissue reactions post-RT.
 SQ3.
Alternative (b) is correct. (The sum of the age at exposure and time since exposure).
 SQ4.
Long latency period between injury and cancer onset; faster radionuclides accumulation in growing bones; high frequency of cell division.
 SQ5.
(a) true, (b) true, (c) false.
 SQ6.
Females.
 SQ7.
Consideration of the individual radiosensitivity of each patient will allow a personalized dose and fractionation adjustment for RT.
 SQ8.
Due to the lack of scientific evidence to support the establishment of different annual dose limitations based on sex, as well as the complex social and societal issues associated with potential implementation of sex specific dose limits.
 SQ9.
Identifying biomarkers of tumor response will allow stratification of patients based on risk and identifying patients who may not respond favorably to treatment. In turn, this will provide tailored and optimized treatment for patients.
 SQ10.
Circulating tumor cells, circulating free DNA, and EVs.
 SQ11.
Liquid biopsies overcome many limitations associated with tumor biopsies, such as minimally invasive sample acquisition, easy repeatability, lower cost, and a rich source of tumor-specific biomarkers.
 SQ12.
The clonogenic assay is still the current gold standard for studying radiosensitivity.
 SQ13.
Vibrational techniques involve minimally invasive sample collection, non-destructive, label free measurement of cells, and results can be produced in a short time frame.
 SQ14.
Patients who are radiosensitive and undergo RT are at a higher risk of developing severe toxicity, and to circumvent this, the doses delivered to these patients will be at a lower dose than is necessary for adequate tumor control and a positive outcome of treatment.


Ataxia telangiectasia (AT) caused by homozygous ATM mutations is associated with fatal tissue reactions post-RT and high cancer proneness after exposure to radiation.


Li-Fraumeni’s syndrome (LFS) caused by heterozygous p53 mutations is associated with high cancer proneness after an exposure to radiation but LFS patients do not show adverse tissue reactions post-RT.


Alternative (b) is correct. (The sum of the age at exposure and time since exposure).


Long latency period between injury and cancer onset; faster radionuclides accumulation in growing bones; high frequency of cell division.


Consideration of the individual radiosensitivity of each patient will allow a personalized dose and fractionation adjustment for RT.


Due to the lack of scientific evidence to support the establishment of different annual dose limitations based on sex, as well as the complex social and societal issues associated with potential implementation of sex specific dose limits.


Identifying biomarkers of tumor response will allow stratification of patients based on risk and identifying patients who may not respond favorably to treatment. In turn, this will provide tailored and optimized treatment for patients.


Liquid biopsies overcome many limitations associated with tumor biopsies, such as minimally invasive sample acquisition, easy repeatability, lower cost, and a rich source of tumor-specific biomarkers.


The clonogenic assay is still the current gold standard for studying radiosensitivity.


Vibrational techniques involve minimally invasive sample collection, non-destructive, label free measurement of cells, and results can be produced in a short time frame.


Patients who are radiosensitive and undergo RT are at a higher risk of developing severe toxicity, and to circumvent this, the doses delivered to these patients will be at a lower dose than is necessary for adequate tumor control and a positive outcome of treatment.


Individuals can be exposed to ionizing radiation in many accidental or intended situations with different ranges of dose, dose rate, and radiation quality. Human exposures can occur directly from external radiation sources or through either internal or external contamination with radioactive materials/substances. In certain circumstances, external radiation exposure may occur concomitantly with external or internal contamination (Fig. 8.1). While the radiation dose from external exposure or internal contamination could be substantial, health risk from external contamination is highly dependent on the penetrating ability of the radionuclide. Since alpha particles can be effectively blocked by a piece of paper or by the upper layer of the skin, risk of external contamination by alpha particles is expected to be negligible. Most external contamination can be eliminated either by cleansing and/or by removing contaminated clothes.

An illustration of the exposure and contamination scenarios of radiation. In external exposure, radiation passes through the body and causes damage. In external contamination, the radiation damages the surface of the body. In the internal contamination, the radiation is incorporated into the body.

Fig. 8.1
External exposure and contamination


An illustration of the exposure and contamination scenarios of radiation. In external exposure, radiation passes through the body and causes damage. In external contamination, the radiation damages the surface of the body. In the internal contamination, the radiation is incorporated into the body.


The following section lists the types of exposure scenarios with specific examples.


Aside from radiation oncology, which has been well described in Chap. 6, medical exposures can occur from diagnostic and therapeutic procedures other than cancer treatment. These procedures can cause exposures to the patient but also exposure in utero to the embryo or fetus. Worldwide medical exposures account for almost 20% of the average human exposure from all the sources [1].


Doses from diagnostic radiology procedures range from very low doses in dental radiography to higher doses from computed tomography or fluoroscopy procedures. In general, radiation doses from diagnostic procedures tend to be low and are therefore unlikely to cause deterministic effects (discussed in Sects. 2.7.2 and 8.2), but especially repeated fluoroscopy-guided procedures like angioplasty may result in substantial skin dose to the patients (see also Sect. 8.1.6). Table 8.1 lists the effective doses (see definition in Sect. 8.7) associated with each of the commonly used diagnostic procedures, but these doses can vary among different countries. The total number of these procedures conducted worldwide to date, is around 4 billion (2.6 billion for radiography, 1.1 billion for dental radiography and 400 million for CT) and the number has been steadily increasing over the past 25 years, especially for CT [2].Table 8.1
Examples of each type of diagnostic procedures and their typical doses (reproduced with permission from [2])

Examination type

Typical effective dose (mSv)a

Dental radiography

Intraoral

0.006

Panoramic

0.024

Projection radiography

Head (skull and facial bones)

0.076

Chest (thoracic spine)

0.45

Mammography

0.22

Lumbar spine

1.0

Pelvis and hips (bone)

0.49

Limbs and joints

0.02

Whole spine (trunk)

1.5

Radiography and fluoroscopy

Gastrointestinal tract

3.4

Cardiac angiography

7.0

Pelvic angiography

3.2

Urogenital tract

2.4

Computed tomography

Head (skull and facial bones)

1.5

Neck (soft tissues)

2.8

a ICRP 60 tissue weighting factors were applied for the effective dose determination [3]


There have been many instances of therapeutic exposures unrelated to cancer treatment in the past including patients treated with radiation for ankylosing spondylitis (total body dose of 0.86–4.62 Gy) to relieve pain and children treated for tinea capitis (ringworm of the scalp) with a brain dose ranging from 0.75 to 1.7 Gy. There is evidence of increased cancers in these populations [4, 5] and alternative treatments have now been adopted that do not involve radiation. Presently, radiotherapy is used in procedures such as to treat benign tumors, pain relief for arthritis, arteriovenous malformations as shown in Fig. 8.2 [6]. These procedures deliver a range of doses from 5 to 60 Gy which can be delivered in single or multiple fractions.

A cyclic chart of the percent for non-malignant conditions. Keloid, 78. Graves' orbitopathy, 69. Heterotopic bone formation, 61. Desmoid and aggressive fibromatosis, 54. Pterygium and Arteriovenous malformation, 41. Histiocytosis, 38. Arthrosis, 37. Nasopharyngeal angiofibroma, 33. Tendinitis, 32.

Fig. 8.2
Non-malignant conditions most commonly treated with radiation therapy as a percentage of all international radiotherapy institutes surveyed (n = 508). (Data extracted with permission from [6])


A cyclic chart of the percent for non-malignant conditions. Keloid, 78. Graves' orbitopathy, 69. Heterotopic bone formation, 61. Desmoid and aggressive fibromatosis, 54. Pterygium and Arteriovenous malformation, 41. Histiocytosis, 38. Arthrosis, 37. Nasopharyngeal angiofibroma, 33. Tendinitis, 32.


Radiation exposures can occur in many occupational settings with the highest average effective doses reported in the nuclear sector although this shows a steadily decreasing trend due to increased knowledge about the effects of radiation and better radiation protection practices over the past decades. Figure 8.3 shows data for the occupational exposures over a 27-year period. The average effective dose per worker is the highest in the nuclear sector. Due to the high number of workers in the medical field (~7500 in 2002) compared to the nuclear sector (~660 in 2002) and the industrial sector (~850 in 2002), collective exposures are the highest in the medical field, followed by those working in nuclear power and industrial uses of radiation.

2 grouped bar graphs of annual effective dose and collective effective dose versus years. The values are plotted for industrial, medical, military, nuclear, and other. 1. Nuclear has the highest value from 1975 to 1979 at 4.4. 2. The medical has the highest value from 1995 to 2002 at 3500.

Fig. 8.3
Data for estimated occupational exposures from 1975 to 2002. (Reproduced with permission from [1, 7])


2 grouped bar graphs of annual effective dose and collective effective dose versus years. The values are plotted for industrial, medical, military, nuclear, and other. 1. Nuclear has the highest value from 1975 to 1979 at 4.4. 2. The medical has the highest value from 1995 to 2002 at 3500.


Out of all the occupational exposures, the medical profession makes up the single largest group of workers exposed in the workplace. This group encompasses nurses, doctors, technicians, and other support workers. The procedures mostly comprise diagnostic imaging and radiation therapy, which have been increasing yearly as technology develops and the benefits become more widespread. Table 8.2 shows some of the specific medical professions with the highest average exposures based on dosimeter readings, in Canada. These values will vary from country to country but are similar in countries with comparable level of health care.Table 8.2
Selection of the highest exposed medical occupations of monitored workers (reproduced with permission from [8])

Occupation

Ave dose (mSv/year) (2008)

Mean effective dose (mSv/year) (2016)

Nuclear medicine technologist

1.56

1.23

Diagnostic radiologist

0.44

0.17

Medical radiation technologist

0.10

0.11

Medical physicist

0.03

0.05

Radiation therapist

0.05

0.04

Dental assistant

0.01

0.01

All medical professions

0.08

0.07


Occupational dose in diagnostic radiology is quite variable due to the wide range of technologies available. For example, most CT technologists have no measurable dose while the individual effective dose for interventional procedures such as vascular surgery supported by fluoroscopy is significant and medical doctors performing these procedures are the most occupationally exposed group from diagnostic radiation. Depending on the procedure, the occupational dose can range from 0.008–2 mSv per interventional procedure. Diagnostic radiation is also frequently used in dental clinics; therefore, the number of devices and workers exposed is extremely large. The average annual effective dose in dental radiology has been decreasing over the last few decades from 0.32 mSv in the late 1970s to 0.06 Sv in the early 1990s due to improved equipment [1]


Nuclear medicine involves the use of radionuclides, particularly 99mTc, to investigate physiological process and organ function. Occupational exposures result from personnel having to be in close contact with patients when injecting them and while positioning them during which time they can be exposed to gamma radiation emitted by the radionuclides. Preparation of the radionuclides can also result in high exposures with annual doses up to 5 mSv and doses to the hands and fingers up to 500 mSv. There are several other nuclear medicine techniques with different exposures such as positron emission tomography using 18F labeled fluorodeoxyglucose and thyroid treatment with 131I to name a few. Worldwide, the annual collective effective dose is on the order of 85 man Sv and had been increasing over the years with increasing number of workers in this field. However, the annual collective dose is no longer increasing [1] since the 1980s as the average annual effective dose was reduced from 1 mSv down to about 0.75 mSv.


Radiotherapy for treating malignant disease delivers the highest dose to the patient; however, occupational doses in this setting remain very low. These procedures have been well described in Chap. 5. The collective annual dose in radiotherapists has decreased substantially since the 1970s despite the increase in workers in this field. This is due to a large drop in the annual average effective dose per worker.


Workers throughout the nuclear fuel cycle are exposed to ionizing radiation, from mining, through milling, enrichment, fuel fabrication, reactor operation, and reprocessing [1]. This group of workers is most closely monitored for their radiation exposure. As there are more workers in mining and reactor operation, the collective effective dose is the highest in this group. The average annual effective dose for nuclear workers has also been decreasing steadily since the mid-1970s from 4.1 to 1.0 mSv currently, and the collective effective dose has decreased since the 1980s from 2500 to 800 man Sv (Fig. 8.4). These reductions are due to implementation of ALARA programs that have improved plant designs, implemented upgrades, and improved operational procedures [1].

3 grouped bar graphs of annual effective dose and collective effective dose versus practice. 1. The milling has the highest value from 1975 to 1979. 2. The mining has the highest value from 1980 to 1984. 3. The reactor operation has the highest value from 1990 to 1994. Values are estimated.

Fig. 8.4
Global trends in the number of monitored workers, and in collective effective doses and effective doses to workers for different practices of the nuclear fuel cycle. (Reproduced with permission from [1])


3 grouped bar graphs of annual effective dose and collective effective dose versus practice. 1. The milling has the highest value from 1975 to 1979. 2. The mining has the highest value from 1980 to 1984. 3. The reactor operation has the highest value from 1990 to 1994. Values are estimated.


Industrial radiography is a non-destructive method used to look at defects in materials such as welded pipeline and castings. This can involve the use of X-rays or gamma ray sources sealed in capsules (e.g., 60Co and 192Ir). Radiation penetrates the object being examined and exposes a detection system behind the object. The devices used are designed to protect the operator and annual effective doses to the workers under normal use are less than 0.5 mSv.


Most military exposures results from the fabrication and testing of nuclear weapons, the use of nuclear energy on naval vessels, and the use of ionizing radiation for activities similar to those used in civilian applications (e.g., research, transport, and non-destructive testing). Data from the USA indicates that the average annual effective dose in monitored military individuals form all military activities is on the order of a few tens of mSv. There has, however, been a substantial decrease in the average collective doses since the 1970s where annual effective doses to monitor military workers were as high as 1 mSv [1].


Enhanced levels of natural radiation are found in several occupational settings. Because the radiation is naturally occurring, workers are not routinely monitored so exposure levels are not well known. Miners make up a large group of these occupational exposures and their estimated collective dose is about 30,000 man Sv [9]. Air crew make up another group of workers exposed to naturally occurring radiation and have been identified as one of the most highly exposed professional groups with exposure levels of 3–8 μSv/h during the flight depending on latitude and altitude. Worldwide, the estimated collective effective dose to aircrew is about 900 man Sv. Overall, there are about 13 million workers worldwide exposed to natural sources of radiation with an estimated average effective dose of 2.9 mSv and an estimated collective effective dose of 37,260 man Sv. This average effective dose from natural exposures is not decreasing as much as with man-made exposures, however, as the number of workers is increasing, the collective dose has been rising between the early 1990s and early 2000s [9].


In addition to those mentioned above, there are a number of other professions where radiation might be involved. These include, but are not limited to, research in academic institutions, management of spent radioactive sources and transport of radioactive material. Academic institutions make up 92% for the monitored workers in this category and about 87% of the collective dose. Overall, the average annual effective dose for all monitored workers in this category is less than 1 mSv and doses, decreasing from 0.5 to 0.1 mSv between 1975 and 2004 [9].


Unintended exposures in medicine are defined as exposures that differ significantly from the exposure intended for the given purpose and are considered medical errors. These events can include operator errors, equipment failures, and other mishaps with consequences that can range from less to more severe. Events can occur with both diagnostic and therapeutic procedures and may also result in unintended doses to an embryo or fetus. The most serious overexposures can result in doses to the skin that are high enough to cause tissue reactions. These typically arise from CT and interventional fluoroscopy procedures, most notably from perfusion studies [10].


Despite the adoption of safety measures to reduce the risk of accidents at Nuclear Power Plants (NPPs), there have been several accidents as well as near misses with varying degrees of impact and radiation exposure to workers and the general population [11]. These accidents are characterized by the release of large amounts of radionuclides with relatively short half-lives [12]. Three such past incidents of high impact are Three Mile Island in 1979 [13], Chernobyl in 1986 [14], and Fukushima in 2011 [15]. Accidents in NPPs can result in high doses to a small population of clean-up workers (e.g., Chernobyl) as well as small doses to a large population living in the vicinity of the NPP (e.g., Fukushima). These NPP accidents, along with other accidents, can be rated according to the International Nuclear Event scale (INES) based on severity and impact of the incident (Fig. 8.5). Accidents can also occur during the transportation of nuclear waste by road or rail with the primary concern of exposure for this waste being 137Cs, a γ-emitter. Although the fuel is well packaged during shipment, the amount of radioactive material may be on the order of PBq per shipment container, so any dispersal would be catastrophic. In general, occupational exposures tend to be low doses and low-dose rates.

A pyramid chart exhibits the 8 layers, from 0 to 7 of N P Ps accidents with its events. It includes below scale, anomaly, incident, serious incident, accident with local consequences, with wider consequences, serious accident, and major accident.

Fig. 8.5
International Nuclear Event scale based on severity and impact of the incident


A pyramid chart exhibits the 8 layers, from 0 to 7 of N P Ps accidents with its events. It includes below scale, anomaly, incident, serious incident, accident with local consequences, with wider consequences, serious accident, and major accident.


During industrial radiography, accidents can occur multiple ways: loss of control of the source of radiation, damage to the source, direct contact with the source or improper use of shielding [16]. Even when operating procedures are correctly followed, dose rates close to the source can be very high causing overexposures in a matter of seconds. Table 8.3 lists a few examples of accidents due to inadequate regulatory control, failure to follow operational procedures, inadequate training, inadequate maintenance, and human error.Table 8.3
Selected accidents in industrial radiography

Year

Primary cause

Exposed population

Source/activity

Scenario

Dose to exposed population

Reference

1989

Inadequate regulatory control

General public

192Ir/260 GBq

Source not removed prior to transportation

Public <5 mSv
Driver—0.31 Sv

USNRC [17]

1992

Failure to follow operational procedures

Operator

Various sealed sources

Unsafe operations with radiographic sources

Lifetime 10 Sv whole body, >100 Sv to hand

Lloyd et al. [18]

1969

Inadequate training, insufficient supervision

Operator

192Ir/900 GBq

Shutter of source left open during transportation

450 mSv whole body, 2.14 Sv to left hip

Harisson et al. [19]

1993

Inadequate maintenance

Operator

192Ir/3600 GBq

Missing roll pins to secure camera lock

6 mSv whole body, 19 Sv to fingers

USNRC [20]

1996

Human error

Operator

X-ray

Wrong cable connected to control panel causing wrong X-ray unit to be activated

600 and 160 mSv to each of two operators

Wheelton [21]


An orphaned source is a self-contained radioactive source that is no longer under proper regulatory control. These sources can come from both therapeutic and industrial radiation machines and can have activities in the TBq range. As long as they remain sealed, they do not cause contamination but when opened can cause high doses and extreme health effects and even death, due to their high activity such as occurred in Thailand in 2000 [22]. Their containment can also become compromised, spreading radioactive material over large areas as occurred in Goiania, Brazil in 1987 [23].


The health consequences after an accidental exposure to radiation will depend on the exposure scenario. Although there is a long list of attacks that could involve radiation, the following three are considered the most probable.


INDs incorporate nuclear material that can produce nuclear explosions. This can cause extensive blast (mechanical), thermal, and radiation injuries with large numbers of fatalities and casualties as well as high doses of radiation to potentially large numbers of individuals, when detonated at or close to a major city. The radiation injury can be a result of the prompt radiation within minutes near the epicenter of the explosion that is predominantly from γ-rays and neutrons. Delayed exposures can result from fallout that is produced by fission products and neutron-induced radionuclides and are dispersed downwind from the epicenter. Finally, ground shine can result from the deposition of radionuclides on the ground of the fallout area that is highly dependent on the wind direction and speed (Fig. 8.6). INDs are considered highly unlikely but possible to be used; hence, it is necessary to be prepared for such events. The result of such an event would be catastrophic. Thousands of people could be killed by the blast and heat, hundreds to thousands could be killed or made ill by radiation effects, and thousands could have an increased long-term risk of leukemia or solid cancer. Furthermore, the psychological and infrastructure effects would also be enormous [24].

A graph plots the kilometers from ground zone with the radioactive fallout pattern. It has 4 concentric circles with their centers at 0. The first circle denotes ground zero, the second one denotes dangerous fallout, the third one denotes moderate damage, and the outer circle denotes light damage.

Fig. 8.6
Approximate prompt and delayed (fallout) effects from a 10-kT detonation. (Reproduced with permission from Lawrence Livermore National Laboratory)


A graph plots the kilometers from ground zone with the radioactive fallout pattern. It has 4 concentric circles with their centers at 0. The first circle denotes ground zero, the second one denotes dangerous fallout, the third one denotes moderate damage, and the outer circle denotes light damage.


The population that has had the greatest impact on risk assessment is the A-bomb survivors. A large population of Japanese were exposed in 1945 during an atomic bomb attack in both Hiroshima and Nagasaki. This cohort comprises the Life Span Study (LSS) that includes 94,000 in-city subjects of all ages and sex with dose estimates ranging up to 4 Sv. There has been a long-term follow-up on this cohort, allowing for high quality mortality and cancer incidence data [25]. The majority of survivors were exposed to doses less than 0.1 Sv and, therefore, provide excellent data in the dose range of interest for radiation protection. This cohort also provided data on in utero and early childhood exposures [26].


RDDs use explosives or mechanical devices to distribute radiological material resulting in radioactive contamination. This is considered a more likely scenario than an IND. With RDDs, a relatively small area would be affected and radiation exposures could take the form of both internal and external contamination; however, exposures are expected to be lower than medically significant. Most likely, a small number of individuals will be contaminated with radioactive material.


REDs involve hidden sealed sources designed to expose people to significant doses without their knowledge and without causing contamination. They are usually hidden in a busy public location, such as under a seat on a bus or in a sports stadium and could remain undetected for long periods. Individuals who come close to these sources can receive significant localized doses but numbers of highly exposed individual are anticipated to be low.


It is generally accepted that the developing embryo and fetus are more radiosensitive than children or adults. In common with other health effects, at low doses (<100 mGy), stochastic risk is the main driver to protect the fetus (see Chap. 1). Deterministic effects or tissue reactions—mainly central nervous system effects and congenital malformations—are reported for higher doses; however, the evidence is somewhat sparse.


Evidence for fetal radiation effects comes mostly from animal studies performed with high doses of in utero radiation. Evidence is limited from the larger scale population exposures such as those of the A-bomb survivors, as well as from other small-scale accidents, and medical uses of radiation (e.g., Gilbert [26]). The relevant animal data suggest thresholds for non-cancer effects including small fetal size, microcephaly, and intellectual disability (see also Sect. 2.7.2). However, due to interspecies differences and different selection pressures, it is impossible to draw conclusions pertaining to the levels of such effects in human studies. As such, in order to draw conclusions for radiation protection purposes at least, epidemiological studies are more reliable.


The human data, however, are limited. There is only one epidemiological study that has been able to provide evidence of brain damage in humans following in utero exposure. From about 10,000 woman who were pregnant at the time of the atomic bombs at Hiroshima and Nagasaki, the children of about 1700 of them have been followed into adulthood. The study identified 27 children with severe “mental retardation” (now more commonly termed intellectual disability), 30 children with small head size without apparent intellectual effects, 24 children who suffered from seizures which appear to have no clinically identifiable precipitating cause, and a larger group of children with reduced intelligence (IQ) scores or with lower than expected scholastic achievement in school, compared to the unexposed population.


While the sample sizes were small and hence the uncertainties were large, the key finding—still much quoted today—was that neurocognitive effects were only observed for those exposed for doses >~0.5 Gy, and only during the 8–15 post-conception period, corresponding to the key period of neurogenesis and neuronal migration [27–29].


For earlier stages of embryogenesis, there is some evidence that preimplantation exposure to doses below 100 mGy may lead to miscarriage. During the major period of organogenesis, approximately 2–15 weeks post-conception, exposures on the order of 0.25 Gy may lead to smaller head sizes and the associated reduction in intellect, with this period also being particularly sensitive for induction of cancer. Post 15 weeks, the threshold for increased risk of cancer would appear to be on the order of 100 mGy, and the threshold for severe intellectual disability is still ~500 mGy (Fig. 8.7).

A comparison of the possible deterministic effects of radiation with days post conception for pre, implantation, major organogenesis, and fetal growth. 4 curves for prenatal death, neuropathology, malformations, and growth retardation risk factors follow a small peak and a decreasing trend.

Fig. 8.7
Relationship between ionizing radiation induced tissue effects and fetal/embryo stage of development. (Reproduced with permission from [30])


A comparison of the possible deterministic effects of radiation with days post conception for pre, implantation, major organogenesis, and fetal growth. 4 curves for prenatal death, neuropathology, malformations, and growth retardation risk factors follow a small peak and a decreasing trend.


In 2001, UNSCEAR concluded there was no definite adverse pregnancy outcomes (malformations, stillbirths, premature births) related to the exposure from the Chernobyl accident. However, in more recent years, there is evidence that 131I internalized by pregnant women following Chernobyl crossed the placenta and resulted in thyroid cancer in their children. Children born to Chernobyl 131I exposed individuals also had dose-dependent longer gestational periods, smaller head, and chest sizes, but normal birth weights. While stunted cerebral growth during critical periods of neurogenesis accounts for microcephaly and the related developmental effects, the biological mechanisms behind the effect on gestational period is still largely unknown [7].


Fetal death following exposure in utero appears only to occur following doses >2 Gy; however, most of the evidence for this still comes from animal studies. There is also limited evidence linking fetal radon exposure to increased risk of disease. For example, excess brain cancer has been observed in children born to pregnant women drinking water with high levels of radon [31].


In terms of cancer risk, there is a clear link between doses received in utero and childhood and adult cancers, including childhood leukemia. In the A-bomb survivors exposed in utero, the most recent evidence using individual estimates of mother’s weighted absorbed uterine dose supports a continued increased risk of solid cancer mortality in females but, not in males. As with the previous data, the effects of radiation on non-cancer disease mortality in this cohort appeared to be mediated through small head size and low birth weight, but also parental survival status. The most recent data suggest that the excess risk of childhood cancer (up to 15 years of age) is on the order of 6% per Gy, with approximately half of the cases being fatal. These data are summarized in Table 8.4.Table 8.4
Health effects as a function of gestational age for humans (reproduced with permission from [29])

Gestational age

Weeks post-conception

Fetal dose, Gy

Effects observed

Preimplantation

0–2

0.05–0.10

Prenatal death (animal data)

Major organogenesis

1–8
2–15

0.20–0.25

Growth restriction
Small head size, intellectual deficit
Sensitive for cancer induction

Rapid neuronal development and migration

8–15

>0.1

Small head size, seizure risk, reduction in IQ (~25 points/Gy)

Post organogenesis

15-full term

>0.1
>0.5

Increased cancer risk
Severe mental disability (16–25 weeks in particular)


It is worth noting that on the basis of the current (albeit limited) evidence, for occupational radiation protection purposes in the UK as in many other countries, the unborn fetus is treated as a member of the public, hence the effective dose limit is 1 mSv/year.


Mutations occur naturally in somatic and germ cells potentially leading to cancers and heritable genetic diseases, respectively. In 1927, Muller and colleagues initially showed the mutagenic effects of X-rays in Drosophila, which were rapidly followed by similar findings reported for other radiation types and organisms. These experimental animal data established the concept of genetic damage-inducing effects of radiation. However, concerns appeared about these genetic effects in large numbers of people, especially after the exposure of people to the detonation of atomic bombs. The UNSCEAR and the BEIR committees decided to follow the potential heritable effects of radiation in the exposed Japanese population, even if other environmental factors can interfere. Indeed, the goal pursued by both committees is to predict additional risk of genetic diseases in humans exposed to radiation. However, no association between radiation exposure and the occurrence of hereditable effects has been observed in humans to date [7]. Like cancers, genetically, diseases such as hemophilia, color-blindness, and congenital abnormalities do not arise specifically from ionizing radiation, but also occur spontaneously or due to other environmental and/or genotoxic factors without any specific clinical appearance.


The concept of “radiation inducible genetic diseases” relies on different parameters. Indeed, every cell contains genetic material in the form of DNA, and mutations observed in DNA may lead to a genetic disease such as malformations, metabolic disorders, or immune deficiencies. Sometimes, however, when mutations are induced in gonads or germ cells (oocytes or sperm or their precursors) of an exposed individual, hereditable effects occur in their offspring. To induce a genetically abnormal offspring, the mutation must successfully pass through many cell divisions to form a viable live-born infant. Further, to be of genetic significance, gonadal exposure must occur before or during the person’s reproductive period. It gives rise to the concept of genetically significant dose. Thus exposure to, for example, a post-menopausal woman, or someone who never intends to have children, carries no associated “heritable” risk [7, 32].


It is important to note that ionizing radiation does not produce new types of genetic diseases or new unique mutations but is assumed to increase the incidence of the same mutations that occur spontaneously. It increases the incidence of the spectrum of known diseases in the population. Hence, it is important, as far as possible, to have a good understanding of the background risks. There are very little direct human data on radiation-induced genetic disease. Pieces of evidence appeared for the heritable genetic effects of radiation almost entirely from animal experiments initially performed at Oak Ridge National Laboratory through the mega mouse project (7 million mice studied to determine specific locus mutation rates in the mice). Animal experiments have led to the development of relevant concepts including the doubling dose, i.e., the dose required to double the background frequency of genetic conditions detectable in the newborn population [33]. This project leads to five main conclusions: (1) a significant factor of about 35 for the radiosensitivity of different mutations; (2) a dose rate effect with fewer mutations induced by chronic exposure compared with acute ones; (3) an exquisite radiosensitivity of the oocytes; (4) reduction of the genetics effects of a given dose when there was a time interval between exposure and conceptions; (5) differences between male and female mice but with a doubling dose on the order of 1 Gy for protracted exposures. Given that conclusions on the background frequency, life span, selection pressures, and spectrum of genetic disease in the laboratory mouse are very different from humans, caution must be applied in using these data for human radiation protection purposes. Nevertheless, such data are important.


Estimates then need to be made for the mutational component of classes of human genetic diseases and clearly, this is considerably different between dominant gene disorders and multifactorial conditions. The selection pressures on mutations being lost by death during embryo/fetus development also need to be assessed. Finally, an assessment of the transmissibility of abnormalities through further generations needs to be made [7].


Evolution depends on the existence of mutations, with beneficial mutations conferring an advantage. However, their random nature ensures that the vast majority of mutations are harmful. Alterations can concern genes or point mutations to the DNA code and chromosomal aberrations.


Diseases caused by mutations in single genes are known as Mendelian diseases. The majority (67%) are caused predominantly by point mutations (base-pair changes in the DNA), followed at 22% by both point mutations and DNA deletions within genes, and by intragenic deletions and large deletions at 13%. They are divided into autosomal dominant, autosomal recessive, and X-linked depending on the chromosomal location and the phenotype resulting from the transmission.


Autosomal dominant: Dominant conditions are where even in the heterozygote state (a person inheriting one mutant and one normal gene) the abnormality is seen in the individual. Their effects in the homozygote (double dose of the mutant gene) are usually more severe, if not lethal. They are expressed in the first generation after its occurrence. An example of a dominant gene condition is Huntingdon’s chorea (HC), which is characterized by nerve cell damage and changes in physical, emotional, and mental state. HC is caused by a faulty gene on chromosome 4. Other examples include achondroplasia, neurofibromatosis, Marfan syndrome, or myotonic dystrophy.

Autosomal recessive: Usually, this condition requires homozygosity, which means two mutant genes at the same locus, to produce the trait disease. The mutant gene must be inherited from each parent. Recessive disorders are usually rare, as the mutation would need to be inherited from both parents. However, some recessive genes even when present in a single dose, i.e., heterozygote accompanied by a dominant normal gene do still confer slight deleterious effects. An example of a recessive gene disorder is cystic fibrosis, which is caused by mutations on a gene located on chromosome 7. Other examples include phenylketonuria, hemochromatosis, Bloom’s syndrome, and ataxia-telangiectasia.

X-linked: Disorders involve genes located on the X chromosome. A large proportion of mutations that are inherited are related to the X chromosome. Since there is only one X chromosome in males, mutant genes here act as dominant genes in males who suffer whereas they are masked in the female with two X chromosomes who act as carriers. Mutations in these genes will exert their effect in females only when present in homozygotes and therefore appear as a recessive condition. Half the male offspring of a carrier mother will suffer and half her female offspring will be carriers. Examples of sex-linked conditions are color-blindness and hemophilia.


Autosomal dominant: Dominant conditions are where even in the heterozygote state (a person inheriting one mutant and one normal gene) the abnormality is seen in the individual. Their effects in the homozygote (double dose of the mutant gene) are usually more severe, if not lethal. They are expressed in the first generation after its occurrence. An example of a dominant gene condition is Huntingdon’s chorea (HC), which is characterized by nerve cell damage and changes in physical, emotional, and mental state. HC is caused by a faulty gene on chromosome 4. Other examples include achondroplasia, neurofibromatosis, Marfan syndrome, or myotonic dystrophy.


Autosomal recessive: Usually, this condition requires homozygosity, which means two mutant genes at the same locus, to produce the trait disease. The mutant gene must be inherited from each parent. Recessive disorders are usually rare, as the mutation would need to be inherited from both parents. However, some recessive genes even when present in a single dose, i.e., heterozygote accompanied by a dominant normal gene do still confer slight deleterious effects. An example of a recessive gene disorder is cystic fibrosis, which is caused by mutations on a gene located on chromosome 7. Other examples include phenylketonuria, hemochromatosis, Bloom’s syndrome, and ataxia-telangiectasia.