Abstract
Current knowledge of stem cell characteristics, maintenance and renewal, evolution with age, location in ‘niches’, and radiosensitivity to acute and protracted exposures is reviewed regarding haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. The identity of the target cells for carcinogenesis continues to point to the more primitive and mostly quiescent stem cell population (able to accumulate the protracted sequence of mutations necessary to result in malignancy), and, in a few tissues, to daughter progenitor cells. Several biological processes could contribute to the protection of stem cells from mutation accumulation: (1) accurate DNA repair; (2) rapid induced death of injured stem cells; (3) retention of the intact parental strand during divisions in some tissues so that mutations are passed to the daughter differentiating cells; and (4) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the vital niche. DNA repair mainly operates within a few days of irradiation, while stem cell replications and competition require weeks or many months depending on the tissue type. This foundation is used to provide a biological insight to protection issues including the linear-non-threshold and relative risk models, differences in cancer risk between tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age.
1. INTRODUCTION
The International Commission on Radiological Protection (ICRP) has reviewed various aspects of cancer induction from radiation, including skin cancer risk in Publication 59 (ICRP, 1992), genetic susceptibility to cancer in Publication 79 (ICRP, 1998), biological effects after prenatal irradiation (embryo and fetus) in Publication 90 (ICRP, 2003), low-dose extrapolation of radiation-related cancer risk in Publication 99 (ICRP, 2005), and lung cancer risk from radon in Publication 115 (ICRP, 2010). In these reports, ICRP has made some judgements and assumptions about the location and radiation response of the target cells responsible for carcinogenesis in various tissues. In most cases, the target cells are considered to be the tissue stem cells, and, in some cases, their daughter progenitor cells. Renewal and radiation response of these cells change with age and are governed largely by exogenous signals from their ‘niche’ residence. The fundamental evidence for stem cells being target cells has been increasing markedly in recent years. This evidence contributes to understanding of the biological basis for carcinogenesis, and helps support modelling of human radiation risk. It was considered that a report on the subject of target/stem cells would be topical and valuable in order to put all the target cell evidence for carcinogenic radiation risk in different tissues into a common framework and perspective for the first time [see Publication 131 (ICRP, 2015) for the full text].
Seven organ systems with different characteristics were chosen for detailed review of their stem cell properties and radiation responses. Selection was made on the basis of importance for radiological protection purposes, and the extent of available radiobiological knowledge and interest. They comprised haematopoietic tissues, mammary gland, thyroid, digestive tract, lung, skin, and bone, and included information on both human and experimental animal systems. Projections were made of the possible role of various stem cell processes concerning particular risk issues of continuing importance to ICRP, namely the linear-non-threshold (LNT) and relative risk (RR) models, dose and dose-rate effectiveness factor (DDREF), location of target cells, tissue risk factors, and age-dependent sensitivity to radiation.
2. STEM CELL CHARACTERISTICS AND RESPONSE
Stem cells are responsible for the maintenance of tissue function in renewing tissues. For supplying a large number of a variety of functional cell types, the tissue cell population has a discrete hierarchical lineage consisting of stem cells, differentiating progenitor cells, and functional mature cells. In the normal steady state, asymmetric division of adult tissue stem cells produces both a stem cell and a progenitor cell. Progenitor cells divide further to increase in number, and they subsequently differentiate into functional cells that are eventually lost from the tissue. In this general scheme of tissue turnover, stem cells are mainly quiescent, while progenitor cells divide more rapidly with a limited proliferative capacity. The number of cell stages in a lineage varies greatly between tissues, from short lineages in, for example, mammary gland, to long lineages in haematopoiesis and spermatogenesis, where more diverse and specialised cell functions are required. Stem cells are defined by their ability to self-renew and to produce progenitor cells of particular lineages. Isolation and cultivation of stem cells are now greatly facilitated by identification of various stem-cell-specific markers coupled with flow cytometry, and the ability of some stem cell types to survive anchorage-independent growth and proliferate under restrictive soluble factor conditions and give rise to discrete spheroidal groups of descendant cells. Several different subtypes of stem cell have been identified in particular tissues (e.g. haematopoietic tissue, intestine, skin, and lung) which is indicative of a hierarchy within the stem cell population. The turnover rate and the number/location of various cell types in a tissue are believed to be important determinants of tissue-specific risk of radiation carcinogenesis.
The radiosensitivity of stem cells/progenitor cells regarding cell killing can be assessed by clonogenic assays in vitro, and also in vivo using transplantation or in-situ techniques. There are various examples of stem cells being more resistant than progenitor cells, partly due to quiescence and providing time to undergo potentially lethal damage repair. Within the stem cell compartment, there are a few cases where certain stem cell types undergo rapid cell death (apoptosis) with high sensitivity to radiation (e.g. in small intestine), considered to be a protective response to delete injured stem cells. DNA repair and damage response play important roles for tissue stem cells to stay quiescent and preserve genomic stability. In non-cycling stem cells, the more accurate form of the error-prone non-homologous end-joining DNA repair pathway is likely the way (in contrast to the error-free homologous recombination DNA repair in cycling S and G2 phase cells) that DNA damage is repaired, and hence associated with potentially lethal damage repair.
Tissue stem cells divide and replenish tissues for the entire life of an individual. Their division potential is enormous, as shown in studies of bone marrow and intestine. The regulation of proliferation and differentiation of stem cells occurs in the stem cell ‘niche’ where they reside. Stem cells have limited telomerase activity so that erosion of telomere ends through rounds of DNA replication is inevitable. One way to prevent the loss of telomeres is to have efficient repair of DNA damage. Failure to do this results in the loss of stem cells, which necessitates compensatory replication. Therefore, damage checkpoints and DNA repair are important, and quiescence in the well-protected microenvironment of the stem cell niche acts to promote the genomic integrity of the stem cells. Telomere shortening takes place in stem cells of an ageing body, and is linked to cell senescence.
3. ROLE OF STEM CELLS IN RADIATION CARCINOGENESIS
Cancer in adulthood is envisaged to arise as a result of accumulation of oncogenic mutations occurring mainly after birth, and during growth and maturational development, whereas some childhood cancers are characterised by mutations acquired during fetal development or inherited from the parents. The incidence of cancer in adults, especially solid cancer, exhibits a steady increase with age. Armitage and Doll (1954) noted that this increase follows approximately the fifth power of age, and proposed the multistage carcinogenesis model. This was later supported by the molecular analysis of human colon cancer, in which the conversion of normal epithelial cells to adenoma and its progression to carcinoma were shown to be associated with a stepwise acquisition of mutations of oncogenes and tumour suppressor genes. Acquisition of multiple mutations by spontaneous processes takes a long time, which may explain why many adulthood cancers arise late in life. A stem cell origin of cancer is suggested because stem cells are likely to be the only type of cells that have a sufficiently long residence time in the body to accumulate multiple mutations and gain malignant phenotypes, while the bodily residence of committed progenitor cells is somewhat compromised.
Regarding cancer risk in natural (unirradiated) conditions, a strong correlation has been reported recently between lifetime tissue-specific cancer risk in (American) populations and the estimated lifetime total number of stem cell divisions in each of a wide variety of 31 tissues/body sites (i.e. the product of estimates of the stem cell number and the lifetime number of cell divisions per stem cell in each tissue) (Tomasetti and Vogelstein, 2015). This study has been discussed variously regarding data selection, risk differences between populations, and method of analysis (Sills, 2015). Nonetheless, apart from the increasing knowledge of specific gene mutations associated with increased susceptibility to particular cancers, the number of lifetime stem cell divisions is the only other biological parameter to date claimed to be associated with cancer risk in a normal human population. Hence, this study highlighted the potential importance of replication-mediated somatic mutation in the aetiology of spontaneous cancer rather than just the traditionally entertained environmental and hereditary components.
Another mechanism that has received much attention is the so-called ‘immortal strand’ hypothesis proposed by Cairns (1975), in which asymmetric segregation of DNA strands was invoked as minimising DNA replication errors in the tissue stem cells. Thus, the stem cell retains the template DNA strand after a round of DNA synthesis, while the progenitor cell inherits the daughter strand with possible errors that are eventually lost by differentiation and maturation as functional cells. There is evidence in support of this mechanism in small intestinal crypts, mammary epithelium, some muscle satellite cells and progenitor cells, and some central nervous system cells (Potten and Wilson, 2007). However, the mechanism has been found not to apply in haematopoietic stem cells (HSCs) (Kiel et al., 2007), and hence does not apply universally. Also, a genetic sequencing approach has been used to estimate the mutation accumulation rate in healthy stem cells of human colon, blood, and head and neck tissues (Tomasetti and Bozic, 2015). Mutations accumulated in those tissues at rates strikingly similar to those expected without any protection from an immortal strand mechanism.
Another important feature described recently is the concept of competition between normal and radiation-injured stem cells for residence in the niche. New studies suggest that stem cells are competing constantly to occupy the niche, which serves as a selective process against damaged stem cells. Interestingly, in one cell type, lymphocytes from in-utero-exposed atomic bomb (A-bomb) survivors and in-utero-exposed mice largely lacked chromosome aberrations after moderate doses of radiation, suggesting a possible competition-mediated elimination of aberrant HSCs (Nakamura, 2005). In contrast, stem cell competition is likely to be less stringent during childhood, when the stem cell/niche units increase in number to cope with the increase in tissue volume during childhood growth. Such behaviour of irradiated stem cells may have relevance to the age-dependent sensitivity to radiation carcinogenesis.
In addition to these targeted actions, radiation is known to act in a non-targeted fashion, which includes bystander effects and the induction of genomic instability (ICRP, 2007). However, the effects are, in most cases, non-linear with dose, thus making extrapolations uncertain, and there are few studies at the dose levels relevant for radiological protection. Hence, the present considerations are focussed primarily on mechanisms of protecting stem cells from mutation accumulation. Also, animal studies on the adaptation phenomenon, which could reduce the effects of protracted irradiations, show variations with dose and tissue type, again making difficult any general identification in a protection system.
4. TARGET CELLS FOR CARCINOGENESIS AMONG TISSUES
4.1. Haematopoietic tissue
Of all leukaemia types, acute myeloid leukaemia (AML) has been studied in most detail. AML comprises <5% of all childhood leukaemias, but is one of three radiation-inducible leukaemia subtypes: AML; chronic myeloid leukaemia (CML); and acute lymphoblastic leukaemia (ALL). Proliferation of haematopoietic malignancy is dependent on the type of tissue niche; HSC-derived leukaemia cells require a bone marrow microenvironment, and lymphoma cells (progenitor cell derived) need a lymph node environment. The multistage theory of carcinogenesis and the importance of the microenvironment in promotional events continue to suggest that the majority of target cells for leukaemia are likely to be the more slowly renewing primitive cells in the lineage. Indeed, the correlation between chronic radionuclide (α-particle) doses/location and incidence of AML was closest for target cells in the central marrow sinusoidal region (Lord et al., 2001), which is one location of such primitive cells. However, further evidence in mice suggests that the initial radiation-induced AML stem cell may originate not only from irradiated HSCs, but also from multipotent and common myeloid progenitor cells (Hirouchi et al., 2011). In addition, hemizygous deletion of dual-specificity protein phosphatase 2 in chromosome 2 may contribute to the self-renewal potential of radiation-induced AML stem cells (Hirouchi et al., 2011). Regarding non-targeted effects, a pertinent example is the use of C57BL/6 and CBA/Ca mice which are resistant or susceptible, respectively, to both radiation-induced myeloid leukaemia and chromosomal instability in bone marrow cells, as well as exhibiting differences in bystander signal generation after higher radiation doses (Zyuzikov et al., 2011). Over an acute and broad dose range of 1.7 mGy to 3 Gy, bystander effects in the bone marrow (assessed by p53 pathway signalling 3 h after irradiation) were only observed after doses >100 mGy, and chromosomal instability at 30 days was only found after doses ≥1 Gy. A detailed study of the ‘immortal strand hypothesis’ in highly purified HSCs revealed that all stem cells segregated their chromosomes randomly, and division of individual stem cells in culture revealed no asymmetric segregation of the DNA label. Hence, HSCs did not retain older DNA strands during division (Kiel et al., 2007). Also, irradiation affects the competition of HSCs for their residence in the bone marrow niche. When one of two marked bone marrow cell populations was exposed to 1 Gy and subsequently mixed with the non-irradiated population prior to grafting into lethally irradiated mice, the latter population predominated in the reconstituted marrow HSCs (Bondar and Medzhitov, 2010). Bone marrow cells with higher levels of p53 protein were outcompeted by those from normal wild-type mice, indicating that stem cell competition for residence in the niche is sensitive to radiation stress, which is sensed by p53. Within the A-bomb survivor cohort, the risk declined appreciably with increasing age at the time of exposure (Preston et al., 1994). In the very young (0–9 y), risk increased steeply during the early years following exposure, whereas in older survivors, the increase in risk was significantly delayed and more gradual. The representative animal model, AML in some strains of mice, does not follow this pattern. The incidence is low for infant exposure, and becomes high for exposure at approximately 10 weeks of age or later.
4.2. Mammary gland
Radiation exposure is a well-documented risk factor for breast cancer. The risk is approximately linear with increasing dose, and inversely related to age at exposure. Exposures after menopausal age appear to carry a reduced excess risk, and fractionating the dose has minimal influence. A number of studies have been published on the effects of dose and dose rate on mammary tumour induction in rodents (UNSCEAR, 1993). With BALB/c mice, the dose–incidence curve at high dose rate was linear-quadratic up to approximately 0.25 Gy, and the linear term was similar to that obtained after low-dose-rate (0.07 mGy min−1) exposures. Dose-fractionation studies showed a significant contribution from the quadratic component at doses as low as 0.1 Gy fraction−1, and acute daily fractions of 0.01 Gy gave a tumour incidence similar to that observed after low-dose-rate exposure to a total dose of 0.25 Gy in both cases (Ullrich et al., 1987). Low doses of radiation increased the mammary repopulating activity significantly, and could thereby increase the number of target cells that could initiate cancer (Nguyen et al., 2011). Understanding the effects of radiation on mammary stem cells is likely to help provide additional key insights into physiological and genetic determinants of cancer risk for an extended variety of solid tumour types. Data in the radiation-chimera mammary model suggest that radiation exposure early in life can alter heterotypic interactions, set the stage for stem cell expansion, and increase the risk of developing oestrogen-receptor-negative breast cancer which is observed in women treated with radiation for childhood cancers (Castiglioni et al., 2007). A plausible scenario is that radiation elicits a transient change in signalling or a persistent change in the inflammatory, macrophage, or vasculature compartment of the gland. This altered microenvironment permanently alters the pool of mammary epithelial stem/progenitor cells. Regarding age-at-exposure effects, the relatively restricted window of carcinogen susceptibility that is evident during or around puberty in both rodents and humans has been postulated to either contain the greatest number of target cells or be a critical period of stem cell regulation. There is a clear hierarchical lineage in mammary epithelium, controlled by many factors. A cell population in mouse mammary epithelium can be selected which is highly enriched in multilineage and self-renewal potential. Also, there is evidence that epithelial label-retaining cells in mouse mammary gland divide asymmetrically and retain their template DNA strands (Smith, 2005). However, the target cell origin of radiation-induced breast cancers in terms of stem and progenitor cells has not been elucidated to date.
4.3. Thyroid
Radiation induces both papillary and follicular carcinomas, but the former type predominates in humans whereas the latter type predominates in the common rat model. Although there is evidence for the presence of a stem cell type lineage in thyroid epithelium, there is no knowledge of whether the different tumour types originate from the same or different target cells in the lineage. Dose–incidence relationships for carcinomas (mostly follicular) in 3000 female Long-Evans rats showed a rising incidence with increasing x-ray dose from 0.8 Gy, flattening off at the higher doses to 10.6 Gy (Lee et al., 1982). However, adenomas were in the majority, and these showed a continuously rising dose–incidence curve. Hence, the curves for the two tumour types appeared to be significantly different in shape. In addition, concurrent studies with 131I and detailed dosimetry showed a similar response to the high-dose-rate x-ray results for the carcinomas, but there was a tendency towards a lower incidence of adenomas at the higher doses of 131I compared with x rays. If the adenoma yields vs dose are interpreted on a linear-quadratic basis, it can be estimated that the linear component (assumed not modified by dose rate) may be at doses up to approximately 0.8 Gy, and a DDREF of approximately 2 may apply at approximately 2 Gy. However, for the aggregated yields of both tumour types, the linear component could be higher and the DDREF lower, albeit with large uncertainties. The similarity of tumour yields in rats at low doses of acute x rays and low-dose-rate 131I is compatible with human data [i.e. the excess relative risk (ERR) for external radiation exposure was compatible with the ERR estimates for internal radiation exposure following the Chernobyl accident].
4.4. Digestive tract
Cancers of the stomach and colon in rodents are only induced by high radiation doses (e.g. ≥8 Gy) (Boice and Fry, 1995), and only rarely in the small intestine. A possible reason invoked for the latter is the radiation-induced apoptosis of mutated stem cells in the small intestine, which is prevented in the large bowel by expression of the survival (anti-apoptotic) gene B-cell lymphoma 2 (Merritt et al., 1995). Nonetheless, the stomach and colon are fairly resistant to cancer induction. Crypt stem cells are still considered to be the target cells for colonic tumours, and several types of stem cells have been described. The potential inclusion of some daughter progenitor cells as target cells is not yet resolved. An interesting recent development is the finding of rare, slowly cycling, long-lived, and radioresistant telomerase-positive stem cells (one per 150 crypts) in both small and large intestine, which can give rise to all differentiated intestinal cell types (Montgomery et al., 2011). These are likely to be important candidate target cells in the colon in terms of the multistage model for carcinogenesis. Germline mutation of the adenomatous polyposis coli (APC) gene predisposes both humans and mice to intestinal carcinogenesis. In humans, inheritance of mutant APC is associated with the cancer predisposing disorder, familial adenomatous polyposis, and mutation of APC is an early somatic event in sporadic colon cancer. Individuals carrying germline mutations in the APC gene develop hundreds to thousands of colorectal adenomatous polyps, some of which will progress to carcinomas if left untreated. The multiple intestinal neoplasia (Min) mouse provides a sensitive model for the study of tumourigenesis in irradiated mice. Min mice are genetically heterozygous for a germline truncating mutation of the APC gene, and develop multiple intestinal tumours and sporadic colon tumours in their intestinal tracts within several weeks of birth. Neonates were more radiosensitive to tumour induction than young adults. The dose–incidence curve for adenomas was linear-quadratic over the range 0–5 Gy x rays, and strikingly, there were more tumours in the small intestine than in the caecum and colorectum (Ellender et al., 2011). Tumour incidence was elevated in the caecum after ≥2 Gy, and in the colorectum after ≥1 Gy. In general, adenomas in the small intestine were sessile while the smaller numbers of adenomas in the large intestine were pedunculated. There was also an incidence of micro-adenomas in the small intestine, which was greater after the higher doses in the range used; however, no micro-adenomas were found in the large intestine.
4.5. Lung
From studies of A-bomb survivors and uranium miners, radiation-induced lung cancers were found to be more likely to be small cell lung carcinomas (SCLCs), and less likely to be adenocarcinomas (ADCs) (Land et al., 1993). SCLCs do not occur in mice, and ADCs are the most common type of lung cancer. The induction of ADCs in female BALB/c mice following acute irradiation was shown to be consistent with a linear-quadratic model in which the linear term was independent of dose rate by comparing responses using 0.4 Gy min−1 and 0.06 mGy min−1. Also, the DDREF was approximately 4.2 at 3 Gy, and approximately 3.2 at 2 Gy. Dose-fractionation studies predicted that the DDREF would be approximately 1.1 at 0.1 Gy (Ullrich et al., 1987). In the respiratory tract, the target cells for radiation-associated carcinogenesis are considered to be basal cells in the trachea and larger bronchi of the central lung, and Clara variant and type II alveolar cells in the peripheral lung. An epithelial stem cell niche has been identified in the zone where airways terminate and form alveoli. The putative mouse bronchoalveolar stem cells at the bronchiolar/alveolar junction co-express secretoglobin-a1a, type II cell marker surfactant protein C, and stem cell antigen-1, and are negative for surface markers CD45 and CD31. Molecular analysis showed that, despite their distinct histopathological phenotypes, genomic profiles showed near-complete overlap in human ADCs and squamous cell carcinomas (SCCs), with only one clear SCC-specific amplicon (Tonon et al., 2005). Hence, the common or different cellular origin of lung cancer types may become better understood. In addition, there may be influences from the irradiated microenvironment. For example, migration of mesenchymal stem cells (MSCs) into irradiated and stressed regions has been invoked as a potential alternative or contributory mechanism in carcinogenesis.
4.6. Skin
Human skin cancers induced by ionising radiation are predominantly basal cell carcinomas (BCCs). The traditional view was that a threshold dose exists for radiation-induced skin cancer in the range of 8–10 Gy, but the A-bomb survivor data indicated that BCCs can be induced by acute exposure at moderate doses, even as low as approximately 1 Gy. In mice, radiation readily produces SCCs but no BCCs, whereas approximately 20% of induced skin tumours in rats are BCCs. The dose–response curve for total tumours in rats was compatible with a linear-quadratic model, albeit with a tendency for adnexal (hair follicle and sebaceous) tumours to be more common. Further, after low doses, adnexal tumours were more common and occurred earlier after high doses compared with epidermoid tumours. With repeated weekly doses of 0.75 or 1.5 Gy over a lifetime, more tumours were produced than expected from single exposure dose responses, suggesting either the number of events increased per unit dose (i.e. induced sensitisation) or that clonal growth expanded the number of early transformed cells (Burns and Albert, 1986). The radiation had to penetrate at least 180 µm to induce tumours, and a depth dose of approximately 300 µm was about optimum irrespective of follicle growth phase and size, demonstrating that the main target cells were in the stem cell zone of the hair follicle. Also, there was a marked effect of age on the incidence of radiation-induced cancer. A model for human skin cancer proposed that stem cells were the likely target cells for BCCs, early progenitor cells for SCCs, and late progenitor cells for papillomas (Sell, 2004). Stem cells have been found to be more radioresistant than daughter progenitor cells, both in humans and mice, which may not only favour tissue maintenance but also influence long-term accumulation of damaged cells. Molecular characterisation of these different cell populations is continuing, and the most potent quiescent stem cells appear to possess high levels of the adhesion molecule integrin β6 and low levels of the transferrin receptor CD71. Quantitative data of mouse follicle-bulge cell divisions marked with bromodeoxyuridine support the long-standing infrequent stem cell division model (Waghmare et al., 2008). However, it was shown that hair follicle stem cells do not retain the older DNA strands or sort their chromosomes. To date, there are no distinct markers for the target cells of the different types of skin cancer.
4.7. Bone
Radiation-induced bone sarcoma has been associated with high doses of ionising radiation from therapeutic or occupation-related exposures. However, the development of bone sarcoma following lower doses remains speculative. Analysis of 80,000 individuals in the Life Span Study cohort to assess the development of bone sarcoma (most commonly osteosarcoma) showed a preferred fit with a dose threshold at approximately 0.85 Gy (95% confidence interval 0.12–1.85 Gy), and a linear dose–response association above this threshold (Samartzis et al., 2011). Chadwick et al. (1995) fitted the radium dial painter data using a two-mutation carcinogenic model with clonal expansion. The analysis showed that a linear-quadratic dose–effect relationship can be applied and, because of the very low natural incidence of bone sarcoma, is consistent with very low absolute risk (AR) at low doses and dose rates. Much of the experimental work on radiation-induced bone cancers has been performed using dogs. For the low-linear-energy-transfer β emitter, 90Sr, the dose response was non-linear with no tumours occurring at doses <18 Gy cumulative average bone dose. This much higher threshold dose may reflect differences in dosimetry, the protraction of the radionuclide dose, and the much shorter life span of dogs compared with humans. Osteogenic MSCs for the osteoblast lineage reside in the bone marrow. MSCs are identified as plastic-adherent pluripotent cells, capable of differentiating into bone, cartilage, and fat cells, and can be isolated from many different tissues in addition to bone marrow. MSCs express high levels of DNA damage repair proteins, are relatively radioresistant, and possess robust antioxidant reactive-oxygen-species scavenging capacity. Exposure to ionising radiation can have an adverse effect on various key cell functions of cultured MSCs (proliferation, differentiation, and senescence) and can also cause loss of bone mass and skeletal fragility, as well as having a secondary impact on haematopoietic functions, in both animals and humans. Both primitive HSCs and mesenchymal precursor cells are possible target cells for radiation-induced bone cancer. Also, these cell types reside within a low oxygen tension environment in situ, which may help protect cells from radiation damage. The target cells for bone-associated α-emitting radionuclides lie within a few tens of micrometres from the endosteal surface, which is the range of α particles.
5. CONCLUSIONS
The following conclusions are the main implications of current stem cell knowledge for the carcinogenesis aspects in the ICRP system of radiological protection (ICRP, 2015).