ICRP Publication 118
ICRP Statement on Tissue Reactions / Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context
Recommended citation
ICRP, 2012 ICRP Statement on Tissue Reactions / Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context. ICRP Publication 118. Ann. ICRP 41(1/2).
Authors on behalf of ICRP
F.A. Stewart, A.V. Akleyev, M. Hauer-Jensen, J.H. Hendry, N.J. Kleiman, T.J. MacVittie, B.M. Aleman, A.B. Edgar, K. Mabuchi, C.R. Muirhead, R.E. Shore, W.H. Wallace
Abstract - This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103, and it provides updated estimates of ‘practical’ threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye.
Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40–50 years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower.
A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1–1.2, and in a few cases 1.5–2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors.
Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5 Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.
© 2012 ICRP. Published by Elsevier Ltd.
Keywords: Normal tissues; Tissue reactions; Threshold doses; Radiation responses of normal tissues; Biological response modifiers.
AUTHORS ON BEHALF OF EHALF OF ICRP F.A. STEWART, A.V. AKLEYEV, M. HAUER-JENSEN, J.H. HENDRY, N.J. KLEIMAN, T.J. MACVITTIE, B.M. ALEMAN, A.B. EDGAR, K. MABUCHI, C.R. MUIRHEAD, R.E. SHORE, W.H. WALLACE
Reference
ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP Publication 103. Ann. ICRP 37(2–4).
Key Points: Not included in this publication
Executive Summary
(a) The Commission issued revised recommendations for a system of radiological protection in Publication 103 (ICRP, 2007). This included consideration of the detriment arising from non-cancer effects of radiation on health. These effects, previously called ‘deterministic effects’, are now referred to as ‘tissue reactions’ because it is increasingly recognised that these effects are not determined solely at the time of irradiation, but that many types of tissue reactions can be modified after radiation exposure. Previously, the Commission reviewed various aspects of non-cancer health effects of low linear-energy-transfer (LET) ionising radiation in Publication 41 (ICRP, 1984), high-LET radiation in Publication 58 (ICRP, 1990), the skin in Publication 59 (ICRP, 1991), and the skin and the eye in Publication 85 (ICRP, 2000).
(b) Recently, the Commission initiated a review of available scientific information on non-cancer health effects attributable to exposure to low-LET ionising radiation. ICRP stated that particular attention should be paid to radiation effects in the lens of the eye and the cardiovascular system because of recent published observations of radiation effects in these systems occurring after much lower doses than reported previously (ICRP, 2007). The full review was based on scientific articles available in the open literature. Major reviews by other organisations, in particular the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR, 2006), were also taken into account.
(c) The main emphasis of this review was to provide estimates of threshold dose, defined for practical purposes as the dose resulting in only 1% incidence of specified tissue or organ reactions (ICRP, 2007). The evidence arises from the effects of radiotherapeutic exposures, radiation incidents and accidents, and chronic exposures to workers or other populations. Follow-up time is recognised as very important in the case of late reactions, because the incidence of most late reactions increases, and hence the threshold dose decreases, with increasing time after irradiation. Both morbidity and mortality endpoints were considered. Many previous estimates were unchanged because of a lack of new informative data, but other estimates required modification. Section 2 is devoted to individual organ systems, first to consider the human evidence and then to support that with evidence from preclinical experimental systems. Section 3 considers the various biological response modifiers that have been used to modify radiation responses. Section 4 discusses all this information with respect to threshold doses for acute, fractionated, and chronic exposures, which are required to recommend dose limits for workers and the public. Annex A contains a series of tables of critique for each of the earlier publications concerning radiation-induced cataracts in order to provide a sound reference basis for the changes in recommended dose limits.
(d) Acute threshold doses of approximately 0.5 Gy and chronic dose rates of 0.4 Gy/year remain the recommended values for depression of haematopoiesis. Also, for mortality, the threshold values of approximately 1 Gy acute dose without medical care and 2–3 Gy with good medical care remain unchanged from previous ICRP values. Protracted doses of 4–8 Gy in 1 week or 10–14 Gy accumulated over 1–3 months are likely to be tolerable. Growth factor administration is considered to be beneficial to help increase survival rates after radiation exposure of the bone marrow, and preclinical studies suggest that threshold doses might be increased up to two-fold by the use of good clinical support and growth factors.
(e) The acute threshold dose for early mortality at 6–9 days after intestinal irradiation is considered to be approximately 6 Gy, and good medical care is expected to increase this value. The incidence and severity of delayed intestinal radiation toxicity depends on radiation dose, volume of bowel irradiated, fractionation schedule, concomitant chemotherapy, comorbidities, and other patient factors. The threshold doses for late injury after irradiation show the greater sensitivity of the salivary glands (parotids) and the liver, for example, compared with the lower sensitivity of the rectum. The most promising enterotrophic strategies with the potential to protect the intestine from radiation injury include some cytokines, gastrointestinal peptide hormones, and a variety of nutrients.
(f) The threshold doses for the male and female reproductive systems for acute, fractionated/protracted, and chronic exposures, and the bases for these doses, remain virtually the same as those recommended previously. For male fertility, there is a trend for the threshold dose to be less for fractionated/protracted exposures compared with single exposures (reverse fractionation effect). Hormonal manipulation of spermatogenic recovery has been investigated in humans, but with little conclusive improvement. In preclinical studies, various biological response modifiers have been investigated including hormonal manipulation, antioxidants, radical scavengers, and natural compounds. However, at present, there is no over-riding conclusion that would favour one compound over others. In females, radioresponsiveness increases with age because of the decline in the size of the oocyte pool with increasing age. Although numerous studies in female patients undergoing chemotherapy (and radiotherapy) have indicated that gonadotropin-releasing hormone (GnRH) analogues might be protective of ovarian function, none of these studies were prospective randomised clinical trials, and thus the evidence was inconclusive.
(g) The salient features of the early and late radiation responses of the skin have not changed since earlier ICRP reports on this topic. The responses depend on the area of skin irradiated, dose fractionation effects, and whether the epidermis alone is irradiated or both the epidermis and the dermis. In humans, the most successful agents for reducing early reactions are anti-inflammatory compounds, and polyunsaturated fatty acids have shown promise in preclinical systems. For reducing late reactions, superoxide dismutase, fibroblast growth factor, captopril, polyunsaturated fatty acids, a-tocopherol, and inhibition of transforming growth factor-beta signalling have shown some promise in both humans and preclinical systems, with dose modification factors (DMFs) of 1.1–1.2 and a maximum of approximately 1.5.
(h) ICRP has not previously listed circulatory disease as a health hazard from radiation exposures to organs and tissues, because it is only in the last few years that there has been greater consolidation of the evidence on this topic. The evidence arises from radiotherapeutic experience and epidemiological studies following nuclear and other radiation activities. There is no clear pattern across studies regarding whether or not the excess relative risk for cardiovascular disease is greater than that for stroke or cerebrovascular disease. From current evidence, a judgement can be made of a threshold acute dose of approximately 0.5 Gy (or 500 mSv, see note about units below) for both cardiovascular disease and cerebrovascular disease. On that basis, 0.5 Gy may lead to approximately 1% of exposed individuals developing the disease in question >10 years after exposure. This is in addition to the high natural incidence rate (circulatory diseases account for 30–50% of all deaths in most developed countries). The value of 0.5 Gy to the heart and cerebrovascular system could be reached during some complex interventional procedures. Hence, medical practitioners need to be aware of this new threshold, and should ensure that particular emphasis is given to optimisation. However, it is emphasised that there are notable uncertainties in determining the risks of these diseases at this level of radiation dose. It is unclear from available evidence whether or not the threshold is the same for acute, fractionated, and chronic exposures. For the present purposes, the threshold dose is assumed to be the same for all three types of exposure (i.e. approximately 0.5 Gy).
(i) For cataracts in the lens of the eye induced by acute exposures, recent studies, where formal estimates of threshold doses have been made after long follow-up periods, indicate values of approximately 0.5 Gy with 90–95% confidence intervals including zero dose. This is lower by a factor of 10 than deduced in earlier studies. Those studies generally had short follow-up periods, failed to consider the increasing latency period as dose decreases, did not have sufficient sensitivity to detect early lens changes using the various techniques employed, and had relatively few subjects with doses below a few Gy. For fractionated and protracted exposures, values of approximately 0.5 Gy have been similarly deduced from recent studies. However, the evidence pertaining to the latter exposures mainly refers to opacities rather than cataracts impairing vision because the follow-up times are shorter in those studies. For chronic exposure over several to many years, much of the evidence refers to minor lens opacities. Nonetheless, there is no indication that threshold accumulated doses are higher in this scenario. There are no established mitigators of lens radiation injury leading to opacities or cataracts, but lens replacement is a well-established surgical procedure.
(j) The threshold values for pneumonitis are derived from whole-lung radiotherapeutic exposures (usually 5 years of follow-up), and the values of 6.5 Gy for acute exposures and <18 Gy for fractionated exposures (2 Gy/fraction) are very similar to previous judgements. Steroids can relieve the symptoms of pneumonitis, but it remains unclear whether they can protect against the development of late fibrosis. In breast and lung cancer patients, there is some evidence for a reduction in both early and late lung toxicity when pentoxifylline was given during the period of radiotherapy, but angiotensin-converting enzyme (ACE) inhibitors had no significant effect.
(k) In the urinary tract, the kidneys are the most sensitive organ, and the bladder and the ureters are more resistant (deduced from radiotherapeutic experience, usually with 5 years of follow-up). The threshold dose for the human kidney is approximately 7–8 Gy acute dose, approaching 20 Gy for doses given as multiple 2-Gy fractions. For late reactions in the bladder and the ureters, the threshold total fractionated (2-Gy fractions) dose is ≤50 Gy. Anti-inflammatory agents have produced equivocal benefits in both human and animal systems. The most promising preclinical agents to date in reducing radiation nephropathy are ACE inhibitors and angiotensin II (AII) receptor antagonists. Preclinical studies have shown DMFs of 1.2–1.5 when given prophylactically from the time of irradiation.
(l) In the musculoskeletal system, radiation exposure can give rise to three different types of non-cancerous bone pathology: osteoradionecrosis, spontaneous fractures or fractures with less than normal trauma, and abnormalities of bone growth. The threshold dose for necrosis of femoral heads and rib fractures (after 5 years) is approximately 50 Gy in 2-Gy fractions, and approximately 55 Gy for skeletal muscle. In contrast to mature bone, growing bone is much more radiosensitive, and 25 Gy in 2-Gy fractions is often suggested as a critical threshold dose. Hyperbaric oxygen remains the only therapy claimed to mitigate such clinical reactions at the present time.
(m) Brain irradiation can have direct radiation effects on the thyroid and pituitary glands, as well as subtle effects on the hypothalamic–pituitary–adrenal axis and the hypothalamic–pituitary–gonadal axis. All of the information comes from radiotherapy experience using fractionated doses of (generally) 2 Gy/fraction. The hypothalamus is more radiosensitive than the pituitary. In children, radiation effects include growth hormone (GH) deficiency, precocious puberty (after lower doses) or delayed puberty (after higher doses), hypopituitarism, and hyperparathyroidism. In adults, radiation effects include hyperprolactinaemia, hypogonadism, obesity, hypothyroidism, hyperthyroidism, and adrenocorticotropic hormone deficiency. Strategies for mitigating the effects of radiation on the endocrine system include GH replacement in children with radiation-induced GH deficiency, thyroid hormone replacement therapy in cases of its deficiency, and repeated intermittent infusion of GnRH in cases of reduced gonadotropin secretion after pituitary damage.
(n) The threshold dose for symptomatic spinal cord injury (myelitis) is approximately 50 Gy delivered in 2-Gy fractions. The injury is highly dependent on dose per fraction, and the threshold dose is greater when very small volumes (<1 cm cord length) are irradiated. The adult brain has been considered rather more resistant in terms of necrosis, but subtle effects have been detected at much lower doses of approximately 10 Gy and clear volume effects are discernable. Low-dose irradiation (1–2 Gy) to the developing brain of children can cause long-term cognitive and behavioural defects, and infants are even more susceptible with cognitive impairment in adult life detected after exposure to doses of >0.1 Gy before 18 months of age. There are no recognised mitigating agents for use in humans to treat spinal cord injury after irradiation. Preclinical studies with anti-inflammatory agents, ACE inhibitors, AII receptor antagonists, some growth factors, and polyunsaturated fatty acids have shown the most promise.
(o) This ICRP report has some changes to indicated threshold doses for tissue reactions compared with those stated in Publication 103 (ICRP, 2007). First, the threshold dose for radiation-induced eye cataracts is now considered to be approximately 0.5 Gy for both acute and fractionated exposures, in line with various recent epidemiological studies. Second, circulatory disease has been recognised as an important late effect of radiation exposure, both for mortality and morbidity. An approximate threshold dose of 0.5 Gy has been proposed for acute and fractionated/protracted exposures on the basis that this might lead to an incidence of the order of 1% of circulatory disease in exposed individuals, although the estimation of risk at this level of dose is particularly uncertain. Third, the threshold dose values for chronic exposures depend on the exposure duration and the follow-up period after exposure. Differences between these time variables among different studies make the values more uncertain. The values quoted for both the lens of the eye and the circulatory system assume the same incidence of injury irrespective of the acute or chronic nature of the exposure over a working life, with >15-20 years follow-up time. Future studies may elucidate this further. Fourth, much more information has become available regarding the effect of biological response modifiers in mitigating tissue reactions, which has the effect of modifying threshold doses. These modifications are agent, tissue, and schedule specific, and they are likely to have increasing impact in the future, concomitant with increases in scientific and medical knowledge.
(p) Lastly, the previous ICRP judgement that acute doses up to approximately 0.1 Gy produce no functional impairment of tissues is maintained. Hence, the stochastic risks of induced cancer and hereditary effects continue to be the principal risks to consider for most applications of ICRP recommendations in occupational or public situations. However, after acute or accumulated doses of >0.5 Gy, the risk of tissue reactions (deterministic effects) becomes increasingly important, particularly for the lens of the eye and the circulatory system, at very long times after radiation exposure.
Note about units
(q) By ICRP convention, doses resulting in tissue reactions (deterministic effects) should be quoted in Gy or relative biological effectiveness (RBE)-weighted dose RBED (Gy), rather than Sv which is reserved for clearly stochastic effects. ICRP states that ‘the quantities, equivalent dose and effective dose, with their unit with the special name sievert (Sv), should not be used in the quantification of radiation doses or in determining the need for any treatment in situations where tissue reactions are caused. In general, in such cases, doses should be given in terms of absorbed dose in gray (Gy), and if high-LET radiations (e.g. neutrons or alpha particles) are involved, an RBE-weighted dose, RBED (Gy), may be used’ (ICRP, 2007). It is recognised that many doses in the literature are quoted in Sv or mSv because of previous usage and the familiarity of many professionals with this unit. Also, there is the fact that the use of a threshold model for the particular endpoints of cataract and circulatory disease remains uncertain. For low-LET radiation, the actual numerical value for either unit is the same.
References
ICRP, 1984. Non-stochastic effects of irradiation. ICRP Publication 41. Ann. ICRP 14(3).
ICRP, 1990. RBE for deterministic effects. ICRP Publication 58. Ann. ICRP 20(4).
ICRP, 1991. Radiation effects on the skin. ICRP Publication 59. Ann. ICRP 22(2).
ICRP, 2000. Radiopathology of skin and eye and radiation risk. ICRP Publication 85. Ann. ICRP 30(2).
ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP Publication 103. Ann. ICRP 37(2–4).
UNSCEAR, 2006. Effects of Ionizing Radiation. Annex D: Effects of Ionizing Radiation on the Immune System. Report to the General Assembly. United Nations, New York.
ICRP, 2012 ICRP Statement on Tissue Reactions / Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context. ICRP Publication 118. Ann. ICRP 41(1/2).
Authors on behalf of ICRP
F.A. Stewart, A.V. Akleyev, M. Hauer-Jensen, J.H. Hendry, N.J. Kleiman, T.J. MacVittie, B.M. Aleman, A.B. Edgar, K. Mabuchi, C.R. Muirhead, R.E. Shore, W.H. Wallace
Abstract - This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103, and it provides updated estimates of ‘practical’ threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye.
Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40–50 years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower.
A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1–1.2, and in a few cases 1.5–2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors.
Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5 Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.
© 2012 ICRP. Published by Elsevier Ltd.
Keywords: Normal tissues; Tissue reactions; Threshold doses; Radiation responses of normal tissues; Biological response modifiers.
AUTHORS ON BEHALF OF EHALF OF ICRP F.A. STEWART, A.V. AKLEYEV, M. HAUER-JENSEN, J.H. HENDRY, N.J. KLEIMAN, T.J. MACVITTIE, B.M. ALEMAN, A.B. EDGAR, K. MABUCHI, C.R. MUIRHEAD, R.E. SHORE, W.H. WALLACE
Reference
ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP Publication 103. Ann. ICRP 37(2–4).
Key Points: Not included in this publication
Executive Summary
(a) The Commission issued revised recommendations for a system of radiological protection in Publication 103 (ICRP, 2007). This included consideration of the detriment arising from non-cancer effects of radiation on health. These effects, previously called ‘deterministic effects’, are now referred to as ‘tissue reactions’ because it is increasingly recognised that these effects are not determined solely at the time of irradiation, but that many types of tissue reactions can be modified after radiation exposure. Previously, the Commission reviewed various aspects of non-cancer health effects of low linear-energy-transfer (LET) ionising radiation in Publication 41 (ICRP, 1984), high-LET radiation in Publication 58 (ICRP, 1990), the skin in Publication 59 (ICRP, 1991), and the skin and the eye in Publication 85 (ICRP, 2000).
(b) Recently, the Commission initiated a review of available scientific information on non-cancer health effects attributable to exposure to low-LET ionising radiation. ICRP stated that particular attention should be paid to radiation effects in the lens of the eye and the cardiovascular system because of recent published observations of radiation effects in these systems occurring after much lower doses than reported previously (ICRP, 2007). The full review was based on scientific articles available in the open literature. Major reviews by other organisations, in particular the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR, 2006), were also taken into account.
(c) The main emphasis of this review was to provide estimates of threshold dose, defined for practical purposes as the dose resulting in only 1% incidence of specified tissue or organ reactions (ICRP, 2007). The evidence arises from the effects of radiotherapeutic exposures, radiation incidents and accidents, and chronic exposures to workers or other populations. Follow-up time is recognised as very important in the case of late reactions, because the incidence of most late reactions increases, and hence the threshold dose decreases, with increasing time after irradiation. Both morbidity and mortality endpoints were considered. Many previous estimates were unchanged because of a lack of new informative data, but other estimates required modification. Section 2 is devoted to individual organ systems, first to consider the human evidence and then to support that with evidence from preclinical experimental systems. Section 3 considers the various biological response modifiers that have been used to modify radiation responses. Section 4 discusses all this information with respect to threshold doses for acute, fractionated, and chronic exposures, which are required to recommend dose limits for workers and the public. Annex A contains a series of tables of critique for each of the earlier publications concerning radiation-induced cataracts in order to provide a sound reference basis for the changes in recommended dose limits.
(d) Acute threshold doses of approximately 0.5 Gy and chronic dose rates of 0.4 Gy/year remain the recommended values for depression of haematopoiesis. Also, for mortality, the threshold values of approximately 1 Gy acute dose without medical care and 2–3 Gy with good medical care remain unchanged from previous ICRP values. Protracted doses of 4–8 Gy in 1 week or 10–14 Gy accumulated over 1–3 months are likely to be tolerable. Growth factor administration is considered to be beneficial to help increase survival rates after radiation exposure of the bone marrow, and preclinical studies suggest that threshold doses might be increased up to two-fold by the use of good clinical support and growth factors.
(e) The acute threshold dose for early mortality at 6–9 days after intestinal irradiation is considered to be approximately 6 Gy, and good medical care is expected to increase this value. The incidence and severity of delayed intestinal radiation toxicity depends on radiation dose, volume of bowel irradiated, fractionation schedule, concomitant chemotherapy, comorbidities, and other patient factors. The threshold doses for late injury after irradiation show the greater sensitivity of the salivary glands (parotids) and the liver, for example, compared with the lower sensitivity of the rectum. The most promising enterotrophic strategies with the potential to protect the intestine from radiation injury include some cytokines, gastrointestinal peptide hormones, and a variety of nutrients.
(f) The threshold doses for the male and female reproductive systems for acute, fractionated/protracted, and chronic exposures, and the bases for these doses, remain virtually the same as those recommended previously. For male fertility, there is a trend for the threshold dose to be less for fractionated/protracted exposures compared with single exposures (reverse fractionation effect). Hormonal manipulation of spermatogenic recovery has been investigated in humans, but with little conclusive improvement. In preclinical studies, various biological response modifiers have been investigated including hormonal manipulation, antioxidants, radical scavengers, and natural compounds. However, at present, there is no over-riding conclusion that would favour one compound over others. In females, radioresponsiveness increases with age because of the decline in the size of the oocyte pool with increasing age. Although numerous studies in female patients undergoing chemotherapy (and radiotherapy) have indicated that gonadotropin-releasing hormone (GnRH) analogues might be protective of ovarian function, none of these studies were prospective randomised clinical trials, and thus the evidence was inconclusive.
(g) The salient features of the early and late radiation responses of the skin have not changed since earlier ICRP reports on this topic. The responses depend on the area of skin irradiated, dose fractionation effects, and whether the epidermis alone is irradiated or both the epidermis and the dermis. In humans, the most successful agents for reducing early reactions are anti-inflammatory compounds, and polyunsaturated fatty acids have shown promise in preclinical systems. For reducing late reactions, superoxide dismutase, fibroblast growth factor, captopril, polyunsaturated fatty acids, a-tocopherol, and inhibition of transforming growth factor-beta signalling have shown some promise in both humans and preclinical systems, with dose modification factors (DMFs) of 1.1–1.2 and a maximum of approximately 1.5.
(h) ICRP has not previously listed circulatory disease as a health hazard from radiation exposures to organs and tissues, because it is only in the last few years that there has been greater consolidation of the evidence on this topic. The evidence arises from radiotherapeutic experience and epidemiological studies following nuclear and other radiation activities. There is no clear pattern across studies regarding whether or not the excess relative risk for cardiovascular disease is greater than that for stroke or cerebrovascular disease. From current evidence, a judgement can be made of a threshold acute dose of approximately 0.5 Gy (or 500 mSv, see note about units below) for both cardiovascular disease and cerebrovascular disease. On that basis, 0.5 Gy may lead to approximately 1% of exposed individuals developing the disease in question >10 years after exposure. This is in addition to the high natural incidence rate (circulatory diseases account for 30–50% of all deaths in most developed countries). The value of 0.5 Gy to the heart and cerebrovascular system could be reached during some complex interventional procedures. Hence, medical practitioners need to be aware of this new threshold, and should ensure that particular emphasis is given to optimisation. However, it is emphasised that there are notable uncertainties in determining the risks of these diseases at this level of radiation dose. It is unclear from available evidence whether or not the threshold is the same for acute, fractionated, and chronic exposures. For the present purposes, the threshold dose is assumed to be the same for all three types of exposure (i.e. approximately 0.5 Gy).
(i) For cataracts in the lens of the eye induced by acute exposures, recent studies, where formal estimates of threshold doses have been made after long follow-up periods, indicate values of approximately 0.5 Gy with 90–95% confidence intervals including zero dose. This is lower by a factor of 10 than deduced in earlier studies. Those studies generally had short follow-up periods, failed to consider the increasing latency period as dose decreases, did not have sufficient sensitivity to detect early lens changes using the various techniques employed, and had relatively few subjects with doses below a few Gy. For fractionated and protracted exposures, values of approximately 0.5 Gy have been similarly deduced from recent studies. However, the evidence pertaining to the latter exposures mainly refers to opacities rather than cataracts impairing vision because the follow-up times are shorter in those studies. For chronic exposure over several to many years, much of the evidence refers to minor lens opacities. Nonetheless, there is no indication that threshold accumulated doses are higher in this scenario. There are no established mitigators of lens radiation injury leading to opacities or cataracts, but lens replacement is a well-established surgical procedure.
(j) The threshold values for pneumonitis are derived from whole-lung radiotherapeutic exposures (usually 5 years of follow-up), and the values of 6.5 Gy for acute exposures and <18 Gy for fractionated exposures (2 Gy/fraction) are very similar to previous judgements. Steroids can relieve the symptoms of pneumonitis, but it remains unclear whether they can protect against the development of late fibrosis. In breast and lung cancer patients, there is some evidence for a reduction in both early and late lung toxicity when pentoxifylline was given during the period of radiotherapy, but angiotensin-converting enzyme (ACE) inhibitors had no significant effect.
(k) In the urinary tract, the kidneys are the most sensitive organ, and the bladder and the ureters are more resistant (deduced from radiotherapeutic experience, usually with 5 years of follow-up). The threshold dose for the human kidney is approximately 7–8 Gy acute dose, approaching 20 Gy for doses given as multiple 2-Gy fractions. For late reactions in the bladder and the ureters, the threshold total fractionated (2-Gy fractions) dose is ≤50 Gy. Anti-inflammatory agents have produced equivocal benefits in both human and animal systems. The most promising preclinical agents to date in reducing radiation nephropathy are ACE inhibitors and angiotensin II (AII) receptor antagonists. Preclinical studies have shown DMFs of 1.2–1.5 when given prophylactically from the time of irradiation.
(l) In the musculoskeletal system, radiation exposure can give rise to three different types of non-cancerous bone pathology: osteoradionecrosis, spontaneous fractures or fractures with less than normal trauma, and abnormalities of bone growth. The threshold dose for necrosis of femoral heads and rib fractures (after 5 years) is approximately 50 Gy in 2-Gy fractions, and approximately 55 Gy for skeletal muscle. In contrast to mature bone, growing bone is much more radiosensitive, and 25 Gy in 2-Gy fractions is often suggested as a critical threshold dose. Hyperbaric oxygen remains the only therapy claimed to mitigate such clinical reactions at the present time.
(m) Brain irradiation can have direct radiation effects on the thyroid and pituitary glands, as well as subtle effects on the hypothalamic–pituitary–adrenal axis and the hypothalamic–pituitary–gonadal axis. All of the information comes from radiotherapy experience using fractionated doses of (generally) 2 Gy/fraction. The hypothalamus is more radiosensitive than the pituitary. In children, radiation effects include growth hormone (GH) deficiency, precocious puberty (after lower doses) or delayed puberty (after higher doses), hypopituitarism, and hyperparathyroidism. In adults, radiation effects include hyperprolactinaemia, hypogonadism, obesity, hypothyroidism, hyperthyroidism, and adrenocorticotropic hormone deficiency. Strategies for mitigating the effects of radiation on the endocrine system include GH replacement in children with radiation-induced GH deficiency, thyroid hormone replacement therapy in cases of its deficiency, and repeated intermittent infusion of GnRH in cases of reduced gonadotropin secretion after pituitary damage.
(n) The threshold dose for symptomatic spinal cord injury (myelitis) is approximately 50 Gy delivered in 2-Gy fractions. The injury is highly dependent on dose per fraction, and the threshold dose is greater when very small volumes (<1 cm cord length) are irradiated. The adult brain has been considered rather more resistant in terms of necrosis, but subtle effects have been detected at much lower doses of approximately 10 Gy and clear volume effects are discernable. Low-dose irradiation (1–2 Gy) to the developing brain of children can cause long-term cognitive and behavioural defects, and infants are even more susceptible with cognitive impairment in adult life detected after exposure to doses of >0.1 Gy before 18 months of age. There are no recognised mitigating agents for use in humans to treat spinal cord injury after irradiation. Preclinical studies with anti-inflammatory agents, ACE inhibitors, AII receptor antagonists, some growth factors, and polyunsaturated fatty acids have shown the most promise.
(o) This ICRP report has some changes to indicated threshold doses for tissue reactions compared with those stated in Publication 103 (ICRP, 2007). First, the threshold dose for radiation-induced eye cataracts is now considered to be approximately 0.5 Gy for both acute and fractionated exposures, in line with various recent epidemiological studies. Second, circulatory disease has been recognised as an important late effect of radiation exposure, both for mortality and morbidity. An approximate threshold dose of 0.5 Gy has been proposed for acute and fractionated/protracted exposures on the basis that this might lead to an incidence of the order of 1% of circulatory disease in exposed individuals, although the estimation of risk at this level of dose is particularly uncertain. Third, the threshold dose values for chronic exposures depend on the exposure duration and the follow-up period after exposure. Differences between these time variables among different studies make the values more uncertain. The values quoted for both the lens of the eye and the circulatory system assume the same incidence of injury irrespective of the acute or chronic nature of the exposure over a working life, with >15-20 years follow-up time. Future studies may elucidate this further. Fourth, much more information has become available regarding the effect of biological response modifiers in mitigating tissue reactions, which has the effect of modifying threshold doses. These modifications are agent, tissue, and schedule specific, and they are likely to have increasing impact in the future, concomitant with increases in scientific and medical knowledge.
(p) Lastly, the previous ICRP judgement that acute doses up to approximately 0.1 Gy produce no functional impairment of tissues is maintained. Hence, the stochastic risks of induced cancer and hereditary effects continue to be the principal risks to consider for most applications of ICRP recommendations in occupational or public situations. However, after acute or accumulated doses of >0.5 Gy, the risk of tissue reactions (deterministic effects) becomes increasingly important, particularly for the lens of the eye and the circulatory system, at very long times after radiation exposure.
Note about units
(q) By ICRP convention, doses resulting in tissue reactions (deterministic effects) should be quoted in Gy or relative biological effectiveness (RBE)-weighted dose RBED (Gy), rather than Sv which is reserved for clearly stochastic effects. ICRP states that ‘the quantities, equivalent dose and effective dose, with their unit with the special name sievert (Sv), should not be used in the quantification of radiation doses or in determining the need for any treatment in situations where tissue reactions are caused. In general, in such cases, doses should be given in terms of absorbed dose in gray (Gy), and if high-LET radiations (e.g. neutrons or alpha particles) are involved, an RBE-weighted dose, RBED (Gy), may be used’ (ICRP, 2007). It is recognised that many doses in the literature are quoted in Sv or mSv because of previous usage and the familiarity of many professionals with this unit. Also, there is the fact that the use of a threshold model for the particular endpoints of cataract and circulatory disease remains uncertain. For low-LET radiation, the actual numerical value for either unit is the same.
References
ICRP, 1984. Non-stochastic effects of irradiation. ICRP Publication 41. Ann. ICRP 14(3).
ICRP, 1990. RBE for deterministic effects. ICRP Publication 58. Ann. ICRP 20(4).
ICRP, 1991. Radiation effects on the skin. ICRP Publication 59. Ann. ICRP 22(2).
ICRP, 2000. Radiopathology of skin and eye and radiation risk. ICRP Publication 85. Ann. ICRP 30(2).
ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP Publication 103. Ann. ICRP 37(2–4).
UNSCEAR, 2006. Effects of Ionizing Radiation. Annex D: Effects of Ionizing Radiation on the Immune System. Report to the General Assembly. United Nations, New York.
