Module Medical IX - Types of radiation effects

Module Medical IX - Types of radiation effects
DOSE-EFFECT CURVES; DETERMINISTIC AND STOCHASTIC EFFECTS OF RADIATION Purpose To provide evidence of particular relationships between dose, dose rate and health effects Objectives To describe biological effect of radiation in time perspectives To define and characterize deterministic and stochastic effects of radiation To discuss dose-response relationships and provide examples of threshold doses To discuss the probability of cancer induction by ionizing radiation, and give examples To explain teratogenic and genetic effects of radiation, and give examples Scope This lecture presents the two main types of health effects of exposure to ionizing radiation with up-to-date examples from recent scientific publications. Activity Lecture, questions and discussion Duration 1 hr References IAEA-WHO: Diagnosis and Treatment of Radiation Injuries. IAEA Safety Reports Series, No. 2, Vienna, 1998 IAEA: Method for Assessment of Probability of Cancer Induction by Radiation, IAEA-TECDOC-879, Vienna, 1996 ICRP Publication 60, Oxford, 1991 Pierce, DA, & Shimizu,Y., Preston, DL. Studies of the mortality of A-bomb survivors, Report 12, Part 1, Cancer: Radiat.Res. 146: 1-27, 1996 Cardis, E. et al, Combined Analyses of Cancer Mortality Among Nuclear Industry Workers in Canada, the UK and the USA. IARC Technical Report No.25, Lyon, 1995 ICRF, LSHTM & LRF: Nuclear Industry Family Study (NIFS). BMJ, Module IX

Biological effects of radiation in time perspective
Module Medical IX - Types of radiation effects Biological effects of radiation in time perspective Time scale Fractions of seconds Seconds Minutes Hours Days Weeks Months Years Decades Generations Effects Energy absorption Changes in biomolecules (DNA, membranes) Biological repair Change of information in cell Mutations in a Germ cell Somatic cell Leukaemia or Cancer Hereditary effects Cell death Organ Clinical death changes Physical and biochemical effects of radiation take place in an extremely short time, in fractions of seconds or in a few seconds, respectively. Repair processes are launched in minutes. Misrepair may lead to change of genetic information in cells within minutes. Clinical symptoms appear in hours-days-weeks or months if large numbers of cells were killed by a high dose of radiation at high dose rate. At low dose or low dose rate the cells are not killed by the absorbed energy of ionizing radiation, but genetically modified, i.e. mutated. Mutation in somatic cells may induce cancer after years or decades, while mutated germ cells may lead to hereditary effects in the next generation. Module Medical IX.

Early (deterministic only) Late Local Radiation injury of individual organs: functional and/or morphological changes within hrs-days-weeks Common Deterministic (Above DQ, cummul.) - Rad. Dermatitis - Rad. Cataracta - Teratogenic (DQ,F~0,1Sv) Stochastic Acute radiation disease Acute radiation syndrome (LD50/60 ~ 3.5Sv LD ~ 5 Sv) (Probability increases with dose) - tumours, leukaemia - genetic effects Radiation effects may appear - early (i.e. within three months) or - late (beyond 3 months, usually in years). Early effects result from high dose radiation to partial body or whole body. They are all of deterministic type. Among the local effects the most frequent is the radiation induced skin injury. Acute exposure of the whole body is early expressed in the rather general symptoms of the acute radiation syndrome (ARS) or acute radiation disease. It leads to death - without treatment - in 3-6 weeks if the radiation absorbed in the whole body dose is above 5 Gy. The LD50/60 dose is about 3.5 Gy when there is no possibility of specialized treatment. However, with specialized haematological treatment and provision of sterile conditions, the effects of doses even twice as high can be cured and the patient can be saved. Note: The table refers to equivalent dose in sieverts, understanding that the biological effect depends on both the absorbed dose and type of radiation (i.e. its ionizing capability). However, in by far most of the cases accidental overexposures are caused by beta-, gamma- or X rays having a radiation weighing factor of unity. In these cases 1 Gy = 1 Sv, while in case of neutron irradiation the absorbed neutron energy (kerma) may be 2-5-times lower (depending of the energy of neutrons) of the threshold values given in the above table! Among the late effects we can distinguish deterministic effects, such as dermatitis, cataracta or teratogenic effects. They develop if the cumulative absorbed dose is above of a cumulative threshold dose required for the given effect. Thus, teratogenic damage may only develop if the absorbed dose in the foetus is above 0.1 Gy. The stochastic late effects are cancer and genetic (hereditary) effects, usually appearing after many years. Module Medical IX.

Deterministic (a) and stochastic (b) effects of radiation Det Deterministic effects: - develop due to cell killing by high dose radiation - appear above a given threshold dose, which is considerably higher than doses from natural radiation or from occupational exposure at normal operation - the severity of the effect depends on the dose - at a given high dose the effect is observed in severe form in all exposed cells, at higher doses the effect cannot increase. Stochastic effects: - develop due to mutation effect of low dose radiation - the threshold dose is not known accurately; it is observed that cancer of different location appears above different dose ranges - the severity of the effect does not depend on the dose, but the frequency of the appearance of the (probabilistic) effect in the exposed population group is dose dependent, (in most cases) linearly increasing with the dose. Module Medical IX.

Sources of data on human effects of radiation overexposure
Module Medical IX - Types of radiation effects Sources of data on human effects of radiation overexposure There are six main types of population groups who provided or could provide information about the radiation effects of overexposure in humans. Certain types or fractions of these groups have been studied for decades, and certain radiation effects were identified among them. In some of these groups the radiation effects have not been proved yet, but have been studied recently. The most studied groups are the A-bomb victims and professionals who received registered (in most cases) occupational exposure. Thus, in the early radiologists and medical physicists (who worked at the beginning of the 20th century at much higher dose limits) a few decades later both leukaemia and the skin cancer appeared at significantly higher rates than in the general population . Radium dial painters developed bone sarcoma due to ingested thorium, uranium miners show a higher risk of lung cancer due to inhalation of radon (when compared with similar cohorts by age and smoking habits) , while a recent study of nuclear industry workers of three countries (Canada, UK & USA) showed their double risk of leukaemia but lower risk of all other cancers than in matched groups of the general population. It is worth mentioning that no detrimental health effects were observed in tens of millions of people living in high natural background radiation areas. Note: *Effects of radiation exposure are not proved in these population groups, but studied recently (M - million) Module Medical IX.

Typical dose-effect relationships for deterministic effects in population As for the deterministic effects, it was already mentioned that they appear above a given threshold dose. This is the threshold of pathological conditions below which no pathological signs (e.g. decrease in blood counts) or symptoms (e.g. vomiting in combination with other non-specific symptoms or skin reddening) are manifest. However, there is a known variation in individual radiosensitivity, i.e. some exposed persons may develop a certain symptom while others will not react to the same dose with the same pathological symptoms. Nevertheless, there is a slightly (usually 20-50%) higher dose when all the exposed persons produce the same reaction, or when all cells of the overexposed part of the body react with the same symptom. Module Medical IX.

Threshold doses for some deterministic effects in the most radiosensitive tissues Tissue and Total dose Annual dose rate received effects single brief in highly fractionated or exposure (Gy) protracted exposure for many years (Gy/y) Bone marrow Depression of > 0.4 haematopoesis Testes Temporary sterility Permanent sterility Threshold doses for deterministic effects - even in the most radiosensitive tissue - are significantly higher than doses received from natural sources. Thus, for example, decrease of blood cell counts is not observed if the dose from acute exposure is below 0.5 Gy, or in cases of chronic or protracted exposure through many years if the dose rate is less then 0.4 Gy/yr. The gonads are the most radiosensitive organs. Temporary sterility (up to three months) was observed after acute exposure dose to the testes of 0.3 Gy. Module Medical IX.

Threshold doses for some deterministic effects Tissue and Total dose Annual dose rate received in received yearly in effects single brief highly fractionated or exposure protracted exposure (Gy) for many years (Gy/y) Ovaries Sterility > 0.2 Lens Detectable opacities > 0.1 Visual impairment > 0.4 (cataract) Temporary sterility was not described in women. Nevertheless, ovaries have manifest a lower threshold for permanent sterility than the testes. It was noted already following an acute dose of 2.5 Gy to the ovaries. In cases of protracted exposure, female sterility was observed at as low a dose rate as 0.2 Gy/yr, however, the cumulative dose absorbed in the ovaries must have exceeded the threshold dose for a single brief exposure. In cases of acute exposure to the lens of the eye, detectable opacity was observed at 2.0 Gy, while cataracts developed above 5 Gy, after a few years of latency. Protracted exposure opacity and cataract were observed at as low dose rate as 0.1 and 0.4 Gy/yr, respectively; however, the cumulative absorbed dose to the must have exceeded the threshold doses for a single brief exposure. Module Medical IX.

Time of onset of clinical signs of skin injury depending on dose received Symptoms Dose range Time of onset (Gy) (day) Erythema Epilation > Dry desquamation Moist desquamation Blister formation Ulceration > Necrosis > >21 Ref.: IAEA-WHO: Diagnosis and Treatment of Radiation Injuries. IAEA Safety Reports Series, No. 2, Vienna, 1998 Dose ranges and time of onset of signs of radiation induced skin injuries are listed in this table cited from a joint IAEA and WHO publication from 1998. Please note that in four out of seven symptoms, dose ranges are given. In these cases the lower value is the threshold dose for the appearance of the given symptom. There is a reciprocal relationship in the dose ranges and the time periods of manifestation of different pathological skin reactions: the higher the dose the faster the onset of the symptom. Module Medical IX.

Acute radiation syndrome (ARS) ARS is the most notable deterministic effect of ionizing radiation Signs and symptoms are not specific for radiation injury but collectively highly characteristic of ARS Combination of symptoms appears in phases during hours to weeks after exposure - prodromal phase - latent phase - manifest illness - recovery (or death) Extent and severity of symptoms determined by - total radiation dose received - how rapidly dose delivered (dose rate) - how dose distributed in body (whole vs partial body irradiation) A separate comprehensive (double, 2-hr) lecture will deal with the diagnosis and treatment of the ARS. The main features are listed here. Module Medical IX.

Principle syndromes contributing to death after acute whole body radiation exposure Three main syndromes are distinguished following an acute whole body exposure. These are listed in the above table and are usually referred to as BM, GIT and NV syndromes. There are also symptoms of BM syndrome in acute whole body exposure above 10 Gy; however, in this dose range the symptoms of the GIT syndrome dominate the clinical picture. The primary cause of death in BM syndrome is infection (following loss of cellular immunity), in GIT syndrome - the severe loss of fluids and intestinal bleeding, in CV syndrome - oedema of brain. Module Medical IX.

Special deterministic effects Teratogenic effects of radiation Basic terminology for Exposure of the developing foetus may lead to teratogenic effect manifest in the neonate. Exposure of the ovaries or testes may lead to genetic effect (or hereditary disease) in any progeny. Module Medical IX.

Frequency of severe mental retardation in prenatally exposed survivors of A-bombing in Hiroshima and Nagasaki % Mental retardation Highest risk during major neuronal migration, on 8-15 weeks. The threshold dose of mental retardation is 0.1 Gy absorbed by the foetus at 8-15 weeks. Incidence increases with dose. At 1 Gy foetal dose, 75% experience severe mental retardation. At weeks, foetus shows no increase in mental retardation at doses < 0.5 Gy. IQ - risk factor associated with diminution of IQ is points at 1 Gy to foetus at 8-15 weeks. Sv Module Medical IX.

Microcephaly: Hiroshima data % Microcephaly observed in 30 children of ~1000 exposed in Hiroshima and Nagasaki pregnant women the effect of <0.1 Gy is not significantly different from the control Ref: W.J. Blot, Radiat. Res. (Suppl.), 16: Foetal dose, mSv Module Medical IX.

Stochastic effects Cancer induction and genetic effects Module Medical IX.

Phases of cancer induction and manifestation If cells are exposed to high dose at high dose rate, they are killed by radiation and eliminated. If cells are exposed to low dose at low dose rate, they are normally repaired and return to normal cell cycle. However, if the repair occurs with certain mistakes, i.e. mutations, the the cells remain viable but mutated and may not perform the usual functions of the given cell line. These mutated cells form the pre-cancer that has no clinical or laboratory signs at all. When a second factor (physical, chemical or viral) affects these cells, the pre-cancer stage may be promoted to minimal cancer (still without any clinical signs). With a new effect of any cancer inducing agent, the minimal cancer may progress to clinically manifest cancer, which may lead to metastasis of malignant cells into other organs (spreading via lymph or blood flow). This multistage-multifactorial theory of cancer induction is the most commonly accepted one today. Module Medical IX.

Stochastic Effects of Radiation Exposure Frequency proportional to dose No threshold dose No method for identification of appearance of effect of ionizing radiation in individuals Increase in occurrence of stochastic effects provable only by epidemiological method No tool to identify similar site cancers from different cause. E.g. no clinical or laboratory means to identify lung cancer of uranium miners from radon or smoking, but it is observed that smoker U miners have ten times higher risk of dying of lung cancer than non-smoker U miners. Stochastic effects can be detected by epidemiological-statistical methods only in large population groups. There is no method available to prove that any cancer of a radiation worker is from the radiation dose received. The real cause even in such cases may be of non-radiological nature. Nevertheless, there are scientific aids available to calculate the degree of probability of cancer induction by radiation from occupational exposure. Even in this case, the calculated value shows only the probability of radiation aetiology but does not prove it. [Ref. and recommended further reading: IAEA: Method for Assessment of Probability of Cancer Induction by Radiation, IAEA-TECDOC-879, Vienna, 1996] Module Medical IX.

Stochastic effects of radiation exposure (continued) Stochastic effects observed in animal experiments Dose-effect relationship for humans can be studied only in human population groups Dose-effect relationship in low dose range (below 100 mSv) not yet verified Extrapolation down to zero excess dose accepted only for radiation protection and safety Both external or internal exposure to ionizing radiation led to cancer induction in animal experiments. The observed effect proved to be dose-dependent. However, the dose-effect relationship described in animal experiments cannot be adopted/extrapolated to human population groups regarding dose dependent frequency of cancer induction. Module Medical IX.

Human data on radiation cancerogenesis Four cancer sites/types were identified in survivors of atomic-bombing in Hiroshima and Nagasaki. These are the leukaemia, thyroid, lung and breast cancer. Bone cancer (of mandible) is known among the radium-dial painters, lung cancer among uranium-miners. Early radiologists (working in the first decades of the 20th century) had a higher mortality of leukaemia and higher incidence of skin cancer. The childhood population living around Chernobyl manifest a ten- to thirty-fold increase of thyroid cancer in Belarus, the northern regions of Ukraine and in two western districts of Russia in the 1990s. Module Medical IX.

Latency periods for radiation-induced cancer Leukaemia is characterized with a short latency period of five years in average (minimum-maximum values are 2-8 years, except in some sporadic cases). All solid tumours have a latency period of one to three decades; however, here some exceptions have also been observed (e.g. childhood cancer may develop in a shorter period of a few years). Module Medical IX.

Risk of leukaemia depending on age at exposure to A-bomb The younger the age at exposure, the greater the risk of developing cancer during lifetime. It can be explained by two reasons: a) the younger organism has more radiosensitivity due to higher rate of cell division, and b) younger persons have a higher chance of overcoming (surviving) the latency period of cancer induction. Module Medical IX.

Age dependency of incidence of leukaemia in British population and radiotherapy patients Incidence of leukaemia in different age groups of the general population and in radiotherapy patients is characterized by a very similar age dependency (the curves are almost parallel, the leukaemia incidence in the radiotherapy patients is one order of magnitude higher than in the general public). Leukaemia is a rare disease. Its incidence among the twenty-year-old Britons is about 20 per million per year, while in the 60-year-old age group it is five times more frequent. Module Medical IX.

Cancer deaths attributable to A-bomb
Module Medical IX - Types of radiation effects Cancer deaths attributable to A-bomb In survivors of Hiroshima and Nagasaki, persons died of cancer in Observed Expected Excess (%) All tumours (4.4) Leukaemia (35.0) All cancers (5.4) Ref: Pierce et al, Rad.Res. 146: 1-27, 1996 In 40 years of follow-up of A-bomb survivors, 421 cancer deaths were registered. It is 5.4 % more than expected cancer mortality in a group of this size and age structure. The 87 excess leukaemia cases support a 35% higher rate of the expected value (162 lethal case of leukaemia in 86.5 thousand Japanese in 40 years). Our knowledge about the stochastic effects of radiation on a human population is primarily based on these lethal cancer cases. Module Medical IX.

No increase in leukaemia cases was detected among those A-bomb survivors (ABS) in Hiroshma and Nagasaki who received doses below 10 mGy. About a 2-fold increase can be demonstrated among the group of exposed ABS to mGy. In the dose range of mGy in ABS of Hiroshima, the increase is about 4-fold, however; in ABS of Nagasaki a 2-fold DECREASE was observed. Above 1 Gy, a significant dose dependent increase was detected in all dose groups at both A-bomb sites. However, the level of increase was considerably higher in Hiroshima than in Nagasaki (in N. the neutron component was higher, so the bone marrow - responsible for developing leukaemia - was less damaged). Module Medical IX.

Cancer mortality of nuclear industry workers The ERR (excess relative risk) per Sv among the nuclear industry workers in Canada, UK and USA (having a mean cumulative dose of 36.6 mSv in the combined cohort for the total period of observation, i.e. 34 yrs in the USA and UK, and 29 years in Canada) is –0.07 for all cancers excluding leukaemia, and 2.18 for leukaemia excluding CLL. In other words, there was no increase observed due to cancer death (excluding leukaemia) in the large group of nuclear industry workers with the above given characteristics. Nevertheless, there were 119 leukaemia death cases observed in nuclear industry workers in the UK and USA in 34 years and in Canada in 29 years. The observed to expected leukaemia death cases show some significant trend of increase depending on the dose (p<0,05, i.e. p=0.046). If each nuclear worker received a dose of 1 Sv, their probability of dying of leukaemia would be 2.18 times higher than in the general population of the same age structure and similar life style. However, the above group of nuclear workers was exposed to a 30 times lower mean cumulative dose of 36.6 mSv, only. Hence, their probability of dying of leukaemia is expected to be higher not by 2.18%, but by 7%. Ref.: Cardis, E. et al: Combined Analyses of Cancer Mortality Among Nuclear Industry Workers in Canada, the UK and the USA. IARC Technical Report No.25, Lyon, 1995 Module Medical IX.

Childhood leukaemia around UK nuclear facilities
Module Medical IX - Types of radiation effects Childhood leukaemia around UK nuclear facilities STUDY GROUP: children (followed till the age of 25 yrs) born to parents working in nuclear industry FINDINGS: 111 cases of acute leukaemia observed, i.e. fewer than expected in a group of this size and age Study found 3 cases of leukaemia in children of male workers who had received a pre-conceptional exposure of 100 mSv or more Two of these three cases had already been identified in the 1990 Gardner report (proposed theory that paternal pre-conception radiation leads to increased risk of leukaemia in offspring) Conclusions No substantial evidence found to support Gardner’s theory Study did not confirm theory Ref. ICRF, LSHTM & LRF: Nuclear Industry Family Study (NIFS). BMJ, Excess cases of childhood leukaemia were observed in the late 80s in village Seascale, near the Sellafield Nulear Reprocessing Plant, UK. According to hypothesis by Prof. Gartner (1990), paternal pre-conception radiation leads to increased risk of leukaemia in the offspring. Thorough investigations have not upheld the hypothesis. Module Medical IX.

Lifetime mortality in population of all ages from cancer after exposure to low doses * For general public (all age groups) only Summary factor of cancer risk for working population taken to be 400x10-4 Sv-1 Reference ICRP, Publ. 60, 1991 Observations on cancer induction by radiation in different organs and tissue in the general population suggested its rate at 5%/Sv, while in the working population at 4%/Sv. Module Medical IX.

Nominal probability coefficients for stochastic radiation effects Detriment from exposure includes, besides fatal cancer, the non-fatal cancer and the nominal probability of the calculated severe hereditary effects associated with exposure to radiation . Ref. ICRP, Publ. 60, 1991 Module Medical IX.

Genetic radiation damage Increase of chromosome aberrations in human spermatogonia following radiation exposure of testes has been detected inheritance of radiation damage in human population (including A-bomb survivors) not yet detected The probability of conception by mutated germ cells is extremely low, as radiation causes loss of gene functions, mainly deletions, essential for life. Thus, by natural selection, radiation induced hereditary effects in human generations have not been proved yet. Module Medical IX.

Review of topics discussed
Module Medical IX - Types of radiation effects Review of topics discussed Biological effects of radiation in time perspective Main characteristics of deterministic and stochastic effects Sources of data on human effects of radiation overexposure Threshold doses of deterministic effects in the most radiosensitive tissues Teratogenic effects of radiation: severe mental retardation, microcephaly Phases of cancer induction Sources of human data on radiation cancerogenesis (3 groups) Latency periods of radiation induced cancers (lag 2 & 10 yrs) Risk of cancer depending on age at exposure (reverse dependence) Cancer deaths attributable to A-bombs – 5.4% in 40-yr follow up Cancer mortality studies of nuclear industry workers and offspring – leukaemia probable in workers Genetic effects of radiation – not proved in human population Quiz: Note: there are two right answers to some of the test questions! 1. Late radiation effects may be: a) deterministic only b) stochastic c) both deterministic and stochastic 2. The severity of radiation effects depends on dose in: a) somatic b) stochastic c) genetic d) deterministic effects 3. Haematological changes may be observed after exposure to: a) 0.1 Gy b) 1 Sv c) 0.5 Gy d) 0.15 Sv 4. Permanent sterility in male workers may appear after exposure to: a) 3.5 Gy b) 6 Gy c) 60 mGy d) 0.6 Gy 5. Skin reddening (erythema) may not be induced by an absorbed dose of: a) 1 Gy b) 3 Gy c) 0.6 Gy d) 6 Gy 6. Cancer death has increased among A-bomb survivors in 40 yrs by: a) 50% b) 15% c) 5% d) 0.5% 7. The threshold dose for mental retardation is: a) 0.1 Gy to foetus b) 1 Gy to pregnant woman c) 0.01 Gy to foetus 8. Genetic effects in human population: a) are clearly proven b) have never been observed c) are seen in A-bomb survivors Module Medical IX.

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