BIOLOGICAL EFFECTS OF IONIZING RADIATION Prof. Igor Y. Galaychuk, MD Head, Department of Oncology and Radiology Ternopil State Medical University

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.

Classification of radiobiological effects Pathologic Gormetic Genetic Somatic Total Local Late Early Determined Stochastic

Radiation effects Early (deterministic only) Late Local Common Radiation injury of individual organs: functional and/or morphological changes within hrs-days-weeks Common Acute radiation disease Acute radiation syndrome Deterministic Radiation dermatitis Radiation cataracta Teratogenic effects Stochastic 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.

Deterministic (a) and stochastic (b) effects of radiation 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.

Deterministic and stochastic effects 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. 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.

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.

Threshold doses for some deterministic effects in case of acute total radiation exposure 0,2 Gy – increase of number of the chromosomal aberration in bone marrow and lymphocytes 0,3 Gy – temporary sterility for man 0,5 Gy – depression of haematopoiesis 1,0 Gy – acute radiation syndrome 2,0 Gy – detectible opacities 5,0 Gy – visual impairment 2,5 – 6,0 Gy – sterility for woman 3,5 – 6,0 Gy – permanent sterility for man 3,0 – 10,0 Gy – skin injury 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. 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.

Threshold doses for some deterministic effects in case of radiation exposure for many years 0,1 Gy – detectible opacities 0,2 Gy – sterility for woman 0,4 Gy – visual impairment 0,4 Gy – temporary sterility for man 0,4 Gy – depression of haematopoiesis 1,0 Gy – chronic radiation syndrome 2,0 Gy – permanent sterility for man 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. 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.

Time of onset of clinical signs of skin injury depending on dose received Symptoms Dose range Time of onset (Gy) (day) Erythema 3-10 14-21 Epilation >3 14-18 Dry desquamation 8-12 25-30 Moist desquamation 15-20 20-28 Blister formation 15-25 15-25 Ulceration >20 14-21 Necrosis >25 >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.

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 or 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.

Critical organs or tissues after acute whole body radiation exposure Whole body dose, Gy Critical organ or tissue Mortality, per cent Time of death, days 1 – 2 Bone marrow – 2 – 4 5 40 – 60 4 – 6 50 30 – 40 6 – 10 95 10 – 20 10 – 30 Gastrointestinal tract 100 7 – 14 > 30 Neurovascular system 1 – 5 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.

Teratogenic effects of radiation as special deterministic effects 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.

The foetus Typical effects of radiation on embryon: Intrauterine growth retardation (IUGR) Embryonic, foetal, or neonatal death Congenital malformations Foetal effects are seen at relatively low doses of radiation. The foetus is a highly proliferative system with many undifferentiated cells. Therefore, it is extremely sensitive to radiation effects. The classic effects of radiation upon the embryo are : intrauterine growth retardation (IUGR) embryonic, foetal, or neonatal death congenital malformation

Effects of radiation according to gestational stage Radiogenic effects 0 - 9 days Preimplantation All or none 10 days - 6 weeks Organogenesis Congenital anomalies, growth retardation 6 weeks - 40 weeks Foetal Growth retardation, microcephly, mental retardation Exposure to ionizing radiation can produce very severe effects on the embryo and foetus. The effects vary depending on the gestation age, the dose, and also the dose rate. Gestation is divided into preimplantation, organogenesis, and foetal periods. In humans, these periods correspond approximately to 0-9 days, 10 days-6 weeks, and 6 weeks-term, respectively. During preimplantation, radiation damage results in either death of the fertilized egg or survival with no measurable effect. Outwardly, no effect would be noticed other than a failure to conceive. Irradiation during organogenesis is the period of most concern. For this reason, it is often noted that radiation should be particularly limited during “the first trimester”. Embryos are sensitive to lethal, teratogenic and growth-retarding effects because of the criticality of cellular activities and the high proportion of radiosensitive cells. Intrauterine growth retardation (IUGR), gross congenital malformations, microcephaly and mental retardation are the predominant effects for doses >0.5 Gy. Radiation induced malformations of bodily structures other than the central nervous system are uncommon in humans, in contrast to what has been seen in animals. Radiation induced damage to the central nervous system in man is first observed at the end of organogenesis (approx. 8 weeks gestation) and extends well into the foetal period. Irradiation in the foetal period leads to the most pronounced permanent growth retardation. Data on atomic-bomb survivors indicate that microcephaly may result from a free-in-air dose of 100-190 mGy. The incidence of pronounced mental retardation as a function of dose is apparently linear without threshold at 8-15 weeks, with a risk coefficient of 0.4 per Gy. The incidence is about four times lower at 16-25 weeks. For other malformations, a threshold is reported to exist.

Specific radiation effects on foetus: mental retardation, microcephaly Most information on mental retardation comes from atomic bomb survivors for whom the principal effects of in utero irradiation was microcephaly (small head size) and mental retardation. The graph indicates that mental retardation was dependent on foetal age at exposure and dose. The most sensitive period was weeks 8-15 (during major neuronal migration) with a 40-70% probability of mental retardation at the 1-Gy dose. At 16-25 weeks, the foetus shows no increase in mental retardation at doses < 0.5 Gy. The risk factor associated with diminution of IQ is 21-33 points at 1 Gy given in the gestational period 8-15 weeks. Microcephaly: Hiroshima data 0 Gy - 4% 0,1-0,2 Gy - 11% 0,2-0,3 Gy - 23% 0,3-0,5 Gy - 36% 0,5-1,5 Gy - 45% > 1,5 Gy - 35% Cases of mental retardation caused by radiation exposure in Hiroshima and Nagasaki

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 16-25 weeks, foetus shows no increase in mental retardation at doses < 0.5 Gy. IQ - risk factor associated with diminution of IQ is 21-33 points at 1 Gy to foetus at 8-15 weeks. Sv

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.), 16:82-88. 1968 Foetal dose, mSv

Considerations for pregnancy termination Threshold dose for developmental teratogenic effects approximately 0,1 Gy Normal rate of preclinical loss > 30 %; at 0,1 Gy – increase of 0,1–1 % The foetal absorbed dose > 0,5 Gy at 7–13 weeks: substantial risk of IUGR and CNS damage 0,25–0,5 Gy at 7–13 weeks: parental decision with physician’s guidance A dose of 0.1 Gy to the embryo during the first 6 weeks after conception is often regarded as the cutoff point above which a therapeutic abortion should be considered to decrease the probability of an abnormal child. The decision to terminate a pregnancy must depend on many factors in addition to the radiation dose, e.g. legal and moral constraints, diabetes, hypertension, maternal age. If the foetal absorbed dose > 0.5 Gy in the 7-13 week window, there is a substantial risk of IUGR and CNS damage, in which case termination of pregnancy is reasonably to be considered. In the range 0.25–0.5 Gy at 7-13 weeks: parental decision with physician’s guidance.

as examples of stochastic effects Cancer induction and genetic effects as examples of stochastic effects of radiation exposure

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]

radiation exposure (continued) 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.

Carcinogenic effects Carcinogenic effects have been known practically since the discovery of radioactivity and since the first case of radiation-induced cancer was described in 1902. The epidemiological assessment was made from over 575 cancers and leukaemias for the 80,000 survivors irradiated at Hiroshima and Nagasaki, and about 2,000 cancers of the thyroid in children in the Chernobyl region. The actual data does not enable us to show a risk of cancer at greater than 0,1 Gy by acute irradiation. Nevertheless, it is considered that risk of cancer and the relationship dose/risk remains linear for doses below 0,1 Gy. Carcinogenic effects These effects have been known practically since the discovery of radioactivity and since the first case of radiation-induced cancer was described in 1902. These cancers do not present any specificity in the sphere of anatomopathology, which makes study of them particularly difficult. The epidemiological assessment was made from over 575 cancers and leukaemias for the 80,000 survivors irradiated at Hiroshima and Nagasaki, and about 2,000 cancers of the thyroid in children in the Chernobyl region. However, the actual data does not enable us to show a risk of cancer at greater than 0.1 Gy by acute irradiation. Nevertheless, it is considered that risk of cancer and the relationship dose/risk remains linear for doses below 0.1 Gy. This relationship is a useful practical tool for the risk assessment, but it is not founded on any scientific certainty.

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.

radiation cancerogenesis 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.

radiation-induced cancer 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).

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.

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.

Cancer deaths attributable to A-bomb In 86 572 survivors of Hiroshima and Nagasaki, 7827 persons died of cancer in 1950-90 Observed Expected Excess (%) All tumours 7578 7244 334 (4.4) Leukaemia 249 162 87 (35.0) All cancers 7827 7406 421 (5.4) Ref: Pierce et al, Rad.Res. 146: 1-27, 1996 In 40 years of follow-up of 86 572 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 421 lethal cancer cases.

Dose dependence of leukemia in A-bomb survivors 140 120 100 80 60 40 20 Leukemia cases, rep 100,000 cent per year 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 10-490 mGy. In the dose range of 500-999 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). Absorbed dose, Gy < 0,01 0,01-0,5 0,5-1,0 1,0-2,0 2,0-4,0 > 4,0

nuclear industry workers Cancer mortality of nuclear industry workers The ERR (excess relative risk) per Sv among the 95 673 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 95 673 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

Childhood leukaemia around UK nuclear facilities STUDY GROUP: 46 000 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, 28-05-1999 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.

Lifetime mortality in population after exposure to low doses 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.

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

Genetic effects Genetic effects might result in lesions of chromosomes in the germinal lineage (ovule and spermatozoid), prone to lead to anomalies in close or distant descendants of the irradiated individual. The mutagenic action of radiation was discovered by Nadson and Philipov (1925) and then in the fly was demonstrated by Muller from 1927 onwards. As it has not been possible to find any study showing a genetic effect in man, the risk is evaluated from the data obtained from animals. Genetic effects Genetic effects might result in lesions of chromosomes in the germinal lineage (ovule and spermatozoid), prone to lead to anomalies in close or distant descendants of the irradiated individual. The mutagenic action of radiation in the fly was demonstrated by Muller from 1927 onwards. As it has not been possible to find any study oshowing a genetic effect in man, the risk is evaluated from the data obtained from animals.

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.

Summary of lection 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. 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.

Summary of lection Teratogenic effects of radiation: severe mental retardation, microcephaly Latency periods of radiation induced cancers occur from 2 to 10 years, 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 Teratogenic effects of radiation: severe mental retardation, microcephaly Latency periods of radiation induced cancers occur from 2 to 10 years, 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

kindly given by doctor Elena Buglova, were used Lecture is ended THANKS FOR ATTENTION 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 In lecture materials of the International Atomic Energy Agency (IAEA), kindly given by doctor Elena Buglova, were used