Cancer incidence and mortality after low-dose radiation exposure: epidemiological aspects

Current recommendations for limiting exposure to ionizing radiation are based on the linear-no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, carries with it some cancer risk. In this review, epidemiological evidences are discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that showed that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than projections based on the LNT model. The discovery of the low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dose region. The further studies in this field will provide new insights about the mechanisms of radiation carcinogenesis.     

Epidemiological studies on radiation carcinogenesis in human populations following acute exposure: nuclear explosions and medical radiation.

The present review provides an understanding of our current knowledge of the carcinogenic effect of low-dose radiation in man, and surveys the epidemiological studies of human populations exposed to nuclear explosions and medical radiation. Discussion centers on the contributions of quantitative epidemiology to present knowledge, the reliability of the dose-incidence data, and those relevant epidemiological studies that provide the most useful information for risk estimation of cancer induction in man. Reference is made to dose-incidence relationships from laboratory animal experiments where they may obtain, for problems and difficulties in extrapolation from data obtained at high doses to low doses, and from animal data to the human situation. The paper describes the methods of application of such epidemiological data for estimation of excess risk of radiation-induced cancer in exposed human populations and discusses the strengths and limitations of epidemiology in guiding radiation protection philosophy and public health policy.     

Epidemiological analysis of testicular malignant neoplasm incidence and mortality in Poland 1963-1986

Epidemiological analysis of both morbidity and mortality rates for testicular cancer in Poland between 1963 and 1986 was carried out. A particular attention was drawn to the period between 1981 and 1986, when a program of combined chemotherapy and surgery was introduced in Poland. The study aimed at analysing an effect of this combined treatment on mortality rate for testicular cancer. Between 1963 and 1986, a constant increase in morbidity for the testicular cancer was noted. Mortality rate increased between 1963 and 1983. This trend was inhibited between 1984 and 1986. "Splitting" of the morbidity and mortality curves was observed between 1984 and 1986. A decrease in mortality rate was noted at the constant morbidity for testicular tumors. It was particularly clear in younger age groups (15-39 years), as well as older age groups (60-64 years and over 75 years). A decrease in mortality rate for testicular tumors within 1984-1986 may be attributed to the introduction of combined treatment in Poland.     

Cancer mortality and incidence in Hungary in relation to international data

In Hungary mortality caused by malignant tumour diseases is very high. It is the second cause of death showing approximately 25% frequency. Statistics on disability has revealed that during the past 25 years the number of patients become invalid because of cancer has nearly doubled.In comparative international statistics cancer mortality and incidence of the Hungarian male population take the first and that of the female population the second place. The alarming public health problems caused by cancer in Hungary have prompted the authors to identify the causes and search for points of outbreak to stop and reverse these unfavourable tendencies. When analysing the current state of this country authors primarily rely on the studies of the European Cancer Centre, Lyon and those of the Hungarian Central Statistical Office (KSH) and National Cancer Registry. By years 2000-2001 the National Cancer Registry has become a reliable well functioning system. Its activities include the registration of all new cancer patients announced in the previous calendar year. Data processing requires information such as: year of diagnosis, tumour localisation and extension, morphological code and therapeutic interventions. It is a promising sign that the first time over the past 25 years cancer mortality decreased in year 2000. The unfavourable cancer mortality and incidence status in Hungary might be improved by the consistent accomplishment of the project "For a Healthy Nation, A Public Health Project for years 2001-2010".     

Protracted radiation exposure and cancer mortality in the Techa River Cohort

In the 1950s many thousands of people living in rural villages on the Techa River received protracted internal and external exposures to ionizing radiation from the release of radioactive material from the Mayak plutonium production complex. The Extended Techa River Cohort includes 29,873 people born before 1950 who lived near the river sometime between 1950 and 1960. Vital status and cause of death are known for most cohort members. Individualized dose estimates have been computed using the Techa River Dosimetry System 2000. The analyses provide strong evidence of long-term carcinogenic effects of protracted low-dose-rate exposures; however, the risk estimates must be interpreted with caution because of uncertainties in the dose estimates. We provide preliminary radiation risk estimates for cancer mortality based on 1,842 solid cancer deaths (excluding bone cancer) and 61 deaths from leukemia. The excess relative risk per gray for solid cancer is 0.92 (95% CI 0.2; 1.7), while those for leukemia, including and excluding chronic lymphocytic leukemia, are 4.2 (CI 95% 1.2; 13) and 6.5 (CI 95% 1.8; 24), respectively. It is estimated that about 2.5% of the solid cancer deaths and 63% of the leukemia deaths are associated with the radiation exposure.     

Analysis of mortality among Canadian nuclear power industry workers after chronic low-dose exposure to ionizing radiation

Studies of radiation-associated risks among workers chronically exposed to low doses of radiation are important, both to estimate risks directly and to assess the adequacy of extrapolations of risk estimates from high-dose studies. This paper presents results based on a cohort of 45,468 nuclear power industry workers from the Canadian National Dose Registry monitored for more than 1 year for chronic low-dose whole-body ionizing radiation exposures sometime between 1957 and 1994 (mean duration of monitoring = 7.4 years, mean cumulative equivalent dose = 13.5 mSv). The excess relative risks for leukemia [excluding chronic lymphocytic leukemia (CLL)] and for all solid cancers were 52.5 [95% confidence interval (CI): 0.205, 291] and 2.80 (95% CI: -0.038, 7.13) per sievert, respectively, both associations having P values close to 0.05. Relative risks by dose categories increased monotonically for leukemia excluding CLL but were less consistent for all solid cancers combined. Although the point estimates are higher than those found in other studies of whole-body irradiation, the difference could well be due to chance. Further follow-up of this cohort or the combination of results from multiple worker studies will produce more stable estimates and thus complement the risk estimates from higher-dose studies.     

Bystander and delayed effects after fractionated radiation exposure

Human immortalized keratinocytes were exposed to a range of single or fractionated doses of gamma rays from (60)Co, to medium harvested from donor cells exposed to these protocols, or to a combination of radiation and irradiated cell conditioned medium (ICCM). The surviving fractions after direct irradiation or exposure to ICCM were determined using a clonogenic assay. The results show that medium harvested from cultures receiving fractionated irradiation gave lower "recovery factors" than direct fractionated irradiation, where normal split-dose recovery occurred. The recovery factor is defined here as the surviving fraction of the cells receiving two doses (direct or ICCM) separated by an interval of 2 h divided by the surviving fraction of cells receiving the same dose in one exposure. After treatment with ICCM, the recovery factors were less than 1 over a range of total doses from 5 mGy-5 Gy. Varying the time between doses from 10 min to 180 min did not alter the effect of ICCM, suggesting that two exposures to ICCM are more toxic than one irrespective of the dose used to generate the response. In certain protocols using mixtures of direct irradiation and ICCM, it was possible to eliminate the bystander effect. If bystander factors are produced in vivo, then they may reduce the sparing effect of the dose fractionation.     

Site-specific cancer incidence and mortality after cerebral angiography with radioactive thorotrast

Few opportunities exist to evaluate the carcinogenic effects of long-term internal exposure to alpha-particle-emitting radionuclides. Patients injected with Thorotrast (thorium-232) during radiographic procedures, beginning in the 1930s, provide one such valuable opportunity. We evaluated site-specific cancer incidence and mortality among an international cohort of 3,042 patients injected during cerebral angiography with either Thorotrast (n = 1,650) or a nonradioactive agent (n = 1,392) and who survived 2 or more years. Standardized incidence ratios (SIR) for Thorotrast and comparison patients (Denmark and Sweden) were estimated and relative risks (RR), adjusted for population, age and sex, were generated with multivariate statistical modeling. For U.S. patients, comparable procedures were used to estimate standardized mortality ratios (SMR) and RR, representing the first evaluation of long-term, site-specific cancer mortality in this group. Compared with nonexposed patients, significantly increased risks in Thorotrast patients were observed for all incident cancers combined (RR = 3.4, 95% CI 2.9-4.1, n = 480, Denmark and Sweden) and for cancer mortality (RR = 4.0, 95% CI 2.5-6.7, n = 114, U.S.). Approximately 335 incident cancers were above expectation, with large excesses seen for cancers of the liver, bile ducts and gallbladder (55% or 185 excess cancers) and leukemias other than CLL (8% or 26 excess cancers). The RR of all incident cancers increased with time since angiography (P < 0.001) and was threefold at 40 or more years; significant excesses (SIR = 4.0) persisted for 50 years. Increasing cumulative dose of radiation was associated with an increasing risk of all incident cancers taken together and with cancers of the liver, gallbladder, and peritoneum and other digestive sites; similar findings were observed for U.S. cancer mortality. A marginally significant dose response was observed for the incidence of pancreas cancer (P = 0.05) but not for lung cancer. Our study confirms the relationship between Thorotrast and increased cancer incidence at sites of Thorotrast deposition and suggests a possible association with pancreas cancer. After injection with >20 ml Thorotrast, the cumulative excess risk of cancer incidence remained elevated for up to 50 years and approached 97%. Caution is needed in interpreting the excess risks observed for site-specific cancers, however, because of the potential bias associated with the selection of cohort participants, noncomparability with respect to the internal or external comparison groups, and confounding by indication. Nonetheless, the substantial risks associated with liver cancer and leukemia indicate that unique and prolonged exposure to alpha-particle-emitting Thorotrast increased carcinogenic risks.     

Cancer morbidity and mortality among the liquidators of the Chernobyl accident: estimation of radiation risks

The work focuses on the results of the analysis of the cancer incidence among the Chernobyl emergency workers residing in Russia during 1991-2001. The analysis is based on the data for the cohort of male emergency workers from 6 regions of Russia including 55718 persons with documented external radiation doses in the range of 0.001-0.3 Gy who worked within the 30-km zone in 1986-1987. The mean age at exposure for these persons was 34.8 years old and the mean external radiation dose 0.13 Gy. In this cohort 1370 cases of solid cancer were diagnosed. Three follow-up periods were considered: 1991-1995, 1996-2001 and 1991-2001. The second follow-up period was chosen to allow for a minimum latency period of 10 years. Risk assessments were performed for two control groups: the first control group ("external") represented incidence rates for corresponding ages in Russia in general and the second control group ("internal") consisted of emergency workers. The estimated standardized incidence ratio (SIR) is in good agreement with that of the control within 95% CI. The values of the excess relative risk per unit dose 1 Gy (ERR/Gy) for solid malignant neoplasms have been estimated to be 0.33 (95% CI: -0.39, 1.22) (internal control) for the follow-up period 1991-2001 and 0.19 (95% CI: -0.66, 1.27) for 1996-2001. The analysis of cancer morbidity was carried out for the cohort of 29003 emergency workers who took part in liquidation of the consequences of the Chernobyl accident from 26 April 1986 to 25 April 1987. It was shown that the excess relative risk of cancer deaths per unit dose 1 Sv (ERR/Sv) is equal to 1.52 (95% CI: 0.20, 2.85).     

Mitigation of lung injury after accidental exposure to radiation

There is a serious need to develop effective mitigators against accidental radiation exposures. In radiation accidents, many people may receive nonuniform whole-body or partial-body irradiation. The lung is one of the more radiosensitive organs, demonstrating pneumonitis and fibrosis that are believed to develop at least partially because of radiation-induced chronic inflammation. Here we addressed the crucial questions of how damage to the lung can be mitigated and whether the response is affected by irradiation to the rest of the body. We examined the widely used dietary supplement genistein given at two dietary levels (750 or 3750 mg/kg) to Fischer rats irradiated with 12 Gy to the lung or 8 Gy to the lung + 4 Gy to the whole body excluding the head and tail (whole torso). We found that genistein had promising mitigating effects on oxidative damage, pneumonitis and fibrosis even at late times (36 weeks) when drug treatment was initiated 1 week after irradiation and stopped at 28 weeks postirradiation. The higher dose of genistein showed no greater beneficial effect. Combined lung and whole-torso irradiation caused more lung-related severe morbidity resulting in euthanasia of the animals than lung irradiation alone.     

Cell survival responses after exposure to modulated radiation fields

In the present study survival responses were determined in cells with differing radiosensitivity, specifically primary fibroblast (AG0-1522B), human breast cancer (MDA-MB-231), human prostate cancer (DU-145) and human glioma (T98G) cells, after exposure to modulated radiation fields delivered by shielding 50% of the tissue culture flask. A significant decrease (P < 0.05) in cell survival was observed in the shielded area, outside the primary treatment field (out-of-field), that was lower than predicted when compared to uniform exposures fitted to the linear-quadratic model. Cellular radiosensitivity was demonstrated to be an important factor in the level of response for both the in- and out-of-field regions. These responses were shown to be dependent on secretion-mediated intercellular communication, because inhibition of cellular secreted factors between the in- and out-of-field regions abrogated the response. Out-of-field cell survival was shown to increase after pretreatment of cells with agents known to inhibit factors involved in mediating radiation-induced bystander signaling (aminoguanidine, DMSO or cPTIO). These data illustrate a significant decrease in survival out-of-field, dependent upon intercellular communication, in several cell lines with varying radiosensitivity after exposure to a modulated radiation field. This study provides further evidence for the importance of intercellular signaling in modulated exposures, where dose gradients are present, and may inform the refinement of established radiobiological models to facilitate the optimization of advanced radiotherapy treatment plans.     

Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study

Objective To examine the relation between body mass index (kg/m²) and cancer incidence and mortality.Design Prospective cohort study.Participants 1.2 million UK women recruited into the Million Women Study, aged 50-64 during 1996-2001, and followed up, on average, for 5.4 years for cancer incidence and 7.0 years for cancer mortality.Main outcome measures Relative risks of incidence and mortality for all cancers, and for 17 specific types of cancer, according to body mass index, adjusted for age, geographical region, socioeconomic status, age at first birth, parity, smoking status, alcohol intake, physical activity, years since menopause, and use of hormone replacement therapy.Results 45 037 incident cancers and 17 203 deaths from cancer occurred over the follow-up period. Increasing body mass index was associated with an increased incidence of endometrial cancer (trend in relative risk per 10 units=2.89, 95% confidence interval 2.62 to 3.18), adenocarcinoma of the oesophagus (2.38, 1.59 to 3.56), kidney cancer (1.53, 1.27 to 1.84), leukaemia (1.50, 1.23 to 1.83), multiple myeloma (1.31, 1.04 to 1.65), pancreatic cancer (1.24, 1.03 to 1.48), non-Hodgkin''s lymphoma (1.17, 1.03 to 1.34), ovarian cancer (1.14, 1.03 to 1.27), all cancers combined (1.12, 1.09 to 1.14), breast cancer in postmenopausal women (1.40, 1.31 to 1.49) and colorectal cancer in premenopausal women (1.61, 1.05 to 2.48). In general, the relation between body mass index and mortality was similar to that for incidence. For colorectal cancer, malignant melanoma, breast cancer, and endometrial cancer, the effect of body mass index on risk differed significantly according to menopausal status.Conclusions Increasing body mass index is associated with a significant increase in the risk of cancer for 10 out of 17 specific types examined. Among postmenopausal women in the UK, 5% of all cancers (about 6000 annually) are attributable to being overweight or obese. For endometrial cancer and adenocarcinoma of the oesophagus, body mass index represents a major modifiable risk factor; about half of all cases in postmenopausal women are attributable to overweight or obesity.