Uncertainties in estimating health risks associated with exposure to ionising radiation.

The information for the present discussion on the uncertainties associated with estimation of radiation risks and probability of disease causation was assembled for the recently published NCRP Report No. 171 on this topic. This memorandum provides a timely overview of the topic, given that quantitative uncertainty analysis is the state of the art in health risk assessment and given its potential importance to developments in radiation protection. Over the past decade the increasing volume of epidemiology data and the supporting radiobiology findings have aided in the reduction of uncertainty in the risk estimates derived. However, it is equally apparent that there remain significant uncertainties related to dose assessment, low dose and low dose-rate extrapolation approaches (e.g. the selection of an appropriate dose and dose-rate effectiveness factor), the biological effectiveness where considerations of the health effects of high-LET and lower-energy low-LET radiations are required and the transfer of risks from a population for which health effects data are available to one for which such data are not available. The impact of radiation on human health has focused in recent years on cancer, although there has been a decided increase in the data for noncancer effects together with more reliable estimates of the risk following radiation exposure, even at relatively low doses (notably for cataracts and cardiovascular disease). New approaches for the estimation of hereditary risk have been developed with the use of human data whenever feasible, although the current estimates of heritable radiation effects still are based on mouse data because of an absence of effects in human studies. Uncertainties associated with estimation of these different types of health effects are discussed in a qualitative and semi-quantitative manner as appropriate. The way forward would seem to require additional epidemiological studies, especially studies of low dose and low dose-rate occupational and perhaps environmental exposures and for exposures to x rays and high-LET radiations used in medicine. The development of models for more reliably combining the epidemiology data with experimental laboratory animal and cellular data can enhance the overall risk assessment approach by providing biologically refined data to strengthen the estimation of effects at low doses as opposed to the sole use of mathematical models of epidemiological data that are primarily driven by medium/high doses. NASA's approach to radiation protection for astronauts, although a unique occupational group, indicates the possible applicability of estimates of risk and their uncertainty in a broader context for developing recommendations on: (1) dose limits for occupational exposure and exposure of members of the public; (2) criteria to limit exposures of workers and members of the public to radon and its short-lived decay products; and (3) the dosimetric quantity (effective dose) used in radiation protection.

Behavior and food consumption pattern of the population exposed in 1949-1962 to fallout from Semipalatinsk nuclear test site in Kazakhstan.

The relationship between radiation exposure from nuclear weapons testing fallout and thyroid disease in a group of 2,994 subjects has been the subject of study by the US National Cancer Institute. In that study, radiation doses to the thyroid were estimated for residents of villages in Kazakhstan possibly exposed to deposition of radioactive fallout from nuclear testing conducted by the Soviet Union at the Semipalatinsk Nuclear Test Site in Kazakhstan between 1949 and 1962. The study subjects included individuals of both Kazakh and Russian origin who were exposed during childhood and adolescence. An initial dose reconstruction used for the risk analysis of Land et al. (Radiat Res 169:373-383, 2008) was based on individual information collected from basic questionnaires administered to the study population in 1998. However, because data on several key questions for accurately estimating doses were not obtained from the 1998 questionnaires, it was decided to conduct a second data collection campaign in 2007. Due to the many years elapsed since exposure, a well-developed strategy was necessary to encourage accurate memory recall. In our recent study, a focus group interview data collection methodology was used to collect historical behavioral and food consumption data. The data collection in 2007 involved interviews conducted within four-eight-person focus groups (three groups of women and one group of men) in each of four exposed villages where thyroid disease screening was conducted in 1998. Population-based data on relevant childhood behaviors including time spent in- and outdoors and consumption rates of milk and other dairy products were collected from women's groups. The data were collected for five age groups of children and adolescents ranging from less than 1 year of age to 21 years of age. Dairy products considered included fresh milk and other products from cows, goats, mares, and sheep. Men's focus group interviews pertained to construction materials of houses and schools, and animal grazing patterns and feeding practices. The response data collected are useful for improving estimates of thyroid radiation dose estimates for the subjects of an ongoing epidemiological study.

Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan.

Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-1962). Cases with thyroid nodules (n = 907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, P = 0.03) and GFRA1 -193C>G (rs not assigned, P = 0.05) and decreased risk with XRCC1 R194W (rs1799782, P trend = 0.03) and TGFB1 T263I (rs1800472, P = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n = 25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% CI 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT P value = 0.02). Polymorphisms in RET signaling, DNA repair and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways such as genes in double-strand break repair, apoptosis and genes related to proliferation should also be pursued.

Multiple diagnostic X-rays for spine deformities and risk of breast cancer.

BACKGROUND: Ionizing radiation is a well-established human mammary carcinogen. Women historically monitored by radiography at young ages for abnormal spinal curvature are an exposed population suitable for investigating radiation-related risk and its variation by modifying factors. In this historic cohort, 95% of daily dose increments (when exposure to the breast occurred) were under 2.4 cGy, with mean 1.1 cGy. METHODS: A retrospective cohort of 3,010 women, diagnosed with spinal curvature between 1912 and 1965 in 14 U.S. pediatric orthopedic centers and who completed a questionnaire by telephone interview or mail survey in 1992, were studied for risk of breast cancer by radiation dose to the breast (mean, 12 cGy) after adjustment for established breast cancer risk factors. RESULTS: A borderline-significant radiation dose response (excess relative risk/Gy = 2.86; P = 0.058; one-tailed P = 0.029) was observed during 118,905 woman-years of follow-up (median, 35.5 years) based on 78 cases of invasive breast cancer. The dose response was significantly greater (P = 0.03) for women who reported a family history of breast cancer in first- or second-degree relatives (excess relative risk/Gy = 8.37; 95% confidence interval, 1.50-28.16). Radiation-related risk did not vary significantly by stage of reproductive development at exposure. CONCLUSIONS: Assuming that repair of radiation-related DNA damage requires at most a few hours, our data argue against existence of a low-dose threshold on the order of 1 to 3 cGy for radiation exposure contributing to breast carcinogenesis. The possibility that a family history of breast cancer may have enhanced a carcinogenic radiation effect requires confirmation in other studies.

Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers.

Radiation exposure at a young age is a strong risk factor for thyroid cancer. We conducted a nested case-control study of 69 thyroid cancer cases and 265 controls from a cohort of 14,054 childhood cancer survivors to evaluate the shape of the radiation dose-response relationship, in particular at high doses, and to assess modification of the radiation effects by patient and treatment characteristics. We considered several types of statistical models to estimate the excess relative risk (ERR), mainly guided by radiobiological models. A two-parameter model with a term linear in dose and a negative exponential in dose squared provided the best parsimonious description with an ERR of 1.3 per gray (95% confidence interval 0.4-4.1) at doses below 6 Gy and a relative decrease in ERR of 0.2% per unit dose squared with increasing dose, that is, decreases in the ERR/Gy of 53% at 20 Gy and 95% at 40 Gy. Further analyses using spline models suggested that the significant nonlinearity at high doses was characterized most appropriately as a true downturn rather than a flattening of the dose-response curve. We found no statistically significant modification of the dose-response relationship by patient characteristics; however, the linear parameter (i.e., the ERR/ Gy at doses less than 6 Gy) did decrease consistently and linearly with increasing age at childhood cancer diagnosis, from 4.45 for 0-1-year-olds to 0.48 for 15-20-year-olds. In summary, we applied models derived from radiobiology to describe the radiation dose-response curve for thyroid cancer in an epidemiological study and found convincing evidence for a downturn in risk at high doses.

Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population.

Individuals who are homozygotes for mutations in DNA repair genes are at high risk for cancer. It is not well documented, however, if the heterozygous carriers of the mutation are also predisposed to cancer. To address the issue, xeroderma pigmentosum (XP) in Japan is an interesting candidate because of three major reasons: XP is an autosomal recessive disorder with an enormously elevated risk of skin cancer, the frequency of XP patients is higher in Japan than in other parts of the world, and more than half of Japanese XP patients are homozygous for the same founder mutation in the XPA gene. We screened archival blood samples from Japanese individuals who resided in Hiroshima or Nagasaki. A simple PCR-RFLP method was developed that is highly specific for detection of XPA heterozygotes carrying the founder mutation. We identified nine XPA heterozygotes among 1,020 individuals screened for a prevalence of 0.88%. This rate, if representative, implies that there are about 1 million carriers of the XPA founder mutation in the Japanese population. Thus, investigation of their cancer risk may be warranted.

A pathology study of malignant and benign ovarian tumors among atomic-bomb survivors--case series report.

The present article describes the series of incident primary ovarian tumors in the Life Span Study (LSS) cohort of the Radiation Effects Research Foundation, with particular emphasis on case ascertainment and characterization of histological features of the tumors. We identified 723 ovarian tumors (260 malignant, 463 benign) in 648 individuals of about 70,000 female LSS subjects; 71 cases had more than one ovarian tumor. We histologically confirmed 601 tumors (182 malignant, 419 benign tumors). The most frequent histological type was common epithelial tumor (90.7% for malignant and 59.7% for benign tumors). The distributions of ovarian tumors by histological type were similar to those from other studies. Among malignancies, the frequency of common epithelial types relative to other tumor types increased with radiation dose (p = 0.02). Among benign tumors, the relative frequency of sex-cord stromal tumors increased with radiation dose (p = 0.04). The women with mucinous cancer had better survival than those with serous cancers (p = 0.03). Within tumor types, there was no consistent pattern of survival by radiation dose. Variations in histological types of ovarian tumors in response to radiation dose, suggested by the case series data need to be followed up by population-based incidence analysis.

External dose estimates for Dolon village: application of the U.S./Russian joint methodology.

Methods to estimate external dose from radioactive fallout from nuclear tests have for many years depended on two types of data: measurements of exposure rate in air and an empirically derived power function to describe the change in exposure rate with time, Over the last four years, a working group with American and Russian participation has developed a bi-national joint methodology that offers an improved capability for estimating external dose. In this method, external dose is estimated using exposure rate functions derived from data from American nuclear tests similar in construction to SNTS (Semipalatinsk Nuclear Test Site) devices. For example, in this paper, we derive doses for test #1 (August 29, 1949) at the SNTS using an exposure rate function for the U.S. TRINITY test. For the case of test #1, the average external dose for a person in Dolon is estimated to have been about 0.5 Gy compared to 1 to 2 Gy estimated in other work. This prediction agrees better with reported EPR measurements in teeth from village residents and with measurements of TL signals in bricks from Dolon buildings. This report presents the basic elements of the joint methodology model for estimation of external dose received from SNTS fallout.

Radiation and breast cancer: a review of current evidence.

This paper summarizes current knowledge on ionizing radiation-associated breast cancer in the context of established breast cancer risk factors, the radiation dose-response relationship, and modifiers of dose response, taking into account epidemiological studies and animal experiments. Available epidemiological data support a linear dose-response relationship down to doses as low as about 100 mSv. However, the magnitude of risk per unit dose depends strongly on when radiation exposure occurs: exposure before the age of 20 years carries the greatest risk. Other characteristics that may influence the magnitude of dose-specific risk include attained age (that is, age at observation for risk), age at first full-term birth, parity, and possibly a history of benign breast disease, exposure to radiation while pregnant, and genetic factors.

Coronary heart disease after radiotherapy for peptic ulcer disease.

PURPOSE: To evaluate the risk of coronary heart disease (CHD) and cerebrovascular disease after radiotherapy (RT) for peptic ulcer disease. METHODS AND MATERIALS: Peptic ulcer disease patients treated with RT (n = 1859) or by other means (n = 1860) at the University of Chicago Medical Center between 1936 and 1965, were followed through 1997. The observed numbers of cause-specific deaths were compared with the expected numbers from the general population rates. During RT, 5% of the heart was in the treatment field and the remainder of the heart mostly received scattered radiation. A volume-weighted cardiac dose was computed to describe the average tissue dose to the entire organ. We used Cox proportional hazards regression analysis to analyze the CHD and cerebrovascular disease risk associated with RT, adjusting for confounding factors. RESULTS: Greater than expected CHD mortality was observed among the irradiated patients. The irradiated patients received volume-weighted cardiac doses ranging from 1.6 to 3.9 Gy and the portion of the heart directly in the field received doses of 7.6-18.4 Gy. The CHD risk increased with the cardiac dose (p trend = 0.01). The cerebrovascular disease risk was not associated with the surrogate carotid dose. CONCLUSION: The excess CHD risk in patients undergoing RT for peptic ulcer disease decades previously indicates the need for long-term follow-up for cardiovascular disease after chest RT.

Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response.

Improving the efficiency of nested case-control studies of interaction by selecting controls using counter matching on exposure.

BACKGROUND: Studies of the effect of exposure to a risk factor measured in an entire cohort may be augmented by nested case-control subsets to investigate confounding or effect modification by additional factors not practically assessed on all cohort members. We compared three control-selection strategies-matching on exposure, counter matching on exposure, and random sampling-to determine which was most efficient in a situation where exposure is a known, continuous variable and high doses are rare. METHODS: We estimated the power to detect interaction using four control-to-case ratios (1:1, 2:1, 4:1, and 8:1) in a planned case-control study of the joint effect of atomic bomb radiation exposure and serum oestradiol levels on breast cancer. Radiation dose is measured in the entire cohort, but because neither serum oestradiol level nor the true degree of interaction was known, we simulated values of oestradiol and hypothetical levels of oestradiol-radiation interaction. RESULTS: Compared with random sampling, power to detect interaction was similarly higher with either matching or counter matching with two or more controls. CONCLUSIONS: Because counter matching is generally at least as efficient as random sampling, whereas matching on exposure can result in loss of efficiency and precludes estimation of exposure risk, we recommend counter matching for selecting controls in nested case-control studies of the joint effects of multiple risk factors when one is previously measured in the full cohort.

Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990.

An incidence survey of the Life Span Study (LSS) population found 1093 breast cancers among 1059 breast cancer cases diagnosed during 1950-1990. As in earlier breast cancer surveys of this population, a linear and statistically highly significant radiation dose response was found. In the analysis, particular attention was paid to modification of radiation dose response by age at exposure (e) and attained age (a). Dose-specific excess relative risk (ERR(1Sv)) decreased with increasing values of e and a. A linear dose-response model analysis, with e and a as exponential age modifiers, did not conclusively discriminate between the two variables as modifiers of dose response. A modified isotonic regression approach, requiring only that ERR(1Sv) be monotonic in age, provides a fresh perspective indicating that both e and a are important modifiers of dose response. Exposure before age 20 was associated with higher ERR(1Sv) compared to exposure at older ages, with no evidence of consistent variation by exposure age for ages under 20. ERR(1Sv) was observed to decline with increasing attained age, with by far the largest drop around age 35. Possible explanations for these observations are discussed, along with research approaches that might provide more information.

Malignant neoplasms after radiation therapy for peptic ulcer.

Most information on radiation-related cancer risk comes from the Life Span Study (LSS) of the Japanese atomic bomb survivors. Stomach cancer mortality rates are much higher in Japan than in the U.S., making the applicability of LSS findings to the U.S. population uncertain. A unique cohort of U.S. patients who were irradiated for peptic ulcer to control gastric secretion provides a different perspective on risk. Cancer mortality data were analyzed and relative risks estimated for 3719 subjects treated by radiotherapy (mean stomach dose 14.8 Gy) and/or by surgery and medication during the period 1936-1965 and followed through 1997 (average 25 years). Compared to the U.S. rates, stomach cancer mortality was significantly increased for irradiated and nonirradiated patients (observed/expected = 3.20 and 1.52, respectively). We observed strong evidence of exposure-related excess mortality from cancer of the stomach (RR 2.6, 95% CI 1.3, 5.1), pancreas (RR 2.7, 95% CI 1.5, 5.1), and lung (RR 1.5, 95% CI 1.1, 2.1), with commensurate radiation dose responses in analyses that included nonexposed patients. However, the dose responses for these cancers were not significant when restricted to exposed patients. Our excess relative risk per gray estimate of 0.20 at doses

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.

Health effects from fallout.

This paper primarily discusses health effects that have resulted from exposures received as a result of above-ground nuclear tests, with emphasis on thyroid disease from exposure to 131I and leukemia and solid cancers from low dose rate external and internal exposure. Results of epidemiological studies of fallout exposures in the Marshall Islands and from the Nevada Test Site are summarized, and studies of persons with exposures similar to those from fallout are briefly reviewed (including patients exposed to 131I for medical reasons and workers exposed externally at low doses and low dose rates). Promising new studies of populations exposed in countries of the former Soviet Union are also discussed and include persons living near the Semipalatinsk Test Site in Kazakhstan, persons exposed as a result of the Chernobyl accident, and persons exposed as a result of operations of the Mayak Nuclear Plant in the Russian Federation. Very preliminary estimates of cancer risks from fallout doses received by the United States population are presented.

Lauriston S. Taylor lecture: Radiation Protection and Public Policy in an Uncertain World.

Ionizing radiation is a known, well-documented, and reasonably well-quantified human cancer risk factor based on a remarkably consistent body of dose-response information from epidemiological studies of exposed populations supported by experimental studies using animal and cellular models. This fact is largely ascribable to the relative ease, compared to other carcinogens, of estimating radiation dose to organs and local tissues. Statistical models for radiation-related cancer risk are increasingly relevant to both radiation protection policy and the adjudication of compensation claims for cancers diagnosed following occupational and environmental exposures to ionizing radiation, as discussed in a number of expert committee reports of national and international organizations concerned with radiation-related risks. These and other publications increasingly emphasize the relevance of well-quantified uncertainties in radiation-related risk projections, including upper and lower confidence or uncertainty bounds, for radiation protection. Finally, the wealth of detailed information provided by such quantitative uncertainty analysis approaches is highly relevant to radiation protection, which might be viewed as a political process that involves a diverse group of stakeholders who, individually, may be primarily concerned with avoiding possible radiation-related risks or with avoiding possibly unnecessary costs of risk reduction or unnecessary denial of benefits that require some radiation exposure, or with balancing both considerations to some degree.

Mortality from cardiovascular diseases in the Semipalatinsk historical cohort, 1960-1999, and its relationship to radiation exposure.

The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose-response analyses were conducted for both the entire cohort and the exposed group only. A dose-response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose-response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation-related mortality from cardiovascular disease.