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.

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.

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.

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.

Breast cancer risk from different mammography screening practices.

Mammography screening is an accepted procedure for early detection of breast tumors among asymptomatic women. Since this procedure involves the use of X rays, it is itself potentially carcinogenic. Although there is general consensus about the benefit of screening for older women, screening practices differ between countries. In this paper radiation risks for these different practices are estimated using a new approach. We model breast cancer induction by ionizing radiation in a cohort of patients exposed to frequent X-ray examinations. The biologically based, mechanistic model provides a better foundation for the extrapolation of risks to different mammography screening practices than empirical models do. The model predicts that the excess relative risk (ERR) doubles when screening starts at age 40 instead of 50 and that a continuation of screening at ages 75 and higher carries little extra risk. The number of induced fatal breast cancers is estimated to be considerably lower than derived from epidemiological studies and from internationally accepted radiation protection risks. The present findings, if used in a risk-benefit analysis for mammography screening, would be more favorable to screening than estimates currently recommended for radiation protection. This has implications for the screening ages that are currently being reconsidered in several countries.

Cancer mortality among women frequently exposed to radiographic examinations for spinal disorders.

We studied cancer mortality in a cohort of 5,573 women with scoliosis and other spine disorders who were diagnosed between 1912 and 1965 and were exposed to frequent diagnostic X-ray procedures. Patients were identified from medical records in 14 orthopedic medical centers in the United States and followed for vital status and address through December 31, 2004, using publicly available regional, state and nationwide databases. Causes of death were obtained from death certificates or through linkage with the National Death Index (NDI). Statistical analyses included standardized mortality ratios (SMR = observed/expected) based on death rates for U.S. females and internal comparisons using Cox regression models with attained age as the time scale. Diagnostic radiation exposure was estimated from radiology files for over 137,000 procedures; estimated average cumulative radiation doses to the breast, lung, thyroid and bone marrow were 10.9, 4.1, 7.4 and 1.0 cGy, respectively. After a median follow-up period of 47 years, 1527 women died, including 355 from cancer. Cancer mortality was 8% higher than expected (95% CI = 0.97-1.20). Mortality from breast cancer was significantly elevated (SMR = 1.68; 95% CI: 1.38-2.02), whereas death rates from several other cancers were below expectation, in particular lung (SMR = 0.77), cervical (SMR = 0.31), and liver (SMR = 0.17). The excess relative risk (ERR) for breast cancer mortality increased significantly with 10-year lagged radiation dose to the breast (ERR/Gy = 3.9; 95% CI: 1.0-9.3).

Radiation doses and cancer risks in the Marshall Islands associated with exposure to radioactive fallout from Bikini and Enewetak nuclear weapons tests: summary.

Nuclear weapons testing conducted at Bikini and Enewetak Atolls during 1946-1958 resulted in exposures of the resident population of the present-day Republic of the Marshall Islands to radioactive fallout. This paper summarizes the results of a thorough and systematic reconstruction of radiation doses to that population, by year, age at exposure, and atoll of residence, and the related cancer risks. Detailed methods and results are presented in a series of companion papers in this volume. From our analysis, we concluded that 20 of the 66 nuclear tests conducted in or near the Marshall Islands resulted in measurable fallout deposition on one or more of the inhabited atolls of the Marshall Islands. In this work, we estimated deposition densities (kBq m(-2)) of all important dose-contributing radionuclides at each of the 32 atolls and separate reef islands of the Marshall Islands. Quantitative deposition estimates were made for 63 radionuclides from each test at each atoll. Those estimates along with reported measurements of exposure rates at various times after fallout were used to estimate radiation absorbed doses to the red bone marrow, thyroid gland, stomach wall, and colon wall of atoll residents from both external and internal exposure. Annual doses were estimated for six age groups ranging from newborns to adults. We found that the total deposition of 137Cs, external dose, internal organ doses, and cancer risks followed the same geographic pattern with the large population of the southern atolls receiving the lowest doses. Permanent residents of the southern atolls who were of adult age at the beginning of the testing period received external doses ranging from 5 to 12 mGy on average; the external doses to adults at the mid-latitude atolls ranged from 22 to 59 mGy on average, while the residents of the northern atolls received external doses in the hundreds to over 1,000 mGy. Internal doses varied significantly by age at exposure, location, and organ. Except for internal doses to the thyroid gland, external exposure was generally the major contributor to organ doses, particularly for red bone marrow and stomach wall. Internal doses to the stomach wall and red bone marrow were similar in magnitude, about 1 mGy to 7 mGy for permanent residents of the southern and mid-latitude atolls. However, adult residents of Utrik and Rongelap Island, which are part of the northern atolls, received much higher internal doses because of intakes of short-lived radionuclides leading to doses from 20 mGy to more than 500 mGy to red bone marrow and stomach wall. In general, internal doses to the colon wall were four to ten times greater than those to the red bone marrow and internal doses to the thyroid gland were 20 to 30 times greater than to the red bone marrow. Adult internal thyroid doses for the Utrik community and for the Rongelap Island community were about 760 mGy and 7,600 mGy, respectively. The highest doses were to the thyroid glands of young children exposed on Rongelap at the time of the Castle Bravo test of 1 March 1954 and were about three times higher than for adults. Internal doses from chronic intakes, related to residual activities of long-lived radionuclides in the environment, were, in general, low in comparison with acute exposure resulting from the intakes of radionuclides immediately or soon after the deposition of fallout. The annual doses and the population sizes at each atoll in each year were used to develop estimates of cancer risks for the permanent residents of all atolls that were inhabited during the testing period as well as for the Marshallese population groups that were relocated prior to the testing or after it had begun. About 170 excess cancers (radiation-related cases) are projected to occur among more than 25,000 Marshallese, half of whom were born before 1948. All but about 65 of those cancers are estimated to have already been expressed. The 170 excess cancers are in comparison to about 10,600 cancers that would spontaneously arise, unrelated to radioactive fallout, among the same cohort of Marshallese people.

Projected lifetime cancer risks from exposure to regional radioactive fallout in the Marshall Islands.

Radioactive fallout from nuclear test detonations during 1946-1958 at Bikini and Enewetak Atolls in the Marshall Islands (MI) exposed populations living elsewhere in the MI archipelago. A comprehensive analysis, presented in seven companion papers, has produced estimates of tissue-specific radiation absorbed dose to MI residents at all historically inhabited atolls from internal (ingested) and external irradiation resulting from exposure to radioactive fallout, by calendar year, and by age of the population at time of exposure. The present report deals, for the first time, with the implications of these doses for cancer risk among exposed members of the MI population. Radiation doses differed by geographic location and year of birth, and radiation-related cancer risk depends upon age at exposure and age at observation for risk. Using dose-response models based on committee reports published by the National Research Council and the National Institutes of Health, we project that, during the lifetimes of members of the MI population potentially exposed to ionizing radiation from weapons test fallout deposited during the testing period (1948-1958) and from residual radioactive sources during the subsequent 12 y (1959-1970), perhaps 1.6% (with 90% uncertainty range 0.4% to 3.4%) of all cancers might be attributable to fallout-related radiation exposures. By sub-population, the projected proportion of cancers attributable to radiation from fallout from all nuclear tests conducted in the Marshall Islands is 55% (28% to 69%) among 82 persons exposed in 1954 on Rongelap and Ailinginae, 10% (2.4% to 22%) for 157 persons exposed on Utrik, and 2.2% (0.5% to 4.8%) and 0.8% (0.2% to 1.8%), respectively, for the much larger populations exposed in mid-latitude locations including Kwajalein and in southern locations including Majuro. By cancer type, point estimates of attributable risk varied, by location, between 12% and 95% for thyroid cancer, between 2% and 78% for leukemia, and between 0.8% and 55% for all cancers combined. The largest projected risks pertain to the Rongelap Island community and the lowest risks pertain to the populations resident on the southern-most atolls. While the projected cancer risks are smaller than those estimated by the National Cancer Institute in a more simplistic analysis conducted in 2004, these estimates of cancer risk are the best available as they are based on the most detailed dose reconstruction to date and comprehensively include populations at all locations and dose contributions from all nuclear tests.

Low-dose extrapolation of radiation health risks: some implications of uncertainty for radiation protection at low doses.

Ionizing radiation is a known and well-quantified human cancer risk factor, based on a remarkably consistent body of information from epidemiological studies of exposed populations. Typical examples of risk estimation include use of Japanese atomic bomb survivor data to estimate future risk from radiation-related cancer among American patients receiving multiple computed tomography scans, persons affected by radioactive fallout, or persons whose livelihoods involve some radiation exposure, such as x-ray technicians, interventional radiologists, or shipyard workers. Our estimates of radiation-related risk are uncertain, reflecting statistical variation and our imperfect understanding of crucial assumptions that must be made if we are to apply existing epidemiological data to particular situations. Fortunately, that uncertainty is also highly quantifiable, and can be presented concisely and transparently. Radiation protection is ultimately a political process that involves consent by stakeholders, a diverse group that includes people who might be expected to be risk-averse and concerned with plausible upper limits on risk (how bad could it be?), cost-averse and concerned with lower limits on risk (can you prove there is a nontrivial risk at current dose levels?), or combining both points of view. How radiation-related risk is viewed by individuals and population subgroups also depends very much on perception of related benefit, which might be (for example) medical, economic, altruistic, or nonexistent. The following presentation follows the lead of National Council on Radiation Protection and Measurements (NCRP) Commentary 14, NCRP Report 126, and later documents in treating radiation protection from the viewpoint of quantitative uncertainty analysis.

Incidence of carcinoma of the major salivary glands according to the WHO classification, 1992 to 2006: a population-based study in the United States.

BACKGROUND: Carcinomas of the major salivary glands (M-SGC) comprise a morphologically diverse group of rare tumors of largely unknown cause. To gain insight into etiology, we evaluated incidence of M-SGC using the WHO classification schema (WHO-2005). METHODS: We calculated age-adjusted incidence rates (IR) and IR ratios (IRR) for M-SGC diagnosed between 1992 and 2006 in the Surveillance, Epidemiology and End Results Program. RESULTS: Overall, 6,391 M-SGC (IR, 11.95/1,000,000 person-years) were diagnosed during 1992 to 2006. Nearly 85% of cases (n = 5,370; IR, 10.00) were encompassed within WHO-2005, and among these, males had higher IRs than females [IRR, 1.51; 95% confidence interval (95% CI), 1.43-1.60]. Squamous cell (IR, 3.44) and mucoepidermoid (IR, 3.23) carcinomas occurred most frequently among males, whereas mucoepidermoid (IR, 2.67), acinic cell (IR, 1.57), and adenoid cystic (IR, 1.40) carcinomas were most common among females. Mucoepidermoid, acinic cell, and adenoid cystic carcinomas predominated in females through age approximately 50 years; thereafter, IRs of acinic cell and adenoid cystic carcinomas were nearly equal among females and males, whereas IRs of mucoepidermoid carcinoma among males exceeded IRs among females (IRR, 1.57; 95% CI, 1.38-1.78). Except for mucoepidermoid and adenoid cystic carcinomas, which occurred equally among all races, other subtypes had significantly lower incidence among Blacks and Asians/Pacific Islanders than among Whites. Adenoid cystic carcinoma occurred equally in the submandibular and parotid glands, and other M-SGC histologic subtypes evaluated had 77% to 98% lower IRs in the submandibular gland. Overall M-SGC IRs remained stable during 1992 to 2006. CONCLUSION: Distinct incidence patterns according to histologic subtype suggest that M-SGC are a diverse group of neoplasms characterized by etiologic and/or biological heterogeneity with varying susceptibility by gender and race.

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.

Interactive RadioEpidemiological Program (IREP): a web-based tool for estimating probability of causation/assigned share of radiogenic cancers.

The Interactive RadioEpidemiological Program (IREP) is a Web-based, interactive computer code that is used to estimate the probability that a given cancer in an individual was induced by given exposures to ionizing radiation. IREP was developed by a Working Group of the National Cancer Institute and Centers for Disease Control and Prevention, and was adopted and modified by the National Institute for Occupational Safety and Health (NIOSH) for use in adjudicating claims for compensation for cancer under the Energy Employees Occupational Illness Compensation Program Act of 2000. In this paper, the quantity calculated in IREP is referred to as "probability of causation/assigned share" (PC/AS). PC/AS for a given cancer in an individual is calculated on the basis of an estimate of the excess relative risk (ERR) associated with given radiation exposures and the relationship PC/AS = ERR/ERR+1. IREP accounts for uncertainties in calculating probability distributions of ERR and PC/AS. An accounting of uncertainty is necessary when decisions about granting claims for compensation for cancer are made on the basis of an estimate of the upper 99% credibility limit of PC/AS to give claimants the "benefit of the doubt." This paper discusses models and methods incorporated in IREP to estimate ERR and PC/AS. Approaches to accounting for uncertainty are emphasized, and limitations of IREP are discussed. Although IREP is intended to provide unbiased estimates of ERR and PC/AS and their uncertainties to represent the current state of knowledge, there are situations described in this paper in which NIOSH, as a matter of policy, makes assumptions that give a higher estimate of the upper 99% credibility limit of PC/AS than other plausible alternatives and, thus, are more favorable to claimants.

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.

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.