More than 30 years ago, population-based tumor registries were established in Hiroshima and Nagasaki. This report, the first of a series of papers on cancer incidence, describes methodological aspects of the tumor registries and discusses issues of data quality in the context of the Life Span Study (LSS) cohort, the major atomic bomb survivor population. The tumor registries in Hiroshima and Nagasaki are characterized by active case ascertainment based on abstraction of medical records at area hospitals, augmented by tissue registries operational in the area and a number of clinical and pathological programs undertaken over the years among the atomic bomb survivors. Using conventional measures of quality, the Hiroshima and Nagasaki tumor registries have a death certificate-only (DCO) rate of less than 9%, a mortality/incidence (M/I) ratio of about 50%, and a histological verification (HV) rate in excess of 70%, which place these registries among the best in Japan and comparable to many established registries worldwide. All tumor registry data pertaining to the LSS population were assembled, reviewed and handled with special attention given to the quality and uniformity of data based on standardized procedures. Special studies and monitoring programs were also introduced to evaluate the quality of the tumor incidence data in the LSS. Analyses were performed to examine the quality of incidence data overall and across various substrata used for risk assessment such as age, time and radiation dose groups. No significant associations were found between radiation dose and data quality as measured by various indices. These findings warrant the use of the present tumor registry-based data for studies of cancer incidence in the atomic bomb survivors.

Adolescent↗

PubMed1994

Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987.

This paper presents an analysis of data on the incidence of leukemia, lymphoma and myeloma in the Life Span Study cohort of atomic bomb survivors during the period from late 1950 through the end of 1987 (93,696 survivors accounting for 2,778,000 person-years). These analyses add 9 additional years of follow-up for leukemia and 12 for myeloma to that in the last comprehensive reports on these diseases. This is the first analysis of the lymphoma incidence data in the cohort. Using both the Leukemia Registry and the Hiroshima and Nagasaki tumor registries, a total of 290 leukemia, 229 lymphoma and 73 myeloma cases were identified. The primary analyses were restricted to first primary tumors diagnosed among residents of the cities or surrounding areas with Dosimetry System 1986 dose estimates between 0 and 4 Gy kerma (231 leukemias, 208 lymphomas and 62 myelomas). Analyses focused on time-dependent models for the excess absolute risk. Separate analyses were carried out for acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelocytic leukemia (CML) and adult T-cell leukemia (ATL). There were few cases of chronic lymphocytic leukemia in this population. There was strong evidence of radiation-induced risks for all subtypes except ATL, and there were significant subtype differences with respect to the effects of age at exposure and sex and in the temporal pattern of risk. The AML dose-response function was nonlinear, whereas there was no evidence against linearity for the other subtypes. When averaged over the follow-up period, the excess absolute risk (EAR) estimates (in cases per 10(4) PY Sv) for the leukemia subtypes were 0.6, 1.1 and 0.9 for ALL, AML and CML, respectively. The corresponding estimated average excess relative risks at 1 Sv are 9.1, 3.3 and 6.2 respectively. There was some evidence of an increased risk of lymphoma in males (EAR = 0.6 cases per 10(4) PY Sv) but no evidence of any excess in females. There was no evidence of an excess risk for multiple myeloma in our standard analyses.

Adolescent↗

PubMed1994

Cancer incidence in atomic bomb survivors. Part IV: Comparison of cancer incidence and mortality.

This report compares cancer incidence and mortality among atomic bomb survivors in the Radiation Effects Research Foundation Life Span Study (LSS) cohort. Because the incidence data are derived from the Hiroshima and Nagasaki tumor registries, case ascertainment is limited to the time (1958-1987) and geographic restrictions (Hiroshima and Nagasaki) of the registries, whereas mortality data are available from 1950-1987 anywhere in Japan. With these conditions, there were 9,014 first primary incident cancer cases identified among LSS cohort members compared with 7,308 deaths for which cancer was listed as the underlying cause of death on death certificates. When deaths were limited to those occurring between 1958-1987 in Hiroshima or Nagasaki, there were 3,155 more incident cancer cases overall, and 1,262 more cancers of the digestive system. For cancers of the oral cavity and pharynx, skin, breast, female and male genital organs, urinary system and thyroid, the incidence series was at least twice as large as the comparable mortality series. Although the incidence and mortality data are dissimilar in many ways, the overall conclusions regarding which solid cancers provide evidence of a significant dose response generally confirm the mortality findings. When either incidence or mortality data are evaluated, significant excess risks are observed for all solid cancers, stomach, colon, liver (when it is defined as primary liver cancer or liver cancer not otherwise specified on the death certificate), lung, breast, ovary and urinary bladder. No significant radiation effect is seen for cancers of the pharynx, rectum, gallbladder, pancreas, nose, larynx, uterus, prostate or kidney in either series. There is evidence of a significant excess of nonmelanoma skin cancer in the incidence data, but not in the mortality series. Cancers of the salivary gland and thyroid are also in excess in the incidence series, but they were not evaluated in the earlier mortality analyses. For all solid tumors the estimated excess relative risk at 1 Sv (ERR1Sv) for incidence (ERR1Sv = 0.63) is 40% larger than the excess relative risk (ERR) based on mortality data from 1950-1987 in all Japan (ERR1Sv = 0.45). The corresponding excess absolute risk (EAR) point estimate is 2.7 times greater for incidence than mortality. For some cancer sites, the difference in the magnitude of risk between incidence and mortality is greater. These differences reflect the greater diagnostic accuracy of the incidence data and the lack of full representation of radiosensitive but relatively nonfatal cancers, such as breast and thyroid, in the mortality data. Analyses of both incidence and mortality data are needed since the two end points provide complementary information for risk assessment.

Adolescent↗

PubMed1992

The effect of diagnostic misclassification on non-cancer and cancer mortality dose response in A-bomb survivors.

We used the EM algorithm in the context of a joint Poisson regression analysis of cancer and non-cancer mortality in the Radiation Effects Research Foundation (RERF) Life Span Study (LSS) to assess whether the observed increased risk of non-cancer death due to radiation exposure (Shimizu et al., RERF Technical Report 02-91, 1991) can be attributed solely to misclassification of cancer as non-cancer on death certificates. We show that greater levels of dose-independent misclassification than are indicated by a series of autopsies conducted on a subset of LSS members would be required to explain the non-cancer dose response, but that a relatively small amount of dose-dependence in the misclassification of cancer would explain the result. The adjustment for misclassification also results in higher risk estimates for cancer mortality. We review applications of similar statistical methods in other contexts and discuss extensions of the methods to more than two causes of death.

Age Factors↗

PubMed1991

Allowing for dose-estimation errors for the A-bomb survivor data.

Unless allowances are made, random errors in radiation dose estimates cause underestimation of linear risk estimates and distort the shape of dose-response curves. These errors also result in spurious associations between radiogenic endpoints, exaggerating possible variations in individual sensitivity to radiation. Statistical methods have been developed which reduce these biases, based on assumptions regarding the nature and magnitude of dose-estimation errors. Some understanding of the underlying statistical basis for these methods is necessary to both those interested in interpreting radiogenic effects and those interested in the dosimetry system. This paper discusses the basic statistical issues and their implications, presents some statistical methods to deal with the problem, and indicates the sensitivity of certain results to assumptions about the magnitude of the dose-estimation errors.

Japan↗

PubMed1991

A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Future research in epidemiology and statistics at RERF.

Explore the source record for details and available documents.

Humans↗

PubMed1991

Analysis of time and age patterns in cancer risk for A-bomb survivors.

This report has two aims: (1) to describe and analyze the age/time patterns of excess cancer risk in the atomic bomb survivor cohort followed up by the Radiation Effects Research Foundation (RERF), and (2) to describe statistical methods which are used in RERF's analyses of data on mortality and morbidity in the cohort. In contrast to previous analyses of the cohort cancer mortality data, substantial use is made of Japanese national cancer rates for the purpose of investigation of the age/time variations in excess risk. This analysis considers mortality from all cancers except leukemia as a group. Primary attention is given to description in terms of the age-specific excess relative risk, but the importance of appropriate descriptions of the absolute excess risk is also emphasized. When models for the excess risk allow variation with age and time, both constant relative and absolute excess risk models provide similar fits to the data. Previous reports have indicated that for a given age at exposure and sex, the excess age-specific relative risk is remarkably constant throughout the current follow-up period. Statistical analysis here indicates that for those less than about 35 years of age at exposure there is no departure from this pattern, beyond ordinary sampling variation. For those over about 35 years of age at exposure, there is modest evidence of an increasing trend in the excess relative risk, which could plausibly be attributed to effects related to minimal latent period. Some brief consideration is given to modeling the absolute excess risk as the product of an age-at-exposure and time-since-exposure effect. Interpretation of these results, particularly in regard to projections beyond the current follow-up, is discussed.

Age Factors↗

PubMed1989

Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis.

The increasing use of mammography to screen asymptomatic women makes it important to know the risk of breast cancer associated with exposure to low levels of ionizing radiation. We examined the mortality from breast cancer in a cohort of 31,710 women who had been treated for tuberculosis at Canadian sanatoriums between 1930 and 1952. A substantial proportion (26.4 percent) had received radiation doses to the breast of 10 cGy or more from repeated fluoroscopic examinations during therapeutic pneumothoraxes. Women exposed to greater than or equal to 10 cGy of radiation had a relative risk of death from breast cancer of 1.36, as compared with those exposed to less than 10 cGy (95 percent confidence interval, 1.11 to 1.67; P = 0.001). The data were most consistent with a linear dose-response relation. The risk was greatest among women who had been exposed to radiation when they were between 10 and 14 years of age; they had a relative risk of 4.5 per gray, and an additive risk of 6.1 per 10(4) person-years per gray. With increasing age at first exposure, there was substantially less excess risk, and the radiation effect appeared to peak approximately 25 to 34 years after the first exposure. Our additive model for lifetime risk predicts that exposure to 1 cGy at the age of 40 increases the number of deaths from breast cancer by 42 per million women. We conclude that the risk of breast cancer associated with radiation decreases sharply with increasing age at exposure and that even a small benefit to women of screening mammography would outweigh any possible risk of radiation-induced breast cancer.

Adolescent↗

PubMed1989

Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 1. Comparison of risk coefficients for site-specific cancer mortality based on the DS86 and T65DR shielded kerma and organ doses.

As a result of the reassessment of the A-bomb dosimetry, new (DS86) doses were calculated in 1986. In this paper, site-specific estimates of cancer mortality in the years 1950-1985, based on these new doses, are compared with those using the T65DR doses. The subjects of the study are 75,991 members of the Life Span Study sample for whom DS86 doses have been calculated. This reevaluation of the exposures does not change the list of radiation-related cancers. Most differences in dose response between Hiroshima and Nagasaki are no longer significant with the DS86 doses. The dose-response curve is closer to linear with the DS86 than the T65DR doses even for leukemia in the entire dose range, though, statistically, many other models cannot be excluded. However, in the low-dose range, the risk of leukemia remains nonlinear. Assuming a linear model at an RBE of 1, and using organ-absorbed doses, the risk coefficients derived from the two dosimetries are very similar, whereas those based on shielded kerma are about 40% higher with the new dosimetry. If RBE values larger than 1 are assumed, the disparity between the two dosimetries increases because the neutron dose is much greater in the T65DR. At an RBE of 10, for the five specific cancers, i.e., female breast, colon, leukemia, lung, and stomach, the increase in excess number of deaths per 10(4) PYSv under the DS86 varies from 12% (colon) to 133% (female breast). The magnitude of the effects of such modifiers of radiation-induced cancer as age at time of bomb and sex do not differ between the two dose systems.

Female↗

PubMed1988

The effect of changes in dosimetry on cancer mortality risk estimates in the atomic bomb survivors.

In the spring of 1986 the Radiation Effects Research Foundation (RERF) received a new atomic bomb dosimetry system. This report presents the comparisons of leukemia and nonleukemia cancer mortality risk estimates under the old and new dosimetries. In terms of total kerma (essentially whole-body gamma plus neutron exposure), risk estimates for both classes of cancer are 75-85% higher with the new dosimetry. This and other summary comparisons allow for possible nonlinearity at high estimated doses. Changes are also considered in relation to organ doses and assumptions about the relative biological effectiveness (RBE) of neutrons. Without regard to RBE, the risk estimates for total organ dose are essentially unchanged by the dosimetry revision. However, with increasing assumed values of RBE, the estimated low-LET risk decreases much less rapidly under the new dosimetry, due to the smaller neutron component. Thus at an assumed constant RBE of 10, for example, the effect of the dosimetry revision is to increase organ dose risk estimates, relative to those based on the old dosimetry, by 30% for nonleukemia and 80% for leukemia. At an RBE of 20 these increases are 72 and 136%, respectively. A number of other issues are discussed. The city difference in dose is no longer statistically significant, even at an RBE of one. Estimation of RBE is even less feasible with new dosimetry. There is substantial question of the linearity in dose response, in the sense of a leveling off at higher doses. Finally, some indication is given of how risks estimated from this dosimetry and the current data may compare to widely used estimates based largely on the RERF data with the previous dosimetry.

Humans↗

PubMed1987

Studies of the mortality of A-bomb survivors. 8. Cancer mortality, 1950-1982.

This study extends an earlier one by 4 years (1979-1982) and includes mortality data on 11,393 additional Nagasaki survivors. Significant dose responses are observed for leukemia, multiple myeloma, and cancers of the lung, female breast, stomach, colon, esophagus, and urinary tract. Due to diagnostic difficulties, results for liver and ovarian cancers, while suggestive of significant dose responses, do not provide convincing evidence for radiogenic effects. No significant dose responses are seen for cancers of the gallbladder, prostate, rectum, pancreas, or uterus, or for lymphoma. For solid tumors, largely due to sex-specific differences in the background rates, the relative risk of radiation-induced mortality is greater for women than for men. For nonleukemic cancers the relative risk seen in those who were young when exposed has decreased with time, while the smaller risks for those who were older at exposure have tended to increase. While the absolute excess risks of radiation-induced mortality due to nonleukemic cancer have increased with time for all age-at-exposure groups, both excess and relative risks of leukemia have generally decreased with time. For leukemia, the rate of decrease in risk and the initial level of risk are inversely related to age at exposure.

Adolescent↗

PubMed1979

Interrelationships of circulating maternal steroid concentrations in third trimester pregnancies. I. C21 steroids: progesterone, 16 alpha-hydroxyprogesterone, 17 alpha-hydroxyprogesterone, 20 alpha-dihydroprogesterone, delta 5-pregnenolone, delta 5-pregnenolone sulfate, and 17-hydroxy delta 5-pregnenolone.

Explore the source record for details and available documents.

17-alpha-Hydroxypregnenolone↗

PubMed1979

Interrelationships of circulating maternal steroid concentrations in third trimester pregnancies. II. C18 and C19 steroids: estradiol, estriol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, delta 5-androstenediol, delta 4-androstenedione, testosterone, and dihydrotestosterone.

This report describes aggregate time trend effects of advancing gestational age on circulating maternal concentrations of 17beta-estradiol (E2), estriol (E3), dehydroepiandrosterone (D), dehydroepiandrosterone sulfate (D-S), delta 5-androstenediol (delta 5 diol), delta 4-androstenedione (delta 4 A), testosterone (T), and dihydrotestosterone (DHT) in a sequential series of 155 blood samples obtained from 19 normal pregnant women ranging from 26-40 weeks gestational age. Only E2, E3, and D-S show aggregate time trend effects. Log (E2) plots as a linear positive sloping curve from 26-40 weeks. Log (E3) plots as a positive sloping curve that is significantly steeper than log (E2) (P less than 0.05). Log (D-S) plots into a negative sloping curve which mirrors the pattern for log (E2) but cannot be statistically associated with log (E2) except for the opposite sign of their slopes, which are both significantly different from a zero slope (P less than 0.05). delta 4 A, T, DHT, delta 5 diol, and D show no aggregate time trends; however wide, comoving undulations for delta 4 A, T, DHT, and delta 5 diol between 26-28 and 38-40 weeks are confirmed in time by comparison of log mean plots and in magnitude by regressing the C19 steroids on one another. D shows virtually no association with the other C19 steroids. All C19 steroids, except for T, circulate at nonpregnant concentrations, implying that there is little placental secretion of these steroids into the maternal circulation.

Androgens↗