New models for evaluation of radiation-induced lifetime cancer risk and its uncertainty employed in the UNSCEAR 2006 report.

Generalized relative and absolute risk models are fitted to the latest Japanese atomic bomb survivor solid cancer and leukemia mortality data (through 2000), with the latest (DS02) dosimetry, by classical (regression calibration) and Bayesian techniques, taking account of errors in dose estimates and other uncertainties. Linear-quadratic and linear-quadratic-exponential models are fitted and used to assess risks for contemporary populations of China, Japan, Puerto Rico, the U.S. and the UK. Many of these models are the same as or very similar to models used in the UNSCEAR 2006 report. For a test dose of 0.1 Sv, the solid cancer mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 5.4% Sv(-1) [90% Bayesian credible interval (BCI) 3.1, 8.0]. At 0.1 Sv, leukemia mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 0.50% Sv(-1) (90% BCI 0.11, 0.97). Risk estimates varied little between populations; at 0.1 Sv the central estimates ranged from 3.7 to 5.4% Sv(-1) for solid cancers and from 0.4 to 0.6% Sv(-1) for leukemia. Analyses using regression calibration techniques yield central estimates of risk very similar to those for the Bayesian approach. The central estimates of population risk were similar for the generalized absolute risk model and the relative risk model. Linear-quadratic-exponential models predict lower risks (at least at low test doses) and appear to fit as well, although for other (theoretical) reasons we favor the simpler linear-quadratic models.

Meta-analysis of standardized incidence and mortality rates of childhood leukaemia in proximity to nuclear facilities.

The meta-analysis combined and statistically analysed studies of childhood leukaemia and nuclear facilities. Focus was on studies that calculated standardized rates for individual facilities. Due to variability between study designs, eight separate analyses were performed stratified by age and zone. One hundred and thirty-six sites were used in at least one analysis. Unadjusted, fixed effects and random effects models were used. Meta-rates greater than one were found in all models at all stratification levels often achieving statistical significance. Caution must be used when interpreting these results. The meta-analysis was able to show an increase in childhood leukaemia near nuclear facilities, but does not support a hypothesis to explain the excess. Each type of model utilized has limitations. Fixed effects models give greater weight to larger studies; however, population density may be a risk factor. Random effects models give greater weight to smaller studies that may be more likely to be affected by publication bias. A limitation of the overall study design is that standardized rates must be available for individual sites which led to exclusion of studies that only calculated rates for multiple sites and those that presented other statistical methods. Further, dose-response studies do not support excess rates found near nuclear facilities. However, it cannot be ignored that the majority of studies have found elevated rates, although not usually statistically significant.

Residential mobility and risk of childhood acute lymphoblastic leukaemia: an ecological study.

We conducted an ecological analysis of childhood acute lymphoblastic leukaemia-incidence data from children or=$5000 as potential predictors. Incidence was lower among black boys (rate ratio (RR)=0.5) and black girls (RR=0.4) than among other children of the same sex; no other significant racial differences were detected. Incidence was elevated among males (but not females) residing in counties where >or=50% of the population relocated (RR=1.5) and among females (but not males) residing in counties where <6% of the households had incomes <$5000 (RR=1.5). These sex differences in risk factors were unexpected.

Relative toxicity of chronic irradiation by 45Ca beta particles and 242Cm alpha particles with respect to the production of lung tumors in CBA/Ca mice.

Approximately 1800 female CBA/Ca mice were exposed by inhalation at three dose levels to beta particles from (45)Ca-labeled fused aluminosilicate particles (FAP), to alpha particles from (242)Cm-labeled FAP, or to carrier control FAP. Another group of mice inhaled no FAP and were designated as untreated cage controls. The FAP in combination with these radionuclides was used to achieve the same spatial and temporal distribution of alpha- and beta-particle dose within the irradiated mice. Some mice were killed to determine the clearance of radiolabeled FAP from their lungs, and the remainder were allocated to a life-span study. All animals were subjected to a detailed necropsy. To facilitate the identification of small tumors, the lungs were rendered transparent in methyl salicylate and examined under back illumination for the presence of lesions. Lung nodules and other microscopic lesions were excised for histological examination. The median survival of mice in all groups was approximately 910 days. The control animals lived longer than those that were irradiated, but it was difficult to determine a dose-response relationship for survival among the exposed mice. Benign adenomas and, less frequently, malignant adenocarcinomas were identified in all animal groups. The prevalence of these tumors was approximately 28.8% in the control mice, which is consistent with the results of other studies using the same strain of mouse. After exposure to radionuclide-labeled FAP, there was a significant dose-related increase in the prevalence of lung tumors in (242)Cm- (peak prevalence 55%) and (45)Ca-exposed (peak prevalence 48.6%) mice. The prevalence of tumors in the mice that received (242)Cm-labeled FAP was approximately twice that in the mice that inhaled (45)Ca-labeled FAP within the range of doses employed (0.55-4.69 Gy). Using the ratio of the slope of the linear component of the dose-response curves, the toxicity of the alpha particles relative to the beta particles was 1.5 (90% CI: 0.7, 9.0) for all adenomas and 9.4 (90% CI: 5.0, 23.0) for the less frequent adenocarcinomas. The relative toxicity for adenocarcinomas was found to decrease with increasing dose.

Residential radon exposure and lung cancer risk: commentary on Cohen's county-based study.

The large United States county-based study () in which an inverse relationship has been suggested between residential low-dose radon levels and lung cancer mortality has been reviewed. While this study has been used to evaluate the validity of the linear nonthreshold theory, the grouped nature of its data limits the usefulness of this application. Our assessment of the study's approach, including a reanalysis of its data, also indicates that the likelihood of strong, undetected confounding effects by cigarette smoking, coupled with approximations of data values and uncertainties in accuracy of data sources regarding levels of radon exposure and intensity of smoking, compromises the study's analytic power. The most clear data for estimating lung cancer risk from low levels of radon exposure continue to rest with higher-dose studies of miner populations in which projections to zero dose are consistent with estimates arising from most case-control studies regarding residential exposure.

Stable chromosome aberrations and ionizing radiation in airline pilots.

INTRODUCTION: The purpose of this study was to determine the frequency of translocations and insertions in the blood of long-term pilots in relation to estimated cumulative radiation dose received while flying, and to compare that to the frequency in a group of similarly aged men without a history of frequent airline travel. METHODS: Healthy, non-smoking male pilots aged 40-60 yr were recruited from a single airline. Non-pilot controls were recruited from healthy, non-smoking professional males in the same age range and without a history of frequent flying. Eligibility was determined based on screening surveys. Career pilot radiation doses were calculated individually using airline flight profiles, personal flight history, and the CARI computer program. Translocation frequency was determined using fluorescence in situ hybridization. RESULTS: Blood samples for chromosome analysis were provided by 19 individuals. The mean number of metaphases counted per subject was 2802 in the pilots and 3000 in the controls. The mean number of translocations per cell (genome equivalent) was significantly higher among the pilots (mean +/- SE; 0.0031 +/- 0.0008) than among the controls (0.0010 +/- 0.0003) (p = 0.03, Mann-Whitney U test). However, within the 26 to 72 millisievert range encountered in this study, observed values among the pilots did not follow the dose-response pattern expected based on available models for chronic low dose radiation exposure. CONCLUSIONS: There was a statistically significant higher number of translocations per cell among pilots than among controls, although the expected dose-response relationship for radiation was not observed among the pilots.

Breast dose variability in a bi-racial population undergoing screening mammography.

This study evaluated individual and population dose variability during screening mammography, among 570 white and black women in South Carolina, USA. Aspects of dosimetry that were considered include compressed breast thickness (CBT), number of films per screening session, and dose in previous or subsequent sessions. Breast dose was log-normally distributed in the population, with a geometric mean of 6.6 mGy per session. Doses were significantly higher for black women, for women with high CBT or who receive more than two views per breast, and for the mediolateral oblique, compared to the craniocaudal, view. No relationship was observed between age and dose. Total dose per breast varied by a factor of 20 across the study population, but the individual's dose varied little among repeat screening sessions, especially after adjusting for the number of films received per session. These results may inform assessments of the projected risks of inducing breast cancer from screening mammography.

Mammography dose in relation to body mass index, race, and menopausal status.

Mammography dose increases with compressed breast thickness (CBT), but few studies have examined other correlates of dose. The purpose of this study was to evaluate the relation between factors such as race, age, body mass index (BMI), CBT, and menopausal status and mammography screening dose, measured for 509 women in a US population. A multiple linear regression model was developed for dose, based on consideration of these factors as well as examination characteristics. BMI and number of films during examination were positively related to dose. After adjusting for these factors, high CBT also leads to higher dose. Whites receive lower doses than black women but differences are slight after controlling for the effects of CBT and BMI, which were significantly higher among black women. Pre-menopausal women receive higher doses, after adjusting for all other factors, than post-menopausal women. Jointly, these factors account for approximately 75% to 80% of the variability in dose among this study population. Because rates of overweight are increasing in the US, average doses from mammography may be increasing as well.

Health among commercial airline pilots.

BACKGROUND: The airline pilot works within a complex exposure environment that may present physiological challenges to long-term health. METHODS: This study investigated self-reported disease outcomes among a large group of active and retired commercial airline pilots in the United States and Canada. A survey methodology was used, including the collection of historical information. RESULTS: Of 10,678 surveys mailed, 6609 were returned (6533 men, 63 women). Given the limitations of survey methodology, increased disease rates among pilots were suggested for melanoma, motor neuron disease, and cataracts. However, rates for other diseases were in general lower than those for the U.S. population. CONCLUSIONS: Further study has been initiated to verify and follow reported cases, to expand the study to a larger group, and to collect more in-depth information on flight histories, occupational exposures, and lifestyle factors.

Biologically-based risk estimation for radiation-induced chronic myeloid leukemia.

Radiation cancer risks are typically determined by the use of simple statistical descriptions of epidemiological data. It is important in risk assessment in general, however, to attempt to incorporate as much biological information into the risk models as possible. We illustrate this by presenting a biologically-based linear-quadratic-exponential (LQE) incidence rate model for radiation-induced chronic myeloid leukemia (CML). The model consists of a linear-quadratic dose-response for the induction of BCR-ABL, a waiting time distribution between BCR-ABL formation and detection of CML, and an exponential cell-killing term that multiplies both the background and induced incidence rates. Using data exclusive of the A-bomb survivor cohort, Bayesian priors are defined for each of the nine parameters in this LQE model. The priors are based on chromosomal translocations in lymphocytes, hematopoietic stem cell survival experiments, CML waiting times in women irradiated for benign disease, the background CML incidence rate in the U.S. population, and genomic DNA target sizes of BCR and ABL. Fixing three of the LQE model parameters to the means of their priors, maximum likelihood estimates of the remaining six parameters were obtained using A-bomb survivor incidence data for Hiroshima males. The likelihood estimates and the corresponding six prior distributions, both approximated as multivariate normal, were then used to form Bayesian posteriors for the six parameters not fixed. With these posteriors the LQE model yields Qgamma*=0.0042 Gy(-1) where Qgamma* is the upper 95% confidence bound of the lifetime CML risk per person-gray in the limit of low doses of gamma-rays. This value is slightly less than Qgamma*=0.0049 Gy(-1) obtained from likelihood estimates of the LQE parameters, and substantially less than Qgamma*=0.0158 Gy(-1) obtained for a simple statistical model linear in dose for kermas less than 4 Gy.

Flight deck magnetic fields in commercial aircraft.

BACKGROUND: Airline pilots are exposed to magnetic fields generated by the aircraft's electrical system. The objectives of this study were (1) to directly measure flight deck magnetic fields in terms of personal exposure to the pilots when flying on different aircraft types over a 75-hour flight-duty month, and (2) to compare magnetic field exposures across flight deck types and job titles. METHODS: Measurements were taken using personal dosimeters carried by either the Captain or the First Officer on Boeing 737/200, Boeing 747/400, Boeing 767/300ER, and Airbus 320 aircraft. RESULTS: Approximately 1,008 block hours were recorded at a sampling frequency of 3 seconds. Total block time exposure to the pilots ranged from a harmonic geometric mean of 6.7 milliGauss (mG) for the Boeing 767/300ER to 12.7 mG for the Boeing 737/200. CONCLUSIONS: Measured flight deck magnetic field levels were substantially above the 0.8-1 mG level typically found in the home or office and suggest the need for further study to evaluate potential health effects of long-term exposure.

Unexplained increases in cancer incidence in the United States from 1975 to 1994: possible sentinel health indicators?

To search for unexplained patterns in cancer incidence, we analyzed data from 1975 to 1994 that represent approximately 10% of the population of the United States. Our analysis focused on long-term time trends in incidence and on deviations from those trends attributable to birth cohorts or to calendar periods. On average, cancer incidence rose 0.8% annually in white women and 1.8% in white men. After removing several cancers related to smoking and increased screening, average annual increases fell to 0.1% in white women but persisted at 1.7% in white men. In particular, yearly increases in non-Hodgkin's lymphoma averaged 2.4% in white women and 4.7% in white men. Among men, incidence changes attributable to cohorts grew progressively larger from one cohort to the next. Cancer incidence patterns among black men and women were similar to those among whites despite smaller population sizes. Unexplained patterns of cancer incidence may signal changes in underlying risk factors and highlight the continuing need for research on cancer etiology and prevention.

Modeling the low-LET dose-response of BCR-ABL formation: predicting stem cell numbers from A-bomb data.

Formation of the BCR-ABL chromosomal translocation t(9;22)(q34;q11) is essential to the genesis of chronic myeloid leukemia (CML). An interest in the dose-response of radiation induced CML therefore leads naturally to an interest in the dose-response of BCR-ABL formation. To predict the BCR-ABL dose-response to low-linear energy transfer (LET) ionizing radiation, three models valid over three different dose ranges are examined: the first for doses greater than 80 Gy, the second for doses less than 5 Gy and the third for doses greater than 2 Gy. The first of the models, due to Holley and Chatterjee, ignores the accidental binary eurejoining of DNA double-strand break (DSB) free ends ('eurejoining' refers to the accidental restitution of DSB free ends with their own proper mates). As a result, the model is valid only in the limit of high doses. The second model is derived directly from cytogenetic data. This model has the attractive feature that it implicitly accounts for single-track effects at low doses. The third model, based on the Sax-Markov binary eurejoining/misrejoining (SMBE) algorithm, does not account for single-track effects and is therefore limited to moderate doses greater than approximately 2 Gy. Comparing the second model to lifetime excess CML risks expected after 1 Gy, estimates of the number of hematopoietic stem cells capable of causing CML were obtained for male and female atomic bomb survivors in Hiroshima and Nagasaki. The stem cell number estimates lie in the range of 5 x 10(7)-3 x 10(8) cells.

Cosmic radiation and magnetic field exposure to airline flight crews.

BACKGROUND: Flight crews are exposed to elevated levels of cosmic radiation and to magnetic fields generated by the aircraft's electrical system. The purpose of this study was to quantify these two occupational exposures. METHODS: Magnetic fields were measured during 37 flights (23 in the cockpit and 14 in the cabin) using an Emdex Lite personal dosimeter. All cockpit measurements were taken on the B737/200. Cabin measurements were taken in several aircraft types, including the B737, B757, DC9, and L1011. Cosmic radiation was computer estimated for 206 flights using the Federal Aviation Administration's program CARI-3C. RESULTS: Magnetic field levels in the cockpit had a mean value of approximately 17 milliGauss (mG), while cabin measurements were lower (mean values of approximately 3 or less in economy, 6 in first class, 8 in front serving areas). Cosmic radiation equivalent dose rates to bone marrow and skeletal tissue ranged from 0.3 to 5.7 microsieverts per hour. CONCLUSIONS: Elevated magnetic field levels in front serving areas and the cockpit suggest the need for further study to evaluate long-term exposure to flight crew members who work in these areas. Cosmic radiation levels are well below occupational limits for adults, but may require some pregnant flight crew members to adjust their flying time or routes.

Mortality among US commercial pilots and navigators.

The airline industry may be an occupational setting with specific health risks. Two environmental agents to which flight crews are known to be exposed are cosmic radiation and magnetic fields generated by the aircraft's electrical system. Other factors to be considered are circadian disruption and conditions specific to air travel, such as noise, vibration, mild hypoxia, reduced atmospheric pressure, low humidity, and air quality. This study investigated mortality among US commercial pilots and navigators, using proportional mortality ratios for cancer and noncancer end points. Proportional cancer mortality ratios and mortality odds ratios were also calculated for comparison to the proportional mortality ratios for cancer causes of death. Results indicated that US pilots and navigators have experienced significantly increased mortality due to cancer of the kidney and renal pelvis, motor neuron disease, and external causes. In addition, increased mortality due to prostate cancer, brain cancer, colon cancer, and cancer of the lip, buccal cavity, and pharynx was suggested. Mortality was significantly decreased for 11 causes. To determine if these health outcomes are related to occupational exposures, it will be necessary to quantify each exposure separately, to study the potential synergy of effects, and to couple this information with disease data on an individual basis.

Threshold models in radiation carcinogenesis.

Cancer incidence and mortality data from the atomic bomb survivors cohort has been analyzed to allow for the possibility of a threshold dose response. The same dose-response models as used in the original papers were fit to the data. The estimated cancer incidence from the fitted models over-predicted the observed cancer incidence in the lowest exposure group. This is consistent with a threshold or non-linear dose-response at low-doses. Thresholds were added to the dose-response models and the range of possible thresholds is shown for both solid tumor cancers as well as the different leukemia types. This analysis suggests that the A-bomb cancer incidence data agree more with a threshold or non-linear dose-response model than a purely linear model although the linear model is statistically equivalent. This observation is not found with the mortality data. For both the incidence data and the mortality data the addition of a threshold term significantly improves the fit to the linear or linear-quadratic dose response for both total leukemias and also for the leukemia subtypes of ALL, AML, and CML.

Size distributions of misrejoining DNA fragments in irradiated cells.

When ionizing radiation strikes a cell it induces DNA double strand breaks (DSBs). Subsequently, some of the DSBs misrejoin and thus cause alterations in the size distribution of the DNA fragments. We derive a system of non-linear integro-differential equations describing the misrejoining interactions of five classes of DNA fragments, including rings and various types of linear fragments. The fragment classes are represented by density functions; the shape of a density function determines the probability that a fragment has a particular size and the amplitude (integral) equals the expected number of such fragments per cell. The equations are solved: analytically for exponentially distributed initial fragment sizes (corresponding to high doses) and numerically for arbitrary initial conditions. Computed final fragment size distributions are applied to situations representative of flow karyotypes and pulsed-field gel assays. For human flow karyotypes, the model can be used to obtain misrejoining estimates at doses too high for conventional methods of data analysis. For pulsed-field gel assays in which human chromosomes are digested with restriction endonucleases to form 'cut-somes' (restriction fragments), the model provides a means of misrejoining estimation when the cut-some sizes are non-random. The model suggests that if the cut-some size distribution for unirradiated cells is completely random, misrejoining of radiation-induced DSBs will not be detectable in the final size distribution.

Is occupational organic solvent exposure a risk factor for scleroderma?

OBJECTIVE: The primary objective was to determine whether occupational exposure to organic solvents is related to an increased risk of systemic sclerosis (SSc; scleroderma). METHODS: Occupational histories were obtained from 178 SSc patients and 200 controls. Exposure scores were computed for each individual using job exposure matrices, which were validated by an industrial expert. RESULTS: Among men, those with SSc were more likely than controls to have a high cumulative intensity score (odds ratio [OR] 2.9, 95% confidence interval [95% CI] 1.1-7.6) and a high maximum intensity score (OR 2.9, 95% CI 1.2-7.1) for any solvent exposure. They were also more likely than controls to have a high maximum intensity score for trichloroethylene exposure (OR 3.3, 95% CI 1.0-10.3). Among men and women, significant solvent-disease associations were observed among SSc patients who tested positive for the anti-Scl-70 autoantibody; these trends were not observed among the men and women who tested negative for anti-Scl-70. CONCLUSION: These results provide evidence that occupational solvent exposure may be associated with an increased risk of SSc.

Recent data obtained by pulsed-field gel electrophoresis suggest two types of double-strand breaks.

The temporal evolution of unrejoined and misrejoined DNA double-strand breaks (DSBs) produced by high doses (80-160 Gy) of X rays has been estimated using pulsed-field gel electrophoresis (PFGE) (Löbrich et al., Proc. Natl. Acad. Sci. USA 92, 12050-12054, 1995). We attempted to fit these data to three models. An RBM ("Revell binary misrejoining") model, based on the usual repair-misrepair and lethal-potentially lethal models, appears to be inconsistent with the data. The main discrepancies are the following: (1) The RBM model predicts that 90% of the misrejoined DSBs form by the time 75% of the DSBs have disappeared, while the data indicate that only 50% are formed by this time; and (2) the model predicts an increasing fraction of DSBs misrejoined at 160 Gy compared to 80 Gy, while the data support approximately equal fractions misrejoined. These discrepancies are alleviated in the Sax subset (SS) and Revell subset (RS) models. In the SS and RS models, two types (or subsets) of DSBs exist: those that are active in misrejoining and those that are not. In the SS model, active DSBs misrejoin by the breakage-and-reunion mechanism described by Sax; in the RS model, active DSBs either repair, or misrejoin according to the complete exchange misrejoining mechanism described by Revell. Both models are consistent with the data set considered.

Misrejoining of double-strand breaks after X irradiation: relating moderate to very high doses by a Markov model.

Misrejoining of double-strand breaks (DSBs) detected with pulsed-field gel electrophoresis (PFGE) after X irradiation of human cells at very high doses (80-160 Gy) is related to dose-response relationships for chromosome aberrations at moderate doses (1-5 Gy) by the Sax-Markov binary eurejoining/misrejoining (SMBE) model. The SMBE model applies Sax's breakage-and-reunion hypothesis to a subset of DSBs active in binary misrejoining and in binary eurejoining (accidental restitution). The model is numerically consistent with both data on chromosome aberrations and the data obtained by PFGE if proximity effects (restrictions on the range of interactions of DSB free ends) are present. Proximity effects are modeled by partitioning the cell's nucleus into approximately 400 interaction sites, with two active DSB free ends capable of rejoining only if they were produced within the same site. Neglecting one-track action, the SMBE model predicts a quadratic-linear dose-response relationship for DSB misrejoining after exposure to low-LET radiation; i.e., there is a quadratic response at moderate doses which becomes linear as the dose becomes large, rather than vice versa. The linear region results because at very high doses almost all of the active DSB free ends misrejoin rather than eurejoin.