Misclassification of causes of death among a small all-autopsied group of former nuclear workers: Death certificates vs. autopsy reports.

The U.S. Transuranium and Uranium Registries performs autopsies on each of its deceased Registrants as a part of its mission to follow up occupationally-exposed individuals. This provides a unique opportunity to explore death certificate misclassification errors, and the factors that influence them, among this small population of former nuclear workers. Underlying causes of death from death certificates and autopsy reports were coded using the 10th revision of the International Classification of Diseases (ICD-10). These codes were then used to quantify misclassification rates among 268 individuals for whom both full autopsy reports and death certificates with legible underlying causes of death were available. When underlying causes of death were compared between death certificates and autopsy reports, death certificates correctly identified the underlying cause of death's ICD-10 disease chapter in 74.6% of cases. The remaining 25.4% of misclassified cases resulted in over-classification rates that ranged from 1.2% for external causes of mortality to 12.2% for circulatory disease, and under-classification rates that ranged from 7.7% for external causes of mortality to 47.4% for respiratory disease. Neoplasms had generally lower misclassification rates with 4.3% over-classification and 13.3% under-classification. A logistic regression revealed that the odds of a match were 2.8 times higher when clinical history was mentioned on the autopsy report than when it was not. Similarly, the odds of a match were 3.4 times higher when death certificates were completed using autopsy findings than when autopsy findings were not used. This analysis excluded cases where it could not be determined if autopsy findings were used to complete death certificates. The findings of this study are useful to investigate the impact of death certificate misclassification errors on radiation risk estimates and, therefore, improve the reliability of epidemiological studies.

Plutonium in Manhattan Project workers: Using autopsy data to evaluate organ content and dose estimates based on urine bioassay with implications for radiation epidemiology.

PURPOSE: Radiation dose estimates in epidemiology typically rely on intake predictions based on urine bioassay measurements. The purpose of this article is to compare the conventional dosimetric estimates for radiation epidemiology with the estimates based on additional post-mortem tissue radiochemical analysis results. METHODS: The comparison was performed on a unique group of 11 former Manhattan Project nuclear workers, who worked with plutonium in the 1940s, and voluntarily donated their bodies to the United States Transuranium and Uranium Registries. RESULTS: Post-mortem organ activities were predicted using different sets of urine data and compared to measured activities. Use of urinalysis data collected during the exposure periods overestimated the systemic (liver+skeleton) deposition of 239Pu by 155±134%, while the average bias from using post-exposure urinalyses was -4±50%. Committed effective doses estimated using early urine data differed from the best estimate by, on average, 196±193%; inclusion of follow-up urine measurements in analyses decreased the mean bias to 0.6±36.3%. Cumulative absorbed doses for the liver, red marrow, bone surface, and brain were calculated for the actual commitment period. CONCLUSION: On average, post-exposure urine bioassay results were in good agreement with post-mortem tissue analyses and were more reliable than results of urine bioassays collected during the exposure.

A Monte Carlo t Test to Evaluate Mesothelioma and Radiation in the US Transuranium and Uranium Registries.

A cluster of nine mesothelioma cases was observed among 341 registrants' deaths in the US Transuranium and Uranium Registries. Descriptive analysis showed that mesothelioma cases had the highest average cumulative external radiation dose compared with lung cancer, other cancer, and noncancer deaths. Further analysis indicated that the mesothelioma cluster was very different demographically from lung cancer, other cancer, and noncancer deaths. Therefore, an internally matched case-control approach was applied to evaluate the differences in an average cumulative external radiation dose between mesothelioma deaths and other causes of death. A Monte Carlo t test was used to examine the statistical significance of the differences. The results showed that there were no significant statistical differences in an average cumulative external radiation dose between mesothelioma and lung cancer, other cancers, or noncancers for the internally matched cases and controls.

Validation of a system of models for plutonium decorporation therapy.

A recently proposed system of models for plutonium decorporation (SPD) was developed using data from an individual occupationally exposed to plutonium via a wound [from United States Transuranium and Uranium Registries (USTUR) Case 0212]. The present study evaluated the SPD using chelation treatment data, urine measurements, and post-mortem plutonium activities in the skeleton and liver from USTUR Case 0269. This individual was occupationally exposed to moderately soluble plutonium via inhalation and extensively treated with chelating agents. The SPD was linked to the International Commission on Radiological Protection (ICRP) Publication 66 Human Respiratory Tract Model (HRTM) and the ICRP Publication 30 Gastrointestinal Tract model to evaluate the goodness-of-fit to the urinary excretion data and the predictions of post-mortem plutonium retention in the skeleton and liver. The goodness-of-fit was also evaluated when the SPD was linked to the ICRP Publication 130 HRTM and the ICRP Publication 100 Human Alimentary Tract Model. The present study showed that the proposed SPD was useful for fitting the entire, chelation-affected and non-affected, urine bioassay data, and for predicting the post-mortem plutonium retention in the skeleton and liver at time of death, 38.5 years after the accident. The results of this work are consistent with the conclusion that Ca-EDTA is less effective than Ca-DTPA for enhancing urinary excretion of plutonium.

The Pseudo-Pelger huët Cell as a Retrospective Dosimeter: Analysis of a Radium Dial Painter Cohort.

Recently, the pseudo-Pelger Huët anomaly in peripheral blood neutrophils has been described as a new radiation-induced, stable biomarker. In this study, pseudo-Pelger Huët anomaly was examined in peripheral blood slides from a cohort of 166 former radium dial painters and ancillary personnel in the radium dial industry, 35 of whom had a marrow dose of zero above background. Members of the radium dial painter cohort ingested Ra and Ra at an early age (average age 20.6 ± 5.4 y; range 13-40 y) during the years 1914-1955. Exposure duration ranged from 1-1,820 wk with marrow dose 1.5-6,750 mGy. Pseudo-Pelger Huët anomaly expressed as a percentage of total neutrophils in this cohort rises in a sigmoidal fashion over five decades of red marrow dose. Six subjects in this cohort eventually developed malignancies: five osteosarcomas and one mastoid cell neoplasm. The pseudo-Pelger Huët anomaly percentage in these cases of neoplasm increases with marrow dose and is best fit with a sigmoid function, suggestive of a threshold effect. No sarcomas are seen for a marrow dose under 2 Gy. These results indicate that pseudo-Pelger Huët anomaly in peripheral blood is a reasonable surrogate for the estimation of alpha dose to bone marrow in historic radiation cases. Hypotheses are discussed to explain late (months to years), early (hours to days), and intermediate (weeks to months) effects of ionizing radiation, respectively, on the expression of genes encoding inner nuclear membrane proteins and their receptors, on the structure and function of nuclear membrane proteins and lipids, and on cytokinesis through chromatin bridge formation.

Ustur Case 0846: Modeling Americium Biokinetics after Intensive Decorporation Therapy.

Decorporation therapy with salts of diethylenetriamine-pentaacetic acid binds actinides, thereby limiting uptake to organs and enhancing the rate at which actinides are excreted in urine. International Commission on Radiological Protection reference biokinetic models cannot be used to fit this enhanced exertion simultaneously with the baseline actinide excretion rate that is observed prior to the start of therapy and/or after the effects of therapy have ceased. In this study, the Coordinated Network on Radiation Dosimetry approach, which was initially developed for modeling decorporation of plutonium, was applied to model decorporation of americium using data from a former radiation worker who agreed to donate his body to the US Transuranium and Uranium Registries for research. This individual was exposed to airborne Am, resulting in a total-body activity of 66.6 kBq. He was treated with calcium-diethylenetriamine-pentaacetic acid for 7 y. The time and duration of intakes are unknown as no incident reports are available. Modeling of different assumptions showed that an acute intake of 5-µm activity median aerodynamic diameter type M aerosols provides the most reasonable description of the available pretherapeutic data; however, the observed Am activity in the lungs at the time of death was higher than the one predicted for type M material. The Coordinated Network on Radiation Dosimetry approach for decorporation modeling was used to model the in vivo chelation process directly. It was found that the Coordinated Network on Radiation Dosimetry approach, which only considered chelation in blood and extracellular fluids, underestimated the urinary excretion of Am during diethylenetriamine-pentaacetic acid treatment; therefore, the approach was extended to include chelation in the liver. Both urinary excretion and whole-body retention could be described when it was assumed that 25% of chelation occurred in the liver, 75% occurred in the blood and ST0 compartment, and the chelation rate constant was 1 × 10 pmol d. It was observed that enhancement of urinary excretion of Am after injection of diethylenetriamine-pentaacetic acid exponentially decreased to the baseline level with an average half-time of 2.2 ± 0.7 d.

Improved Modeling of Plutonium-DTPA Decorporation.

Individuals with significant intakes of plutonium (Pu) are typically treated with chelating agents, such as the trisodium salt form of calcium diethylenetriaminepentaacetate (CaNa3-DTPA, referred to hereafter as Ca-DTPA). Currently, there is no recommended approach for simultaneously modeling plutonium biokinetics during and after chelation therapy. In this study, an improved modeling system for plutonium decorporation was developed. The system comprises three individual model structures describing, separately, the distinct biokinetic behaviors of systemic plutonium, intravenously injected Ca-DTPA and in vivo-formed Pu-DTPA chelate. The system was linked to ICRP Publication 100, "Human Alimentary Tract Model for Radiological Protection" and NCRP Report 156, Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedures for Their Assessment, Dosimetry and Treatment." Urine bioassay and chelation treatment data from an occupationally-exposed individual were used for model development. Chelation was assumed to occur in the blood, soft tissues, liver and skeleton. The coordinated network for radiation dosimetry approach to decorporation modeling was applied using a chelation constant describing the secondorder, time-dependent kinetics of the in vivo chelation reaction. When using the proposed system of models for plutonium decorporation, a significant improvement of the goodness-of-fit to the urinary excretion data was observed and more accurate predictions of postmortem plutonium retention in the skeleton, liver and wound site were achieved.

US Transuranium and Uranium Registries case study on accidental exposure to uranium hexafluoride.

The United States Transuranium and Uranium Registries' (USTUR) whole-body donor (Case 1031) was exposed to an acute inhalation of uranium hexafluoride (UF6) produced from an explosion at a uranium processing plant 65 years prior to his death. The USTUR measurements of tissue samples collected at the autopsy indicated long-term retention of inhaled slightly enriched uranium material (0.85% (235)U) in the deep lungs and thoracic lymph nodes. In the present study, the authors combined the tissue measurement results with historical bioassay data, and analysed them with International Commission on Radiological Protection (ICRP) respiratory tract models and the ICRP Publication 69 systemic model for uranium using maximum likelihood and Bayesian statistical methods. The purpose of the analysis was to estimate intakes and model parameter values that best describe the data, and evaluate their effect on dose assessment. The maximum likelihood analysis, which used the ICRP Publication 66 human respiratory tract model, resulted in a point estimate of 79 mg of uranium for the occupational intake composed of 86% soluble, type F material and 14% insoluble, type S material. For the Bayesian approach, the authors applied the Markov Chain Monte Carlo method, but this time used the revised human respiratory tract model, which is currently being used by ICRP to calculate new dose coefficients for workers. The Bayesian analysis estimated that the mean uranium intake was 160 mg, and calculated the case-specific lung dissolution parameters with their associated uncertainties. The parameters were consistent with the inhaled uranium material being predominantly soluble with a small but significant insoluble component. The 95% posterior range of the rapid dissolution fraction (the fraction of deposited material that is absorbed to blood rapidly) was 0.12 to 0.91 with a median of 0.37. The remaining fraction was absorbed slowly, with a 95% range of 0.000 22 d(-1) to 0.000 36 d(-1) and a median of 0.000 31 d(-1). The effective dose per unit intake calculated using the dissolution parameters derived from the maximum likelihood and the Bayesian analyses was higher than the current ICRP dose coefficient for type F uranium by a factor of 2 or 7, respectively; the higher value of the latter was due to use of the revised respiratory tract model. The dissolution parameter values obtained here may be more appropriate to use for radiation protection purposes when individuals are exposed to a UF6 mixture that contains an insoluble uranium component.

Carcinogenic and inflammatory effects of plutonium-nitrate retention in an exposed nuclear worker and beagle dogs.

PURPOSE: Plutonium-nitrate has a moderately rapid translocation rate from the lung to blood stream. Previous studies have shown an unexpected retention of soluble plutonium in the beagles and human case studied here. The inflammatory responses that may be associated with long-term exposure to ionizing radiation were characterized. These pathways include tissue injury, apoptosis, and gene expression modifications. Other protein modifications related to carcinogenesis and inflammation and the various factors that may play a role in orchestrating complex interactions which influence tissue integrity following irradiation were investigated. MATERIALS AND METHODS: We have examined numerous lung samples from a plutonium-exposed worker, a human control, and a variety of plutonium-exposed beagle dogs using immunohistochemistry and quantitative Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). RESULTS: The exposed human showed interstitial fibrosis in peripheral regions of the lung, but no pulmonary tumors. Beagles with similar doses were diagnosed with tumors in bronchiolo-alveolar, peripheral and sub-pleural alveolar regions of the lung. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed an elevation of apoptosis in tracheal mucosa, tumor cells, and nuclear debris in the alveoli and lymph nodes of the beagles but not in the human case. In both the beagles and human there were statistically significant modifications in the expression of Fas ligand (FASLG), B-cell lymphoma 2 (BCL2), and Caspase 3 (CASP3). CONCLUSIONS: The data suggests that FASLG, BCL2, CASP3 and apoptosis play a role in the inflammatory responses following prolonged plutonium exposure. Utilizing these unique tissues revealed which pathways are triggered following the internal deposition and long-term retention of plutonium-nitrate in a human and a large animal model.