Mallinckrodt Chemical Works was a uranium processing facility during the Manhattan Project from 1942 to 1966. Thousands of workers were exposed to low-dose-rates of ionizing radiation from external ...and internal sources. This third follow-up of 2514 White male employees updates cancer and noncancer mortality potentially associated with radiation and silica dust.
Individual, annualized organ doses were estimated from film badge records (
monitored = 2514), occupational chest x-rays (
= 2514), uranium urinalysis (
= 1868), radium intake through radon breath measurements (
= 487), and radon ambient measurements (
= 1356). Silica dust exposure from pitchblende processing was estimated (
= 1317). Vital status and cause of death determination through 2019 relied upon the National Death Index and Social Security Administration Epidemiological Vital Status Service. The analysis included standardized mortality ratios (SMRs), Cox proportional hazards, and Poisson regression models.
Vital status was confirmed for 99.4% of workers (84.0% deceased). For a dose weighting factor of 1 for intakes of uranium, radium, and radon decay products, the mean and median lung doses were 65.6 and 29.9 mGy, respectively. SMRs indicated a difference in health outcomes between salaried and hourly workers, and more brain cancer deaths than expected SMR: 1.79; 95% confidence interval (CI): 1.14, 2.70. No association was seen between radiation and lung cancer hazard ratio (HR) at 100 mGy: 0.93; 95%CI: 0.78, 1.11. The relationship between radiation and kidney cancer observed in the previous follow-up was maintained (HR at 100 mGy: 2.07; 95%CI: 1.12, 3.79). Cardiovascular disease (CVD) also increased significantly with heart dose (HR at 100 mGy: 1.11; 95%CI: 1.02, 1.21). Exposures to dust ≥23.6 mg/m
-year were associated with nonmalignant kidney disease (NMKD) (HR: 3.02; 95%CI: 1.12, 8.16) and kidney cancer combined with NMKD (HR: 2.46; 95%CI: 1.04, 5.81), though without evidence of a dose-response per 100 mg/m
-year.
This third follow-up of Mallinckrodt uranium processors reinforced the results of the previous studies. There was an excess of brain cancers compared with the US population, although no radiation dose-response was detected. The association between radiation and kidney cancer remained, though potentially due to few cases at higher doses. The association between levels of silica dust ≥23.6 mg/m
-year and NMKD also remained. No association was observed between radiation and lung cancer. A positive dose-response was observed between radiation and CVD; however, this association may be confounded by smoking, which was unmeasured. Future work will pool these data with other uranium processing worker cohorts within the Million Person Study.
Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a ...fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.
Esculetin (6,7-dihydroxy coumarin), is a potent antioxidant that is present in several plant species. The aim of this study was to investigate the mechanism of protection of esculetin in human ...hepatoma HepG2 cells against reactive oxygen species (ROS) induced by hydrogen peroxide. Cell viability, cell integrity, intracellular glutathione levels, generation of reactive oxygen species and expression of antioxidant enzymes were used as markers to measure cellular oxidative stress and response to ROS. The protective effect of esculetin was compared to a well-characterized chemoprotective compound quercetin. Pre-treatment of HepG2 cells with sub-lethal (10–25
μM) esculetin for 8
h prevented cell death and maintained cell integrity following exposure to 0.9
mM hydrogen peroxide. An increase in the generation of ROS following hydrogen peroxide treatment was significantly attenuated by 8
h pre-treatment with esculetin. In addition, esculetin ameliorated the decrease in intracellular glutathione caused by hydrogen peroxide exposure. Moreover, treatment with 25 μM esculetin for 8
h increased the expression of NAD(P)H: quinone oxidoreductase (NQO1) at both protein and mRNA levels significantly, by 12-fold and 15-fold, respectively. Esculetin treatment also increased nuclear accumulation of Nrf2 by 8-fold indicating that increased NQO1 expression is Nrf2-mediated. These results indicate that esculetin protects human hepatoma HepG2 cells from hydrogen peroxide induced oxidative injury and that this protection is provided through the induction of protective enzymes as part of an adaptive response mediated by Nrf2 nuclear accumulation.
Virtual collaborative models are a practical way to implement a supportive environment for multi-team learning. In this project, we aimed to describe the processes and outcomes of a virtual ...deprescribing collaborative that facilitated implementation of deprescribing interventions around the country.
Two successive cohorts comprised of multidisciplinary teams from geographically diverse veterans affairs (VA) sites were selected via an application process to participate in a virtual deprescribing collaborative. Each site developed its own deprescribing protocol and took part in regular meetings, mentoring groups, monthly data reporting, and other learning activities over an approximate 9 month period, per cohort. Standard measures were number of veterans served and medications deprescribed. Descriptive and qualitative analyses were utilized.
Twenty-one total VA sites were selected to participate in the deprescribing collaborative in two cohorts (Cohort 1, n = 12 sites; Cohort 2, n = 9 sites). The majority of sites' practice areas directly served the older adult population, and the majority of site leads were pharmacists. The most utilized tool used by the collaborative sites was the VA VIONE decision support tool (n = 14) and the most common strategy was individualized medication review. Combining outcomes from both Cohorts 1 and 2, a total of n = 4770 veterans were served, with 8332 medications deprescribed. Eighty-two percent of Cohort 1 sites surveyed reported their deprescribing program was still being utilized after 1 year follow up.
This virtual deprescribing collaborative aided in the successful implementation of both established and novel deprescribing practices across a variety of VA practice sites that care for older adults. The shared learning experience enhanced problem solving and allowed for interdisciplinary teamwork. Overall the collaborative was successful in improving polypharmacy for several thousand older adults.
The purpose of this paper is to present an overview of ongoing work on the Million Worker Study (MWS), highlighting some of the key methods and progress so far as exemplified by the study of workers ...at the Mallinckrodt Chemical Works (MCW). The MWS began nearly 25 y ago and continues in a stepwise fashion, evaluating one study cohort at a time. It includes workers from U.S. Department of Energy (DOE) Manhattan Project facilities, U.S. Nuclear Regulatory Commission (NRC) regulated nuclear power plants, industrial radiographers, U.S. Department of Defense (DoD) nuclear weapons test participants, and physicians and technologists working with medical radiation. The purpose is to fill the major gap in radiation protection and science: What is the risk when exposure is received gradually over time rather than briefly as for the atomic bomb survivors? Studies published or planned in 2018 include leukemia (and dosimetry) among atomic veterans, leukemia among nuclear power plant workers, mortality among workers at the MCW, and a comprehensive National Council on Radiation Protection and Measurements (NCRP) Report on dosimetry for the MWS. MCW has a singular place in history: the 40 tons (T) of uranium oxide produced at MCW were used by Enrico Fermi on 2 December 1942 to produce the first manmade sustained and controlled nuclear reaction, and the atomic age was born. Seventy-six years later, the authors followed the over 2,500 MCW workers for mortality and reconstructed dose from six sources of exposure: external gamma rays from the radioactive elements in pitchblende; medical x rays from occupationally required chest examinations; intakes of pitchblende (uranium, radium, and silica) measured by urine samples; radon breath analyses and dust surveys overseen by Robley Evans and Merril Eisenbud; occupational exposures received before and after employment at MCW; and cumulative radon concentrations and lung dose from the decay of radium in the work environment. The unique exposure reconstructions allow for multiple evaluations, including estimates of silica dust. The study results are relevant today. For example, NASA is interested that radium, deposited in the brain, releases high-LET alpha particles - the only human analogue, though limited, for high energy, high-Z particles (galactic cosmic rays) traveling through space that might affect astronauts on Mars missions. Don't discount the past; it's the prologue to the future!
Background:
Deep brain stimulation is a highly effective treatment of dystonia but is invasive and associated with risks, such as intraoperative bleeding and infections. Previous research has used ...non-invasive brain stimulation (NIBS) in an attempt to alleviate symptoms of dystonia. The results of these studies, however, have been variable, leaving efficacy unclear.
Objectives:
This study aimed to evaluate the effects of NIBS on symptoms of dystonia and determine whether methodological characteristics are associated with variability in effect size.
Methods:
Web of Science, Embase, and MEDLINE Complete databases were searched for articles using any type of NIBS as an intervention in dystonia patients, with changes in dystonia symptoms the primary outcome of interest.
Results:
Meta-analysis of 27 studies demonstrated a small effect size for NIBS in reducing symptoms of dystonia (random-effects Hedges’ g = 0.21, p = .002). Differences in the type of NIBS, type of dystonia, and brain region stimulated had a significant effect on dystonia symptoms. Meta-regression revealed that 10 sessions of active stimulation and the application of concurrent motor training programs resulted in significantly larger mean effect sizes.
Conclusion:
NIBS has yielded small improvements to dystonic symptoms, but effect sizes depended on methodological characteristics, with more sessions of stimulation producing a larger response. Future research should further investigate the application of NIBS parallel to motor training, in addition to providing a greater quantity of sessions, to help define optimal parameters for NIBS protocols in dystonia.
Registration:
PROSPERO 2020, CRD42020175944.
There are few occupational studies of women exposed to ionizing radiation. During World War II, the Tennessee Eastman Corporation (TEC) operated an electromagnetic field separation facility of 1152 ...calutrons to obtain enriched uranium (
235
U) used for the Hiroshima atomic bomb. Thousands of women were involved in these operations.
A new study was conducted of 13,951 women and 12,699 men employed at TEC between 1943 and 1947 for at least 90 days. Comprehensive dose reconstruction techniques were used to estimate lung doses from the inhalation of uranium dust based on airborne measurements. Vital status through 2018/2019 was obtained from the National Death Index, Social Security Death Index, Tennessee death records and online public record databases. Analyses included standardized mortality ratios (SMRs) and Cox proportional hazards models.
Most workers were hourly (77.7%), white (95.6%), born before 1920 (58.3%), worked in dusty environments (57.0%), and had died (94.9%). Vital status was confirmed for 97.4% of the workers. Women were younger than men when first employed: mean ages 25.0 years and 33.0 years, respectively. The estimated mean absorbed dose to the lung was 32.7 mGy (max 1048 mGy) for women and 18.9 mGy (max 501 mGy) for men. The mean dose to thoracic lymph nodes (TLNs) was 127 mGy. Statistically significant SMRs were observed for lung cancer (SMR 1.25; 95% CI 1.19, 1.31; n = 1654), nonmalignant respiratory diseases (NMRDs) (1.23; 95% CI 1.19, 1.28; n = 2585), and cerebrovascular disease (CeVD) (1.13; 95% CI 1.08, 1.18; n = 1945). For lung cancer, the excess relative rate (ERR) at 100 mGy (95% CI) was 0.01 (-0.10, 0.12; n = 652) among women, and −0.15 (-0.38, 0.07; n = 1002) among men based on a preferred model for men with lung doses <300 mGy. NMRD and non-Hodgkin lymphoma were not associated with estimated absorbed dose to the lung or TLN.
There was little evidence that radiation increased the risk of lung cancer, suggesting that inhalation of uranium dust and the associated high-LET alpha particle exposure to lung tissue experienced over a few years is less effective in causing lung cancer than other types of exposures. There was no statistically significant difference in the lung cancer risk estimates between men and women. The elevation of certain causes of death such as CeVD is unexplained and will require additional scrutiny of workplace or lifestyle factors given that radiation is an unlikely contributor since only the lung and lymph nodes received appreciable dose.
OBJECTIVE:A review of studies of occupational titanium dioxide (TiO2) exposure was conducted, and results from the three industry-based cohort mortality studies were summarized using meta-analysis.
...METHODS:Summary standardized mortality ratios (SSMR) and summary Cox regression coefficients from exposure–response models were derived using random effects models.
RESULTS:Results from studies of 24,312 TiO2 production workers were combined. SSMRs for lung cancer, all causes, all cancer, and non-malignant respiratory disease were 1.10 (95% confidence interval CI0.91 to 1.32), 0.85 (95% CI0.81 to 0.89), 0.92 (95% CI0.82 to 1.03), and 0.85 (95% CI0.71 to 1.02), respectively. For lung cancer, the summary hazard ratio for a 1 mg/m year increase in cumulative exposure was 0.999 (0.997 to 1.002).
CONCLUSIONS:Consistent with other published qualitative reviews, there is no clear evidence of an association between occupational exposure to TiO2 and lung cancer.
Pooling of individual-level data for workers involved in uranium refining and processing (excluding enrichment) may provide valuable insights into risks from occupational uranium and external ...ionizing radiation exposures.
Data were pooled for workers from four uranium processing facilities (Fernald, Mallinckrodt and Middlesex from the U.S.; and Port Hope, Canada). Employment began as early as the 1930s and follow-up was as late as 2017. Workers were exposed to high concentrations of uranium, radium, and their decay products, as well as gamma radiation and ambient radon decay products. Exposure and outcome data were harmonized using similar definitions and dose reconstruction methods. Standardized mortality ratios (SMR) were estimated.
In total, 560 deaths from lung cancer, 503 non-malignant respiratory diseases, 67 renal diseases, 1,596 ischemic heart diseases, and 101 dementia and Alzheimer's disease (AD) were detected in the pooled cohort of over 12,400 workers (∼1,300 females). Mean cumulative doses were 45 millisievert for whole-body external ionizing radiation exposure and 172 milligray for lung dose from radon decay products. Only SMR for dementia and AD among males was statistically significant (SMR=1.29; 95% confidence interval: 1.04, 1.54).
This is the largest study to date to examine long-term health risks of uranium processing workers.
Updated analyses of mortality data are presented on 46,970 workers employed 1948–1999 at Rocketdyne (Atomics International). Overall, 5,801 workers were involved in radiation activities, including ...2,232 who were monitored for intakes of radionuclides, and 41,169 workers were engaged in rocket testing or other non-radiation activities. The worker population is unique in that lifetime occupational doses from all places of employment were sought, updated and incorporated into the analyses. Further, radiation doses from intakes of 14 different radionuclides were calculated for 16 organs or tissues using biokinetic models of the International Commission on Radiation Protection (ICRP). Because only negligible exposures were received by the 247 workers monitored for radiation activities after 1999, the mean dose from external radiation remained essentially the same at 13.5 mSv (maximum 1 Sv) as reported previously, as did the mean lung dose from external and internal radiation combined at 19.0 mSv (maximum 3.6 Sv). An additional 9 years of follow-up, from December 31,1999 through 2008, increased the person-years of observation for the radiation workers by 21.7% to 196,674 (mean 33.9 years) and the number of cancer deaths by 50% to 684. Analyses included external comparisons with the general population and the computation of standardized mortality ratios (SMRs) and internal comparisons using proportional hazards models and the computation of relative risks (RRs). A low SMR for all causes of death (SMR 0.82; 95% CI 0.78–0.85) continued to indicate that the Rocketdyne radiation workers were healthier than the general population and were less likely to die. The SMRs for all cancers taken together (SMR 0.88; 95% CI 0.81–0.95), lung cancer (SMR 0.87; 95% CI 0.76–1.00) and leukemia other than chronic lymphocytic leukemia (CLL) (SMR 1.04; 95% 0.67–1.53) were not significantly elevated. Cox regression analyses revealed no significant dose–response trends for any cancer. For all cancers excluding leukemia, the RR at 100 mSv was estimated as 0.98 (95% CI 0.82–1.17), and for all leukemia other than CLL it was 1.06 (95% CI 0.50–2.23). Uranium was the primary radionuclide contributing to internal exposures, but no significant increases in lung and kidney disease were seen. The extended follow-up reinforces the findings in the previous study in failing to observe a detectable increase in cancer deaths associated with radiation, but strong conclusions still cannot be drawn because of small numbers and relatively low career doses. Larger combined studies of early workers in the United States using similar methodologies are warranted to refine and clarify radiation risks after protracted exposures.
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