USTUR Special Session Roundtable-US Transuranium and Uranium Registries (USTUR): A Five-decade Follow-up of Plutonium and Uranium Workers.

The US Transuranium and Uranium Registries is a human tissue program that collects tissues posthumously from former nuclear workers and radiochemically analyzes them for actinides such as plutonium, americium, and uranium. It was established in 1968 with the goal of advancing science and improving the safety of future workers. Roundtable participants recalled various aspects of this multidisciplinary research program, from establishing consistent autopsy protocols to comparing the registries' findings to those of other programs, such as the historical beagle dog studies and the Russian Radiobiological Human Tissue Repository. The importance of meeting ethical and legal requirements, including written consent forms, was emphasized, as was the need to know whether workers were exposed to nonradiological hazards such as beryllium or asbestos. At Rocky Flats, a bioassay program was established to follow workers after they terminated employment. The resulting data continue to help researchers to improve the biokinetic models that are used to estimate intakes and radiation doses. After 50 y, the US Transuranium and Uranium Registries continues to contribute to our understanding of actinides in humans, which is a testament to the vision of its founders, the generosity of its tissue donors, and the many dedicated scientists who have worked together to achieve a common goal.

Reanalysis of Diesel Engine Exhaust and Lung Cancer Mortality in the Diesel Exhaust in Miners Study Cohort Using Alternative Exposure Estimates and Radon Adjustment.

The Diesel Exhaust in Miners Study (DEMS) (United States, 1947-1997) reported positive associations between diesel engine exhaust exposure, estimated as respirable elemental carbon (REC), and lung cancer mortality. This reanalysis of the DEMS cohort used an alternative estimate of REC exposure incorporating historical data on diesel equipment, engine horsepower, ventilation rates, and declines in particulate matter emissions per horsepower. Associations with cumulative REC and average REC intensity using the alternative REC estimate and other exposure estimates were generally attenuated compared with original DEMS REC estimates. Most findings were statistically nonsignificant; control for radon exposure substantially weakened associations with the original and alternative REC estimates. No association with original or alternative REC estimates was detected among miners who worked exclusively underground. Positive associations were detected among limestone workers, whereas no association with REC or radon was found among workers in the other 7 mines. The differences in results based on alternative exposure estimates, control for radon, and stratification by worker location or mine type highlight areas of uncertainty in the DEMS data.

Long-term outcome of dasatinib first-line treatment in gastrointestinal stromal tumor: A multicenter, 2-stage phase 2 trial (Swiss Group for Clinical Cancer Research 56/07).

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction. METHODS: This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naïve, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response. RESULTS: Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached. CONCLUSIONS: Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54. © 2018 American Cancer Society.

Influence of Alternative Exposure Estimates in the Diesel Exhaust Miners Study: Diesel Exhaust and Lung Cancer.

The landmark Diesel Exhaust in Miners Study (DEMS) studied the relationship between diesel exhaust exposure (DEE) and lung cancer mortality of workers at eight nonmetal mines who were followed from beginning of dieselization of the mines (1947-1967) through December 31, 1997. The original analyses quantified DEE exposures using exposure to respirable elemental carbon (REC) to represent DEE, and CO as a surrogate for REC. However, this use of CO data, and the CO data themselves, have numerous shortcomings. We developed new estimates of REC exposures using historical data on use of diesel equipment, diesel engine horsepower (HP), mine ventilation rates, and the documented reduction in particulate matter emissions per HP in diesel engines from 1975 through 1995. These new REC estimates were applied in a conditional logistic regression of the DEMS nested case-control data very similar to the one applied in the original DEMS analyses. None of the trend slopes calculated using the new REC estimates were statistically significant (p > 0.05). Moreover, these trend slopes were smaller by roughly factors of five without control for radon exposure and factors of 12 with control for radon exposure compared to those estimated in the original DEMS analyses. Also, the 95% confidence intervals for these trend slopes had only minimal overlap with those for the slopes in the original DEMS analyses. These results underscore the uncertainty in estimates of the potency of diesel exhaust in causing lung cancer based on analysis of the DEMS data due to uncertainty in estimates of exposures to diesel exhaust.

Knee kinematics is altered post-fatigue while performing a crossover task.

PURPOSE: To examine the effect of a sequential fatigue protocol on lower extremity biomechanics during a crossover cutting task in female soccer players. METHODS: Eighteen female collegiate soccer players alternated between a fatigue protocol and two consecutive unanticipated crossover trials until fatigue was reached. Lower extremity biomechanics were evaluated during the crossover using a 3D motion capture system and two force plates. Repeated-measures ANOVAs analysed differences between three sequential stages of fatigue (pre, 50, 100%) for each dependent variable (α = 0.05). RESULTS: Knee flexion angles at initial contact (IC) for pre (-32 ± 9°) and 50% (-29 ± 11°) were significantly higher than at 100% fatigue (-22 ± 9°) (p < 0.001 and p = 0.015, respectively). Knee adduction angles at IC for pre (9 ± 5°) and 50% (8 ± 4°) were significantly higher (p = 0.006 and p = 0.049, respectively) than at 100% fatigue (6 ± 4°). CONCLUSIONS: Fatigue altered sagittal and frontal knee kinematics after 50% fatigue whereupon participants had diminished knee control at initial contact. Interventions should attempt to reduce the negative effects of fatigue on lower extremity biomechanics by promoting appropriate frontal plane alignment and increased knee flexion during fatigue status. LEVEL OF EVIDENCE: III.

Toxicity of lunar dust assessed in inhalation-exposed rats.

Humans will again set foot on the moon. The moon is covered by a layer of fine dust, which can pose a respiratory hazard. We investigated the pulmonary toxicity of lunar dust in rats exposed to 0, 2.1, 6.8, 20.8 and 60.6 mg/m(3) of respirable-size lunar dust for 4 weeks (6 h/day, 5 days/week); the aerosols in the nose-only exposure chambers were generated from a jet-mill ground preparation of a lunar soil collected during the Apollo 14 mission. After 4 weeks of exposure to air or lunar dust, groups of five rats were euthanized 1 day, 1 week, 4 weeks or 13 weeks after the last exposure for assessment of pulmonary toxicity. Biomarkers of toxicity assessed in bronchoalveolar fluids showed concentration-dependent changes; biomarkers that showed treatment effects were total cell and neutrophil counts, total protein concentrations and cellular enzymes (lactate dehydrogenase, glutamyl transferase and aspartate transaminase). No statistically significant differences in these biomarkers were detected between rats exposed to air and those exposed to the two low concentrations of lunar dust. Dose-dependent histopathology, including inflammation, septal thickening, fibrosis and granulomas, in the lung was observed at the two higher exposure concentrations. No lesions were detected in rats exposed to ≤6.8 mg/m(3). This 4-week exposure study in rats showed that 6.8 mg/m(3) was the highest no-observable-adverse-effect level (NOAEL). These results will be useful for assessing the health risk to humans of exposure to lunar dust, establishing human exposure limits and guiding the design of dust mitigation systems in lunar landers or habitats.

Health effects research and regulation of diesel exhaust: an historical overview focused on lung cancer risk.

The mutagenicity of organic solvent extracts from diesel exhaust particulate (DEP), first noted more than 55 years ago, initiated an avalanche of diesel exhaust (DE) health effects research that now totals more than 6000 published studies. Despite an extensive body of results, scientific debate continues regarding the nature of the lung cancer risk posed by inhalation of occupational and environmental DE, with much of the debate focused on DEP. Decades of scientific scrutiny and increasingly stringent regulation have resulted in major advances in diesel engine technologies. The changed particulate matter (PM) emissions in "New Technology Diesel Exhaust (NTDE)" from today's modern low-emission, advanced-technology on-road heavy-duty diesel engines now resemble the PM emissions in contemporary gasoline engine exhaust (GEE) and compressed natural gas engine exhaust more than those in the "traditional diesel exhaust" (TDE) characteristic of older diesel engines. Even with the continued publication of epidemiologic analyses of TDE-exposed populations, this database remains characterized by findings of small increased lung cancer risks and inconsistent evidence of exposure-response trends, both within occupational cohorts and across occupational groups considered to have markedly different exposures (e.g. truckers versus railroad shopworkers versus underground miners). The recently published National Institute for Occupational Safety and Health (NIOSH)-National Cancer Institute (NCI) epidemiologic studies of miners provide some of the strongest findings to date regarding a DE-lung cancer association, but some inconsistent exposure-response findings and possible effects of bias and exposure misclassification raise questions regarding their interpretation. Laboratory animal studies are negative for lung tumors in all species, except for rats under lifetime TDE-exposure conditions with durations and concentrations that lead to "lung overload." The species specificity of the rat lung response to overload, and its occurrence with other particle types, is now well-understood. It is thus generally accepted that the rat bioassay for inhaled particles under conditions of lung overload is not predictive of human lung cancer hazard. Overall, despite an abundance of epidemiologic and experimental data, there remain questions as to whether TDE exposure causes increased lung cancers in humans. An abundance of emissions characterization data, as well as preliminary toxicological data, support NTDE as being toxicologically distinct from TDE. Currently, neither epidemiologic data nor animal bioassay data yet exist that directly bear on NTDE carcinogenic potential. A chronic bioassay of NTDE currently in progress will provide data on whether NTDE poses a carcinogenic hazard, but based on the significant reductions in PM mass emissions and the major changes in PM composition, it has been hypothesized that NTDE has a low carcinogenic potential. When the International Agency for Research on Cancer (IARC) reevaluates DE (along with GEE and nitroarenes) in June 2012, it will be the first authoritative body to assess DE carcinogenic health hazards since the emergence of NTDE and the accumulation of data differentiating NTDE from TDE.

Evaluation of carcinogenic hazard of diesel engine exhaust needs to consider revolutionary changes in diesel technology.

Diesel engines, a special type of internal combustion engine, use heat of compression, rather than electric spark, to ignite hydrocarbon fuels injected into the combustion chamber. Diesel engines have high thermal efficiency and thus, high fuel efficiency. They are widely used in commerce prompting continuous improvement in diesel engines and fuels. Concern for health effects from exposure to diesel exhaust arose in the mid-1900s and stimulated development of emissions regulations and research to improve the technology and characterize potential health hazards. This included epidemiological, controlled human exposure, laboratory animal and mechanistic studies to evaluate potential hazards of whole diesel exhaust. The International Agency for Research on Cancer (1989) classified whole diesel exhaust as - "probably carcinogenic to humans". This classification stimulated even more stringent regulations for particulate matter that required further technological developments. These included improved engine control, improved fuel injection system, enhanced exhaust cooling, use of ultra low sulfur fuel, wall-flow high-efficiency exhaust particulate filters, exhaust catalysts, and crankcase ventilation filtration. The composition of New Technology Diesel Exhaust (NTDE) is qualitatively different and the concentrations of particulate constituents are more than 90% lower than for Traditional Diesel Exhaust (TDE). We recommend that future reviews of carcinogenic hazards of diesel exhaust evaluate NTDE separately from TDE.

Product stewardship and science: safe manufacture and use of fiber glass.

This paper describes a proactive product stewardship program for glass fibers. That effort included epidemiological studies of workers, establishment of stringent workplace exposure limits, liaison with customers on safe use of products and, most importantly, a research program to evaluate the safety of existing glass fiber products and guide development of new even safer products. Chronic inhalation exposure bioassays were conducted with rodents and hamsters. Amosite and crocidolite asbestos produced respiratory tract cancers as did exposure to "biopersistent" synthetic vitreous fibers. "less biopersistent" glass fibers did not cause respiratory tract cancers. Corollary studies demonstrated the role of slow fiber dissolution rates and biopersistence in cancer induction. These results guided development of safer glass fiber products and have been used in Europe to regulate fibers and by IARC and NTP in classifying fibers. IARC concluded special purpose fibers and refractory ceramic fibers are "possibly carcinogenic to humans" and insulation glass wool, continuous glass filament, rock wool and slag wool are "not classifiable as to their carcinogenicity to human." The NTP's 12th report on carcinogens lists "Certain Glass Wool Fibers (Inhalable)" as "reasonably anticipated to be a human carcinogen." "Certain" in the descriptor refers to "biopersistent" glass fibers and excludes "less biopersistent" glass fibers.

Particulate matter in new technology diesel exhaust (NTDE) is quantitatively and qualitatively very different from that found in traditional diesel exhaust (TDE).

Diesel exhaust (DE) characteristic of pre-1988 engines is classified as a "probable" human carcinogen (Group 2A) by the International Agency for Research on Cancer (IARC), and the U.S. Environmental Protection Agency has classified DE as "likely to be carcinogenic to humans." These classifications were based on the large body of health effect studies conducted on DE over the past 30 or so years. However, increasingly stringent U.S. emissions standards (1988-2010) for particulate matter (PM) and nitrogen oxides (NOx) in diesel exhaust have helped stimulate major technological advances in diesel engine technology and diesel fuel/lubricant composition, resulting in the emergence of what has been termed New Technology Diesel Exhaust, or NTDE. NTDE is defined as DE from post-2006 and older retrofit diesel engines that incorporate a variety of technological advancements, including electronic controls, ultra-low-sulfur diesel fuel, oxidation catalysts, and wall-flow diesel particulate filters (DPFs). As discussed in a prior review (T. W. Hesterberg et al.; Environ. Sci. Technol. 2008, 42, 6437-6445), numerous emissions characterization studies have demonstrated marked differences in regulated and unregulated emissions between NTDE and "traditional diesel exhaust" (TDE) from pre-1988 diesel engines. Now there exist even more data demonstrating significant chemical and physical distinctions between the diesel exhaust particulate (DEP) in NTDE versus DEP from pre-2007 diesel technology, and its greater resemblance to particulate emissions from compressed natural gas (CNG) or gasoline engines. Furthermore, preliminary toxicological data suggest that the changes to the physical and chemical composition of NTDE lead to differences in biological responses between NTDE versus TDE exposure. Ongoing studies are expected to address some of the remaining data gaps in the understanding of possible NTDE health effects, but there is now sufficient evidence to conclude that health effects studies of pre-2007 DE likely have little relevance in assessing the potential health risks of NTDE exposures.

Linear low-dose extrapolation for noncancer heath effects is the exception, not the rule.

The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic endpoints should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general "additivity-to-background" argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties-properties that would not be expected for most noncancer effects. Second, the "heterogeneity in the population" argument states that variations in sensitivity among members of the target population tend to "flatten out and linearize" the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true nonthreshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed.

Single injection of a low dose of pentylenetetrazole leads to epileptogenesis in an animal model of cortical dysplasia.

PURPOSE: Cortical dysplasia (CD) is one of the most frequent causes of pharmacoresistent focal epilepsy. Despite significant advances in various diagnostic and therapeutic methods, the basic mechanisms of higher susceptibility for seizures in patients with CD are unknown. Animal models of CD present with a lower threshold for seizure induction. The purpose of this study is to further characterize the animal model of in utero radiation-induced CD and to illustrate the effect of a late postnatal second hit (low dose of pentylenetetrazole, PTZ) on the development of spontaneous seizures. METHODS: Pregnant Sprague-Dawley rats were irradiated on E17 (145 cGy; control group was left untreated). Litters were implanted with bifrontal epidural and hippocampal depth electrodes. After baseline electroencephalography (EEG) recording, animals received 30 mg/kg PTZ and were chronically monitored. Histopathology of the brains was verified. RESULTS: No seizures were detected in animals that did not receive PTZ. PTZ-injected irradiated (XRT) rats showed severe prolonged, repetitive seizures during the acute period. During the chronic period, XRT rats had recurrent seizures and epileptiform spikes. PTZ-injected control animals exhibited milder and fewer acute seizures and did not show seizures during the chronic period. Histology was consistent with cortical and hippocampal dysplasia. CONCLUSIONS: This study shows that a single treatment with a low dose of PTZ renders XRT rats (but not age-matched controls) epileptic, exhibiting spontaneous epileptiform spikes and seizures on EEG. These results might mirror the natural history of patients with CD thought to be caused by prenatal/congenital or perinatal insults.

Detection of human herpesviruses HHV-6, HHV-7 and HHV-8 in whole blood by real-time PCR using the new CMV, HHV-6, 7, 8 R-gene kit.

Human herpesviruses 6 (HHV-6), 7 (HHV-7) and 8 (HHV-8) are lymphotropic herpesviruses that may cause opportunistic diseases in immunosuppressed patients such as transplant or AIDS patients. The new commercial CMV HHV-6, 7, 8 R-gene kit (Argene, Varilhes, France) for the simultaneous quantitation of HHV-6 and qualitative detection of HHV-7 and HHV-8 was evaluated using whole blood samples (respectively, n=175, 100 and 161) and using different extraction and real-time PCR platforms in two Centers A and B. In comparison with HHV-6 in-house real-time PCR the commercial kit showed agreements of 96% (n=75) and 85% (n=100) in A and B, respectively, with significant Spearman's correlation between both techniques (in A: r=0.97 [p<0.001]; in B: r=0.70 [p<0.001]). The Bland-Altman test results and prospective monitoring of patients confirmed the accuracy of these HHV-6 real-time PCR techniques. The agreement between the in-house HHV-7 PCR and commercial kit was of 86% (n=100). In comparison with in-house HHV-8 real-time PCRs, the commercial kit showed agreements of 100% (n=61) and 93.7% (n=96) in A and B, respectively. These results demonstrate that the new commercial CMV HHV-6, 7, 8 R-gene kit was an efficient and reliable tool for the diagnosis of herpesvirus 6, 7, 8 infections.

Carcinogenicity studies of diesel engine exhausts in laboratory animals: a review of past studies and a discussion of future research needs.

Diesel engines play a vital role in world economy, especially in transportation. Exhaust from traditional diesel engines using high-sulfur fuel contains high concentrations of respirable carbonaceous particles with absorbed organic compounds. Recognition that some of these compounds are mutagenic has raised concern for the cancer-causing potential of diesel exhaust exposure. Extensive research addressing this issue has been conducted during the last three decades. This critical review is offered to facilitate an updated assessment of the carcinogenicity of diesel exhaust and to provide a rationale for future animal research of new diesel technology. Life-span bioassays in rats, mice, and Syrian hamsters demonstrated that chronic inhalation of high concentrations of diesel exhaust caused lung tumors in rats but not in mice or Syrian hamsters. In 1989, the International Agency for Research on Cancer (IARC) characterized the rat findings as "sufficient evidence of animal carcinogenicity," and, with "limited" evidence from epidemiological studies, classified diesel exhaust Category 2A, a "probable human carcinogen." Subsequent research has shown that similar chronic high concentration exposure to particulate matter generally considered innocuous (such as carbon black and titanium dioxide) also caused lung tumors in rats. Thus, in 2002, the U.S. Environmental Protection Agency (EPA) concluded that the findings in the rats should not be used to characterize the cancer hazard or quantify the cancer risk of diesel exhaust. Concurrent with the conduct of the health effects studies, progressively more stringent standards have been promulgated for diesel exhaust particles and NOx. Engine manufacturers have responded with new technology diesel (improved engines, fuel injection, fuels, lubricants, and exhaust treatments) to meet the standards. This review concludes with an outline of research to evaluate the health effects of the new technology, research that is consistent with recommendations included in the U.S. EPA 2002 health assessment document. When this research has been completed, it will be appropriate for IARC to evaluate the potential cancer hazard of the new technology diesel.