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At least 469 records · Page 26
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

Evaluation of the use of common sculpin (Myoxocephalus scorpius) organ histology as bioindicator for element exposure in the fjord of the mining area Maarmorilik, West Greenland

The former Black Angel lead–zinc mine in Maarmorilik, West Greenland, is a historic example of how mining activity may result in a significant impact on the surrounding fjord system in terms of elevated concentrations of especially lead (Pb) and zinc (Zn) in seawater, sediments and surrounding biota. In order to shed light on the present contamination and possible effects in the fjord we initiated a range of studies including a pilot study on gill and liver morphology of common sculpins (Myoxocephalus scorpius) around Maarmorilik. Sculpins were caught and sampled at five different stations known to represent a gradient of Pb concentrations. Fish livers from all specimens were analyzed for relevant elements in the area: Fe, Zn, As, Cu, Se, Cd, Pb, Ag, Hg, Co and Ni. Lead, As and Hg showed significant differences among the five stations. For 20% of the sculpins, Hg concentrations were in the range of lowest observed effect dose (LOED) of 0.1–0.5 μg/g ww for toxic threshold on reproduction and subclinical endpoints. Likewise LOEDs for tissue lesions, LOEDs for biochemistry, growth, survival and reproduction were exceeded for Cd (0.42–1.8 μg/g ww) and for As (11.6 μg/g ww) in 28% and 85% of the sculpins, respectively. Similar to this, the no observed effect dose (NOED) for biochemistry was exceeded for Pb (0.32 μg/g ww) and for growth, mortality and reproduction for Zn (60–68 μg/g ww) in 33% and 24% of the sculpins, respectively. For all sculpins, females were significantly larger than males and for five of the elements (Fe, Co, Ni, Cu, Se) females had higher concentrations. The chronic lesions observed in liver (mononuclear cell infiltrates, necrosis, vacuolar hepatocytes, portal fibrosis, bile duct hyperplasia, active melanomacrophage centers) and gills (fusion and edema of secondary lamellae, laminar telangiectasis, mononuclear cell infiltrates, blebs) were similar to those in the literature studies for both wild and laboratory exposed sculpins and other fish species carrying similar or higher Hg concentrations. Ignoring sex and size, specimens with hepatic cell infiltrates had the highest concentrations of most elements, a relation that was also found for gill telangiectasis and Hg (all p<0.05). When controlling for sex and size, the prevalence of vacuolar hepatocytes and endoparasites was significantly highest at the three most contaminated stations and similar differences were found for liver necrosis. We suggest that beside exposure to mining-related elements, other environmental factors, such as parasites, might be co-factors in the development of the observed liver and gill lesions. Therefore, sculpin liver and gill pathology are likely to be suitable health indicators when biomonitoring gradients of mining and other element related activity effects; while a larger study is required to fully evaluate the relationships. - Highlights: • Black Angel Pb–Zn mine in West Greenland has led to significant metal pollution. • Gill and liver morphology of common sculpins was evaluated as bioindicators. • Significant pathologies were found and were related to metal concentrations. • Sculpin pathology may be suitable health indicators for mining activity effects. • These should be enrolled in EIAs of raw material industrialization in the Arctic.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Association of hypothyroidism with low-level arsenic exposure in rural West Texas

It has been reported recently that a higher airborne arsenic level was correlated with higher urinary arsenic concentration and lower serum thyroxin level among urban policemen and rural highway workmen in Italy. The current study was to determine whether exposure to low-level arsenic groundwater (2–22 µg/L) is associated with hypothyroidism among 723 participants (118 male and 267 female Hispanics; 108 male and 230 female non-Hispanic whites, NHW) living in rural West Texas counties. Arsenic and iodine levels in their groundwater used for drinking and or cooking were estimated by the inverse distance weighted (IDW) interpolation technique. Groundwater arsenic was ≥8 µg/L in 36% of the subjects' wells while iodine concentration was <1 µg/L in 91% of their wells. Logistic regression analysis showed that arsenic in groundwater ≥8 µg/L and cumulative arsenic exposure (groundwater arsenic concentration multiplied by the number of years living in the current address) but not groundwater iodine concentration were significant predictors for hypothyroidism among Hispanics (p<0.05) but not NHW after adjusting for covariates such as age, gender, annual household income and health insurance coverage. The ethnic difference may be due to a marginally higher percentage of Hispanics (p=0.0622) who lived in areas with groundwater arsenic ≥8 µg/L compared with NHW. The prevalence of hypothyroidism was significantly higher in Hispanics or NHW of this rural cohort than the national prevalence. Measures should be taken to reduce arsenic in drinking water in order to prevent hypothyroidism in rural areas. - Highlights: • We determined if arsenic exposure is associated with hypothyroidism in rural Texas. • Groundwater arsenic level is associated with hypothyroidism among Hispanics only. • The rate of hypothyroidism in rural Texas was higher than the US general population.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Tracking the sources of polybrominated diphenyl ethers in birds: Foraging in waste management facilities results in higher DecaBDE exposure in males

Differences in feeding ecology are now recognized as major determinants of inter-individual variations in contaminant profiles of free-ranging animals, but exceedingly little attention has been devoted to the role of habitat use. Marked inter-individual variations and high levels of polybrominated diphenyl ethers (PBDEs) (e.g., DecaBDE) have previously been documented in ring-billed gulls (Larus delawarensis) breeding in a colony near Montreal (QC, Canada). However, the environmental sources of these compounds, and thus the reasons causing these large inter-individual variations remain unidentified. In the present study, we used GPS-based telemetry (±5 to 10 m precision) to track ring-billed gulls from this colony to reconstruct their movements at the landscape level. We related habitat use of individual gulls (n=76) to plasma concentrations (ng/g ww) and relative contributions (percentages) to Σ{sub 38}PBDEs of major congeners in the internationally restricted PentaBDE and current-use DecaBDE mixtures. Male gulls that visited waste management facilities (WMFs; i.e., landfills, wastewater treatment plants and related facilities; 25% of all GPS-tracked males) exhibited greater DecaBDE (concentrations and percentages) and lower PentaBDE (percentages) relative to those that did not. In contrast, no such relationships were found in females. Moreover, in males, DecaBDE (concentrations and percentages) increased with percentages of time spent in WMFs (i.e., ~5% of total foraging time), while PentaBDE (percentages) decreased. No relationships between percentages of time spent in other habitats (i.e., urban areas, agriculture fields, and St. Lawrence River) were found in either sex. These findings suggest that animals breeding in the vicinity of WMFs as well as mobile species that only use these sites for short stopovers to forage, could be at risk of enhanced DecaBDE exposure. - Highlights: • The study was conducted on breeding gulls with high levels of flame retardants. • Ring-billed gulls were GPS-tracked to associate habitat use with plasma PBDEs. • Males that visited waste management facilities had greater DecaBDE. • DecaBDE also increased with time spent in waste management facilities in males. • No relationships between habitat use and PBDEs were found in females.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb

Baseline blood concentrations of metals are important references for monitoring metal exposure in environmental and occupational settings. The purpose of this study was to determine the blood levels of manganese (Mn), copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) among the residents (aged 12–60 years old) living in the suburb southwest of Beijing in China and to compare the outcomes with reported values in various developed countries. Blood samples were collected from 648 subjects from March 2009 to February 2010. Metal concentrations in the whole blood were determined by ICP-MS. The geometric means of blood levels of Mn, Cu, Zn, Pb and Cd were 11.4, 802.4, 4665, 42.6, and 0.68 µg/L, respectively. Male subjects had higher blood Pb than the females, while the females had higher blood Mn and Cu than the males. There was no gender difference for blood Cd and Zn. Smokers had higher blood Cu, Zn, and Cd than nonsmokers. There were significant age-related differences in blood levels of all metals studied; subjects in the 17–30 age group had higher blood levels of Mn, Pb, Cu, and Zn, while those in the 46–60 age group had higher Cd than the other age groups. A remarkably lower blood level of Cu and Zn in this population as compared with residents of other developed countries was noticed. Based on the current study, the normal reference ranges for the blood Mn were estimated to be 5.80–25.2 μg/L; for blood Cu, 541–1475 μg/L; for blood Zn, 2349–9492 μg/L; for blood Pb, <100 μg/L; and for blood Cd, <5.30 μg/L in the general population living in Beijing suburbs. - Highlights: • Baseline blood levels of metals in residents of Beijing suburb are investigated. • BMn and BPb in this cohort are higher than those in other developed countries. • Remarkably lower blood levels of Cu and Zn in this Chinese cohort are noticed. • The reference values for blood levels of Mn, Cu, Zn, Pb, and Cd are established.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Risk assessment based on urinary bisphenol A levels in the general Korean population

Bisphenol A (BPA) is a high-volume industrial chemical used in the global production of polycarbonate plastics and epoxy resins, which are used in food and drink containers, such as tableware (plates and mugs). Due to its broad applications, BPA has been detected in human blood, urine and breast milk as well as environmental substances, including water, indoor and outdoor air, and dust. Indeed, exposure to high concentrations of BPA can result in a variety of harmful effects, including reproductive toxicity, through a mechanism of endocrine disruption. Our comparison of reported BPA urinary concentrations among different countries revealed that exposures in Korea may be higher than those in other Asian countries and North America, but lower than or similar to those in European countries. The current study included a total of 2044 eligible subjects of all ages. The subjects were evenly divided between males and females (48.58% and 51.42%, respectively). The geometric mean (GM) of pre-adjusted (adjusted) urinary BPA concentrations was 1.83 μg/L (2.01 μg/g creatinine) for subjects of all ages, and there was no statistically difference in BPA concentrations between males (1.90 μg/L, 1.87 μg/g creatinine) and females (1.76 μg/L, 2.16 μg/g creatinine). Multiple regression analysis revealed only one positive association between creatinine pre-adjusted urinary BPA concentration and age (β=−0.0868, p<0.001). The 95th percentile levels of 24-hour recall (HR), food frequency questionnaires (FFQ) and estimated daily intake (EDI) through urinary BPA concentrations were 0.14, 0.13, and 0.22 μg/kg bw/day, respectively. According to the Ministry of Food and Drug Safety (MFDS), a tolerable daily intake (tDI) of 20 μg/kg bw/day was established for BPA from the available toxicological data. Recently, the European Food Safety Authority (EFSA) established a temporary TDI of 4 μg/kg bw/day based on current toxicological data. By comparing these TDIs with subjects' exposure, we conclude that there are no health concerns for any age group as a result of current levels of dietary exposure to BPA. - Highlights: • We compared urinary bisphenol A (BPA) levels among different countries. • We evaluated the urinary BPA levels of the general Korean population. • We found that the overall GM of urinary BPA concentration was 1.83 μg/L. • We derived a TDI of 20 μg/kg bw/day for BPA. • There is no health concern for any age group from current levels of exposure to BPA.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Prenatal and postnatal polybrominated diphenyl ether exposure and visual spatial abilities in children

Polybrominated diphenyl ethers (PBDEs) are associated with impaired visual spatial abilities in toxicological studies, but no epidemiologic study has investigated PBDEs and visual spatial abilities in children. The Health Outcomes and Measures of the Environment Study, a prospective birth cohort (2003–2006, Cincinnati, OH), was used to examine prenatal and childhood PBDEs and visual spatial abilities in 199 children. PBDEs were measured at 16±3 weeks gestation and at 1, 2, 3, 5, and 8 years using gas chromatography/isotope dilution high-resolution mass spectrometry. We used the Virtual Morris Water Maze to measure visual spatial abilities at 8 years. In covariate-adjusted models, 10-fold increases in BDE-47, −99, and −100 at 5 years were associated with shorter completion times by 5.2 s (95% Confidence Interval [CI] −9.3, −1.1), 4.5 s (95% CI −8.1, −0.9), and 4.7 s (95% CI −9.0, −0.3), respectively. However, children with higher BDE-153 at 3 years had longer completion times (β=5.4 s, 95% CI −0.3, 11.1). Prenatal PBDEs were associated with improved visual spatial memory retention, with children spending a higher percentage of their search path in the correct quadrant. Child sex modified some associations between PBDEs and visual spatial learning. Longer path lengths were observed among males with increased BDE-47 at 2 and 3 years, while females had shorter paths. In conclusion, prenatal and postnatal BDE-28, −47, −99, and −100 at 5 and 8 years were associated with improved visual spatial abilities, whereas a pattern of impairments in visual spatial learning was noted with early childhood BDE-153 concentrations. - Highlights: • The VMWM test was used to assess visual spatial abilities in children at 8 years. • BDE-153 at 3 years was adversely associated with visual spatial learning. • BDE-47, −99, and −100 at 5 years was associated with better visual spatial learning. • Prenatal PBDEs were associated with improved visual spatial memory retention. • Male children were observed to perform more poorly on the VMWM than females.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Associations between cadmium levels in blood and urine, blood pressure and hypertension among Canadian adults

Background: Cadmium has been inconsistently related to blood pressure and hypertension. The present study seeks to clarify the relationship between cadmium levels found in blood and urine, blood pressure and hypertension in a large sample of adults. Methods: The study sample included participants ages 20 through 79 from multiple cycles of the Canadian Health Measures Survey (2007 through 2013) with measured blood cadmium (n=10,099) and urinary cadmium (n=6988). Linear regression models examined the association between natural logarithm transformed cadmium levels and blood pressure (separate models for systolic and diastolic blood pressure) after controlling for known covariates. Logistic regression models were used to examine the association between cadmium and hypertension. Models were run separately by sex, smoking status, and body mass index category. Results: Men had higher mean systolic (114.8 vs. 110.8 mmHg, p<0.01) and diastolic (74.0 vs. 69.6 mmHg, p<0.01) blood pressure compared to women. Although, geometric mean blood (0.46 vs. 0.38 µg/L, p<0.01) and creatinine-adjusted standardized urinary cadmium levels (0.48 vs. 0.38 µg/L, p<0.01) were higher among those with hypertension, these differences were no longer significant after adjustment for age, sex and smoking status. In overall regression models, increases in blood cadmium were associated with increased systolic (0.70 mmHg, 95% confidence interval [CI]=0.25–1.16, p<0.01) and diastolic blood pressure (0.74 mmHg, 95% CI=0.30–1.19, p<0.01). The associations between urinary cadmium, blood pressure and hypertension were not significant in overall models. Model stratification revealed significant and negative associations between urinary cadmium and hypertension among current smokers (OR=0.61, 95% CI=0.44–0.85, p<0.01), particularly female current smokers (OR=0.52, 95% CI=0.32–0.85, p=0.01). Conclusion: This study provides evidence of a significant association between cadmium levels, blood pressure and hypertension. However, the significance and direction of this association differs by sex, smoking status, and body mass index category. - Highlights: • Blood and urinary cadmium levels higher among those with hypertension. • Evidence of association between cadmium levels, blood pressure and hypertension. • Significance and direction of association differs by sex, smoking status, and BMI. • Higher urinary cadmium levels lower hypertension risk for current (female) smokers.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Relationship between serum trimethylamine N-oxide and exposure to dioxin-like pollutants

Highlights: • TMAO has been linked to cardiovascular disease risk in human studies and animal models. • TMAO was positively associated with 22 indexes of dioxin-like pollutant exposures in ACHS-II. • Associations with TMAO were significant among females (except at high BMIs) but not among males. • The dioxin TEQ: TMAO association was unaltered by adjustment for independent covariates of TMAO. Trimethylamine N-oxide (TMAO) is a diet and gut microbiota-derived metabolite that has been linked to cardiovascular disease risk in human studies and animal models. TMAO levels show wide inter and intra individual variability in humans that can likely be accounted for by multiple factors including diet, the gut microbiota, levels of the TMAO generating liver enzyme Flavin-containing monooxygenase 3 (FMO3) and kidney function. We recently found that dioxin-like (DL) environmental pollutants increased FMO3 expression to elevate circulating diet-derived TMAO in mice, suggesting that exposure to this class of pollutants might also contribute to inter-individual variability in circulating TMAO levels in humans. To begin to explore this possibility we examined the relationship between body burden of DL pollutants (reported by serum lipid concentrations) and serum TMAO levels (n = 340) in the Anniston, AL cohort, which was highly exposed to polychlorinated biphenyls (PCBs). TMAO concentrations in archived serum samples from the Anniston Community Health Survey (ACHS-II) were measured, and associations of TMAO with 28 indices of pollutant body burden, including total dioxins toxic equivalent (TEQ), were quantified. Twenty-three (22 after adjustment for multiple comparisons) of the 28 indices were significantly positively associated with TMAO. Although the design of ACHS-II does not enable quantitative assessment of the contributions of previously known determinants of TMAO variability to this relationship, limited multivariate modeling revealed that total dioxins TEQ was significantly associated with TMAO among females (except at high BMIs) but not among males. Our results from this cross-sectional study indicate that exposure to DL pollutants may contribute to elevated serum TMAO levels. Prospective longitudinal studies will be required to assess the joint relationship between DL pollutant exposures, other determinants of TMAO, and health outcomes.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Air pollution and emergency department visits for respiratory diseases: A multi-city case crossover study

Highlights: • Extensive research exists on the effects of ambient air pollution on respiratory diseases. • Emergency department visits for respiratory diseases increase after days with higher concentrations of air pollution. • Ambient pollution, even at low concentrations, appear to adversely affect the respiratory system. Increasing evidence suggests that ambient air pollution is a major risk factor for both acute and chronic respiratory disease exacerbations and emergencies. The objective of this study was to determine the association between ambient air pollutants and emergency department (ED) visits for respiratory conditions in nine districts across the province of Ontario in Canada. Health, air pollutant (PM{sub 2.5}, NO{sub 2}, O{sub 3}, and SO{sub 2}), and meteorological data were retrieved from April 2004 to December 2011. Respiratory diseases were categorized as: chronic obstructive pulmonary disease (COPD, including bronchiectasis) and acute upper respiratory diseases. A case-crossover design was used to test the associations between ED visits and ambient air pollutants, stratified by sex and season. For COPD among males, positive results were observed for NO{sub 2} with lags of 3–6 days, for PM{sub 2.5} with lags 1–8, and for SO{sub 2} with lags of 4–8 days. For COPD among females, positive results were observed for O{sub 3} with lags 2–4 days, and for SO{sub 2} among lags of 3–6 days. For upper respiratory disease emergencies among males, positive results were observed for NO{sub 2} (lags 5–8 days), for O{sub 3}, (lags 0–6 days), PM{sub 2.5} (all lags), and SO{sub 2} (lag 8), and among females, positive results were observed for NO{sub 2} for lag 8 days, for O{sub 3}, PM{sub 2.5} among all lags. Our study provides evidence of the associations between short-term exposure to air pollution and increased risk of ED visits for upper and lower respiratory diseases in an environment where air pollutant concentrations are relatively low.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Assessment of human nuclear and mitochondrial DNA qPCR assays for quantification accuracy utilizing NIST SRM 2372a

In forensic DNA casework, a highly accurate real-time quantitative polymerase chain reaction (qPCR) assay is recommended per the Scientific Working Group on DNA Analysis Methods (SWGDAM) (SWGDAM Validation Guidelines for DNA Analysis Methods [1]) to determine whether a DNA sample is of sufficient quantity and robust quality to move forward with downstream short tandem repeats (STR) or sequencing analyses. Most of these assays rely on a standard curve, referred to herein and traditionally as absolute qPCR, in which an unknown is compared, relative to that curve. However, one fundamental issue with absolute qPCR is the quantifiable concentration of commercial assay standards can vary depending on (1) origin, i.e., whether from a cell line or a human subject, (2) supplier, (3) lot number, (4) shipping method, etc. In 2018, the National Institute for Standards and Technology (NIST) released a human DNA standard reference material for evaluating qPCR quantification standards, Standard Reference Material (SRM) 2372a, Romsos et al. (2018) [2] which contains three well-characterized human genomic DNA samples: Component A) a single male1 donor, Component B) a single female 1 donor, and Component C) a 1:3 male 2 :female 2 donor, each with certification data for nDNA and informational mitochondrial DNA(mtDNA)/nuclear DNA (nDNA) ratio data. The SRM 2372a was used to assess four qPCR assays: (1) Quantifiler Trio (Thermo Fisher Scientific, Waltham, MA) for nDNA quantification, (2) NovaQUANT (EMD Millipore Corporation, San Diego, CA) for nDNA and mtDNA quantification, (3) a custom duplex mtDNA assay, and (4) a custom triplex mtDNA assay. Additionally, extracts from eighteen (18) skeletal remains were tested with the latter three assays for concordance of DNA concentration and with assays (2) and (3), for the degradation state. Our assessment revealed that an accurate, efficient, and reproducible qPCR assay is dependent on (1) the quality and reliability of the DNA standard, (2) the qPCR chemistry, and (3) the specific primers, and probes (if applicable), used in an assay. Finally, our findings indicate qPCR assays may not always quantify as expected and that performance of each lot should be verified using a well-characterized DNA standard such as the NIST SRM 2372a and adjusted if warranted.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Gender Trends in Radiation Oncology in the United States: A 30-Year Analysis

Purpose: Although considerable research exists regarding the role of women in the medical profession in the United States, little work has described the participation of women in academic radiation oncology. We examined women's participation in authorship of radiation oncology literature, a visible and influential activity that merits specific attention. Methods and Materials: We examined the gender of first and senior US physician-authors of articles published in the Red Journal in 1980, 1990, 2000, 2004, 2010, and 2012. The significance of trends over time was evaluated using logistic regression. Results were compared with female representation in journals of general medicine and other major medical specialties. Findings were also placed in the context of trends in the representation of women among radiation oncology faculty and residents over the past 3 decades, using Association of American Medical Colleges data. Results: The proportion of women among Red Journal first authors increased from 13.4% in 1980 to 29.7% in 2012, and the proportion among senior authors increased from 3.2% to 22.6%. The proportion of women among radiation oncology full-time faculty increased from 11% to 26.7% from 1980 to 2012. The proportion of women among radiation oncology residents increased from 27.1% to 33.3% from 1980 to 2010. Conclusions: Female first and senior authorship in the Red Journal has increased significantly, as has women's participation among full-time faculty, but women remain underrepresented among radiation oncology residents compared with their representation in the medical student body. Understanding such trends is necessary to develop appropriately targeted interventions to improve gender equity in radiation oncology.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Clinical and Dosimetric Predictors of Acute Severe Lymphopenia During Radiation Therapy and Concurrent Temozolomide for High-Grade Glioma

Purpose: Acute severe lymphopenia (ASL) frequently develops during radiation therapy (RT) and concurrent temozolomide (TMZ) for high-grade glioma (HGG) and is associated with decreased survival. The current study was designed to identify potential predictors of ASL, with a focus on actionable RT-specific dosimetric parameters. Methods and Materials: From January 2007 to December 2012, 183 patients with HGG were treated with RT+TMZ and had available data including total lymphocyte count (TLC) and radiation dose-volume histogram parameters. ASL was defined as TLC of <500/μL within the first 3 months from the start of RT. Stepwise logistic regression analysis was used to determine the most important predictors of ASL. Results: Fifty-three patients (29%) developed ASL. Patients with ASL had significantly worse overall survival than those without (median: 12.5 vs 20.2 months, respectively, P<.001). Stepwise logistic regression analysis identified female sex (odds ratio [OR]: 5.30; 95% confidence interval [CI]: 2.46-11.41), older age (OR: 1.05; 95% CI: 1.02-1.09), lower baseline TLC (OR: 0.92; 95% CI: 0.87-0.98), and higher brain volume receiving 25 Gy (V{sub 25Gy}) (OR: 1.03; 95% CI: 1.003-1.05) as the most significant predictors for ASL. Brain V{sub 25Gy} <56% appeared to be the optimal threshold (OR: 2.36; 95% CI: 1.11-5.01), with an ASL rate of 38% versus 20% above and below this threshold, respectively (P=.006). Conclusions: Female sex, older age, lower baseline TLC, and higher brain V{sub 25Gy} are significant predictors of ASL during RT+TMZ therapy for HGG. Maintaining the V{sub 25Gy} of brain below 56% may reduce the risk of ASL.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival

Purpose: The purpose of this study was to compare long-term disease control and overall survival between children treated with proton and photon radiation therapy (RT) for standard-risk medulloblastoma. Methods and Materials: This multi-institution cohort study includes 88 children treated with chemotherapy and proton (n=45) or photon (n=43) RT between 2000 and 2009. Overall survival (OS), recurrence-free survival (RFS), and patterns of failure were compared between the 2 cohorts. Results: Median (range) age was 6 years old at diagnosis (3-21 years) for proton patients versus 8 years (3-19 years) for photon patients (P=.011). Cohorts were similar with respect to sex, histology, extent of surgical resection, craniospinal irradiation (CSI) RT dose, total RT dose, whether the RT boost was delivered to the posterior fossa (PF) or tumor bed (TB), time from surgery to RT start, or total duration of RT. RT consisted of a median (range) CSI dose of 23.4 Gy (18-27 Gy) and a boost of 30.6 Gy (27-37.8 Gy). Median follow-up time is 6.2 years (95% confidence interval [CI]: 5.1-6.6 years) for proton patients versus 7.0 years (95% CI: 5.8-8.9 years) for photon patients. There was no significant difference in RFS or OS between patients treated with proton versus photon RT; 6-year RFS was 78.8% versus 76.5% (P=.948) and 6-year OS was 82.0% versus 87.6%, respectively (P=.285). On multivariate analysis, there was a trend for longer RFS with females (P=.058) and higher CSI dose (P=.096) and for longer OS with females (P=.093). Patterns of failure were similar between the 2 cohorts (P=.908). Conclusions: Disease control with proton and photon radiation therapy appears equivalent for standard risk medulloblastoma.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Lung Size and the Risk of Radiation Pneumonitis

Purpose: The purpose of this study was to identify patient populations treated for non-small cell lung cancer (NSCLC) who may be more at risk of radiation pneumonitis. Methods and Materials: A total of 579 patients receiving fractionated 3D conformal or intensity modulated radiation therapy (IMRT) for NSCLC were included in the study. Statistical analysis was performed to search for cohorts of patients with higher incidences of radiation pneumonitis. In addition to conventional risk factors, total and spared lung volumes were analyzed. The Lyman-Kutcher-Burman (LKB) and cure models were then used to fit the incidence of radiation pneumonitis as a function of lung dose and other factors. Results: Total lung volumes with a sparing of less than 1854 cc at 40 Gy were associated with a significantly higher incidence of radiation pneumonitis at 6 months (38% vs 12% for patients with larger volumes, P<.001). This patient cohort was overwhelmingly female and represented 22% of the total female population of patients and nearly 30% of the cases of radiation pneumonitis. An LKB fit to normal tissue complication probability (NTCP) including volume as a dose modifying factor resulted in a dose that results in a 50% probability of complication for the smaller spared volume cohort that was 9 Gy lower than the fit to all mean lung dose data and improved the ability to predict radiation pneumonitis (P<.001). Using an effective dose parameter of n=0.42 instead of mean lung dose further improved the LKB fit. Fits to the data using the cure model produced similar results. Conclusions: Spared lung volume should be considered when treating NSCLC patients. Separate dose constraints based on smaller spared lung volume should be considered. Smaller spared lung volume patients should be followed closely for signs of radiation pneumonitis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Development and Validation of Consensus Contouring Guidelines for Adjuvant Radiation Therapy for Bladder Cancer After Radical Cystectomy

Purpose: To develop multi-institutional consensus clinical target volumes (CTVs) and organs at risk (OARs) for male and female bladder cancer patients undergoing adjuvant radiation therapy (RT) in clinical trials. Methods and Materials: We convened a multidisciplinary group of bladder cancer specialists from 15 centers and 5 countries. Six radiation oncologists and 7 urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on computed tomography scans of a male and female cystectomy patient with input from ≥1 urologist. On the basis of the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another 6 radiation oncologists, and the cystectomy bed contouring language was again updated. To determine whether the revised language produced consistent contours, CTVs and OARs were redrawn by 6 additional radiation oncologists. We evaluated their contours for level of agreement using the Landis-Koch interpretation of the κ statistic. Results: The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral), whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours. Conclusions: Consensus descriptions of CTVs and OARs were successfully developed and can be used in clinical trials of adjuvant radiation therapy for bladder cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2026

Acute wood smoke exposure is associated with cell-specific hippocampal transcriptomic responses in an accelerated ovarian failure mouse model

Background Wildfire events are increasing in frequency and intensity, and aging individuals demonstrate heightened biological susceptibility to air pollution exposures including increased risk of neurological sequelae. Declining ovarian hormones levels that occur with aging in females along with associated systemic physiological and inflammatory changes may contribute to increased cerebral vulnerability to air pollution, representing a potential but underexplored mechanism. Menopause and the menopausal transition represent a period of profound physiological change that affects cardiovascular, neurological, and immune health. Methods We tested whether peri-menopausal–like hormonal status amplifies hippocampal responses to acute wood smoke (WS) using an ovary-intact, 4-vinylcyclohexene diepoxide (VCD) model of moderate accelerated ovarian failure (AOF) in female C57BL/6 mice. Animals were exposed to HEPA-filtered air (FA) or WS for 4 h/day over 2 consecutive days (∼0.5 mg/m³). Exposure characterization confirmed a complex mixture of combustion products with significant levels of both trace metals and gas release during WS exposure. Results Spatial transcriptomics (10x Visium; n = 4 sections/group) with automated cell-type annotation identified astrocytes, GABAergic and glutamatergic neurons, oligodendrocytes, revealed cell type-specific transcriptional alterations following WS exposure. Distinct transcriptional patterns were observed across all identified neuronal and glial cell populations. Conclusion Together, these findings define a cell-type specific transcriptomic framework describing how WS exposure and ovarian hormone decline interact to influence hippocampal responses and identify potential cellular pathways relevant to hippocampal vulnerability.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2013

Involvement of ERK1/2 signaling pathway in atrazine action on FSH-stimulated LHR and CYP19A1 expression in rat granulosa cells

Worldwide used herbicide atrazine is linked to reproductive dysfunction in females. In this study, we investigated the effects and the mechanism of atrazine action in the ovary using a primary culture of immature granulosa cells. In granulosa cells, follicle-stimulating hormone (FSH) activates both cyclic adenosine monophosphate (cAMP) and extracellular-regulated kinase 1/2 (ERK1/2) cascades, with cAMP pathway being more important for luteinizing hormone receptor (LHR) and aromatase (CYP19A1) mRNA expression. We report that 48 h after atrazine exposure the FSH-stimulated LHR and CYP19A1 mRNA expression and estradiol synthesis were decreased, with LHR mRNA being more sensitive to atrazine than CYP19A1 mRNA. Inadequate acquisition of LHR in the FSH-stimulated and atrazine-exposed granulosa cells renders human chorionic gonadotropin (hCG) ineffective to stimulate amphiregulin (Areg), epiregulin (Ereg), and progesterone receptor (Pgr) mRNA expression, suggesting anti-ovulatory effect of atrazine. To dissect the signaling cascade involved in atrazine action in granulosa cells, we used U0126, a pharmacological inhibitor of ERK1/2. U0126 prevents atrazine-induced decrease in LHR and CYP19A1 mRNA levels and estradiol production in the FSH-stimulated granulosa cells. ERK1/2 inactivation restores the ability of hCG to induce expression of the ovulatory genes in atrazine-exposed granulosa cells. Cell-based ELISA assay revealed that atrazine does not change the FSH-stimulated ERK1/2 phosphorylation in granulosa cells. The results from this study reveal that atrazine does not affect but requires ERK1/2 phosphorylation to cause decrease in the FSH-induced LHR and CYP19A1 mRNA levels and estradiol production in immature granulosa cells, thus compromising ovulation and female fertility. - Highlights: • Atrazine inhibits estradiol production in FSH-stimulated granulosa cells. • Atrazine inhibits LHR and Cyp19a1 mRNA expression in FSH-stimulated granulosa cells. • Atrazine prevents hCG-induced expression of the ovulatory genes. • ERK1/2 activation is required for atrazine action in granulosa cells. • Atrazine does not interfere with FSH-stimulated ERK1/2 phosphorylation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Scrambled and fried: Cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress

Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction. - Highlights: • Cigarette smoke exposure targets developing follicle oocytes. • The antral follicle oocyte is a primary site of ovarian cigarette smoke metabolism. • Cyp2e1 is a major enzyme involved in ameliorating smoke-induced ovotoxicity. • Cigarette smoke causes oocyte mitochondrial ROS, impairing fertilisation.

60 APPLIED LIFE SCIENCES↗