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Leukemia, lymphoma and multiple myeloma mortality (1950–1999) and incidence (1969–1999) in the Eldorado uranium workers cohort

Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932–1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months and the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation. - Highlights: • We analyzed long-term follow-up for hematologic cancers of the Eldorado uranium workers. • Workers were exposed to a unique combination of radon decay products (RDP) and gamma (γ) ray doses. • Exposures to RDP and γ-ray doses were not associated with significantly increased risks of cancers. • Radiation risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma were increased. • Study findings provide additional support for radiation-related risks of CLL.

54 ENVIRONMENTAL SCIENCES↗

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↗

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↗

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↗

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↗

Iodine nutritional status and thyroid effects of exposure to ethylenebisdithiocarbamates

Introduction: Italy is still characterized by a mild iodine deficiency and is among the most intensive users of chemical products for agriculture in Europe. The aim of this study was i) to evaluate thyroid effects of exposure to mancozeb, a fungicide widely used in agriculture, in a sample of Italian grapevine workers, and ii) to verify whether the iodine intake may modulate the risk of thyroid disruption due to the mancozeb metabolite ethylenthiourea (ETU). Methods: One hundred seventy-seven occupationally exposed male workers (29 from Chianti, a mild iodine deficient area, and 148 from Bolzano an iodine sufficient province) and 74 non-occupationally exposed male controls (34 from Chianti and 40 from Bolzano) were enrolled in the study. Serum biomarkers of thyroid function, as well as urinary iodine and ETU concentrations were assessed. Moreover all the recruited subjects underwent clinical examination and thyroid ultrasound. Results: Multivariate comparisons showed lower mean serum levels of FT4 in Chianti-workers as compared to Bolzano-workers. Moreover, an increased urinary iodine excretion (>250 µg/L) was more frequently found among more exposed workers (ETU>20 µg/L) than among less exposed ones and this effect was more pronounced in Chianti- than in Bolzano-workers. Chianti-workers also showed a significantly higher frequency of very low thyroid volume (≤6.0 ml) as compared to controls. Conclusions: These findings showed a mild thyroid disrupting effect due to occupational exposure to mancozeb, more pronounced in workers residing in an area characterized by a mild to moderate iodine deficiency as compared to workers residing in an area covered by a long-lasting iodine prophylaxis program. - Highlights: • Thyroid is vulnerable to endocrine disrupting effects due to environmental exposures. • Mancozeb is a fungicide widely used in agriculture worldwide. • Mancozeb is broken down into ethylenthiourea (ETU) which has anti-thyroid activity. • Iodine intake may modulate thyroid disruption due to occupational exposure to ETU.

54 ENVIRONMENTAL SCIENCES↗

Environmental exposures to lead, mercury, and cadmium among South Korean teenagers (KNHANES 2010–2013): Body burden and risk factors

Introduction: Limited information is available on the association of age and sex with blood concentrations of heavy metals in teenagers. In addition, factors such as a shared family environment may have an association. We analyzed data from the Korean National Health and Nutrition Examination Survey (KNHANES, 2010–2013) to determine whether blood levels of heavy metals differ by risk factors such as age, sex, and shared family environment in a representative sample of teenagers. Methods: This study used data obtained in the KNHANES 2010–2013, which had a rolling sampling design that involved a complex, stratified, multistage, probability-cluster survey of a representative sample of the non-institutionalized civilian population in South Korea. Our cross-sectional analysis was restricted to teenagers and their parents who completed the health examination survey, and for whom blood measurements of cadmium, lead, and mercury were available. The final analytical sample consisted of 1585 teenagers, and 376 fathers and 399 mothers who provided measurements of blood heavy metal concentrations. Results: Male teenagers had greater blood levels of lead and mercury, but sex had no association with blood cadmium level. There were age-related increases in blood cadmium, but blood lead decreased with age, and age had little association with blood mercury. The concentrations of cadmium and mercury declined from 2010 to 2013. The blood concentrations of lead, cadmium, and mercury in teenagers were positively associated with the levels in their parents after adjustment for covariates. Conclusion: Our results show that blood heavy metal concentrations differ by risk factors such as age, sex, and shared family environment in teenagers. - Highlights: • This study was based on data obtained by KNHANES 2010–2013. • Male had greater blood levels of lead and mercury, and there were age-related increases in blood cadmium in Korean adolescents. • The blood concentrations of lead, cadmium, and mercury in adolescents were positively associated with the levels in their parents.

54 ENVIRONMENTAL SCIENCES↗

Behavioural phenotypes in mice after prenatal and early postnatal exposure to intermediate frequency magnetic fields

Highlights: • Human exposure to intermediate frequency magnetic fields (MF) is increasing. • We exposed prenatal and early postnatal male mice to 7.5 kHz MFs at 12 and 120 μT. • A behavioural teratology study focused on the developing nervous system. • No consistent adverse effects were observed. Electromagnetic fields are ubiquitous in the environment. Human exposure to intermediate frequency (IF) fields is increasing due to applications like electronic article surveillance systems, wireless power transfer, and induction heating cooking hobs. However, there are limited data on possible health effects of exposure to IF magnetic fields (MF). In the present study, we set out to assess cognitive and behavioural effects of IF MF in mice exposed during prenatal and early postnatal periods. Pregnant female mice were exposed continuously to 7.5 kHz MFs at 12 and 120 μT, from mating until weaning of pups. Sham exposed pregnant mice were used as a control group. A behavioural teratology study was conducted on the male offspring at two months of age to detect possible effects on the developing nervous system. Body weight development did not differ between the exposure groups. The exposure did not alter spontaneous motor activity when exploring a novel cage or anxiety in novelty-suppressed feeding or marble burying tests. Improved performance in the Rotarod task was observed in the 12 µT group, while the 120 μT exposure group swam more slowly than the sham exposed group in the Morris swim navigation task. However, indices of learning and memory (path length and escape latency during task acquisition and search bias during the probe test) did not differ between the exposure groups. Furthermore, the passive avoidance task did not indicate any impairment of long-term memory over a 48 h interval in the exposed groups. In a post-mortem histopathological analysis, there was no evidence for an effect of IF MF exposure on astroglial reactivity or hippocampal neurogenesis. The results suggest that the IF MF used did not have detrimental effects on spatial learning and memory or histological markers of tissue reaction. The two statistically significant findings that were observed (improved performance in the Rotarod task in the 12 µT group and decreased swimming speed in the 120 µT group) are likely to be chance findings, as they do not form an internally consistent, dose-dependent pattern indicative of specific developmental effects.

54 ENVIRONMENTAL SCIENCES↗

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↗

Sperm quality biomarkers complement reproductive and endocrine parameters in investigating environmental contaminants in common carp (Cyprinus carpio) from the Lake Mead National Recreation Area

Highlights: • Reproductive and endocrine biomarkers were differentially altered in carp in Lake Mead National Recreational Area. • Sex steroid hormone, sperm motility, and vitellogenin biomarker data pointed to lessened endocrine disrupting effects in 2006 versus late 1990's. • Among sub-basins, fish in Gregg Basin were least affected by endocrine disrupting compounds. • Compounds indicating risks in LMNRA included galaxolide, methyl triclosan, polybrominated diphenyl ether-47, hexachlorobenzene, and polychlorinated biphenyls. • Male germplasm provides pertinent cell and molecular biomarkers for endocrine disrupting compound studies. Lake Mead National Recreational Area (LMNRA) serves as critical habitat for several federally listed species and supplies water for municipal, domestic, and agricultural use in the Southwestern U.S. Contaminant sources and concentrations vary among the sub-basins within LMNRA. To investigate whether exposure to environmental contaminants is associated with alterations in male common carp (Cyprinus carpio) gamete quality and endocrine- and reproductive parameters, data were collected among sub-basins over 7 years (1999–2006). Endpoints included sperm quality parameters of motility, viability, mitochondrial membrane potential, count, morphology, and DNA fragmentation; plasma components were vitellogenin (VTG), 17ß-estradiol, 11-keto-testosterone, triiodothyronine, and thyroxine. Fish condition factor, gonadosomatic index, and gonadal histology parameters were also measured. Diminished biomarker effects were noted in 2006, and sub-basin differences were indicated by the irregular occurrences of contaminants and by several associations between chemicals (e.g., polychlorinated biphenyls, hexachlorobenzene, galaxolide, and methyl triclosan) and biomarkers (e.g., plasma thyroxine, sperm motility and DNA fragmentation). By 2006, sex steroid hormone and VTG levels decreased with subsequent reduced endocrine disrupting effects. The sperm quality bioassays developed and applied with carp complemented endocrine and reproductive data, and can be adapted for use with other species.

54 ENVIRONMENTAL SCIENCES↗

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↗

Long-term exposure to ambient air pollution (including PM1) and metabolic syndrome: The 33 Communities Chinese Health Study (33CCHS)

Highlights: • Associations of ambient air pollution with metabolic syndrome were scarcely studied. • Data from 15,477 Chinese adults were analyzed. • Long-term exposure to air pollution was associated with metabolic syndrome. • Demographic and lifestyle factors modified the association between metabolic syndrome and air pollution. Little evidence exists about the effects of long-term exposure to ambient air pollution on metabolic syndrome (MetS). This study aimed to determine the association between long-term ambient air pollution and MetS in China. A total of 15,477 adults who participated in the 33 Communities Chinese Health Study (33CCHS) in 2009 were evaluated. MetS was defined based on the recommendation by the Joint Interim Societies. Exposure to air pollutants was assessed using data from monitoring stations and a spatial statistical model (including particles with diameters ≤ 1.0 µm (PM{sub 1}), ≤ 2.5 µm (PM{sub 2.5}), and ≤ 10 µm (PM{sub 10}), sulfur dioxide (SO{sub 2}), nitrogen dioxide (NO{sub 2}), and ozone (O{sub 3})). Two-level logistic regression analyses were utilized to assess the associations between air pollutants and MetS. The prevalence of MetS was 30.37%. The adjusted odds ratio of MetS per 10 µg/m{sup 3} increase in PM{sub 1}, PM{sub 2.5}, PM{sub 10}, SO{sub 2}, NO{sub 2}, and O{sub 3} were 1.12 (95% CI = 1.00–1.24), 1.09 (95% CI = 1.00–1.18), 1.13 (95% CI = 1.08–1.19), 1.10 (95% CI = 1.02–1.18), 1.33 (95% CI = 1.12–1.57), and 1.10 (95% CI = 1.01–1.18), respectively. Stratified analyses indicated that the above associations were stronger in participants with the demographic variables of males, < 50 years of age, and higher income, as well as with the behavioral characteristics of smoking, drinking, and consuming sugar-sweetened soft drinks frequently. This study indicates that long-term exposure to ambient air pollutants may increase the risk of MetS, especially among males, the young to middle aged, those of low income, and those with unhealthy lifestyles.

54 ENVIRONMENTAL SCIENCES↗

Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring

Highlights: • Low-dose developmental exposure to BPA alters fatty acid composition in rats. • Increased fatty acid markers of SCD-1 activity in male offspring. • Decreased levels of linoleic acid, an essential fatty acid, in male offspring. • Increased body weight was found in female offspring. • The observed altered fatty acid composition may reflect insulin resistance. Bisphenol A (BPA) is an endocrine disruptor and also a suggested obesogen and metabolism-disrupting chemical. Accumulating data indicates that the fatty acid (FA) profile and their ratios in plasma and other metabolic tissues are associated with metabolic disorders. Stearoyl-CoA desaturase 1 (SCD-1) is a key regulator of lipid metabolism and its activity can be estimated by dividing the FA product by its precursor measured in blood or other tissues.

60 APPLIED LIFE SCIENCES↗

Do Angiotensin-Converting Enzyme Inhibitors Reduce the Risk of Symptomatic Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer After Definitive Radiation Therapy? Analysis of a Single-Institution Database

Purpose: Preclinical studies have suggested that angiotensin-converting enzyme inhibitors (ACEIs) can mitigate radiation-induced lung injury. We sought here to investigate possible associations between ACEI use and the risk of symptomatic radiation pneumonitis (RP) among patients undergoing radiation therapy (RT) for non–small cell lung cancer (NSCLC). Methods and Materials: We retrospectively identified patients who received definitive radiation therapy for stages I to III NSCLC between 2004 and 2010 at a single tertiary cancer center. Patients must have received a radiation dose of at least 60 Gy for a single primary lung tumor and have had imaging and dosimetric data available for analysis. RP was quantified according to Common Terminology Criteria for Adverse Events, version 3.0. A Cox proportional hazard model was used to assess potential associations between ACEI use and risk of symptomatic RP. Results: Of 413 patients analyzed, 65 were using ACEIs during RT. In univariate analysis, the rate of RP grade ≥2 seemed lower in ACEI users than in nonusers (34% vs 46%), but this apparent difference was not statistically significant (P=.06). In multivariate analysis of all patients, ACEI use was not associated with the risk of symptomatic RP (hazard ratio [HR] = 0.66; P=.07) after adjustment for sex, smoking status, mean lung dose (MLD), and concurrent carboplatin and paclitaxel chemotherapy. Subgroup analysis showed that ACEI use did have a protective effect from RP grade ≥2 among patients who received a low (≤20-Gy) MLD (P<.01) or were male (P=.04). Conclusions: A trend toward reduction in symptomatic RP among patients taking ACEIs during RT for NSCLC was not statistically significant on univariate or multivariate analyses, although certain subgroups may benefit from use (ie, male patients and those receiving low MLD). The evidence at this point is insufficient to establish whether the use of ACEIs does or does not reduce the risk of RP.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

American Society for Radiation Oncology (ASTRO) 2012 Workforce Study: The Radiation Oncologists' and Residents' Perspectives

Purpose: The American Society for Radiation Oncology (ASTRO) conducted the 2012 Radiation Oncology Workforce Survey to obtain an up-to-date picture of the workforce, assess its needs and concerns, and identify quality and safety improvement opportunities. The results pertaining to radiation oncologists (ROs) and residents (RORs) are presented here. Methods: The ASTRO Workforce Subcommittee, in collaboration with allied radiation oncology professional societies, conducted a survey study in early 2012. An online survey questionnaire was sent to all segments of the radiation oncology workforce. Respondents who were actively working were included in the analysis. This manuscript describes the data for ROs and RORs. Results: A total of 3618 ROs and 568 RORs were surveyed. The response rate for both groups was 29%, with 1047 RO and 165 ROR responses. Among ROs, the 2 most common racial groups were white (80%) and Asian (15%), and the male-to-female ratio was 2.85 (74% male). The median age of ROs was 51. ROs averaged 253.4 new patient consults in a year and 22.9 on-treatment patients. More than 86% of ROs reported being satisfied or very satisfied overall with their career. Close to half of ROs reported having burnout feelings. There was a trend toward more frequent burnout feelings with increasing numbers of new patient consults. ROs' top concerns were related to documentation, reimbursement, and patients' health insurance coverage. Ninety-five percent of ROs felt confident when implementing new technology. Fifty-one percent of ROs thought that the supply of ROs was balanced with demand, and 33% perceived an oversupply. Conclusions: This study provides a current snapshot of the 2012 radiation oncology physician workforce. There was a predominance of whites and men. Job satisfaction level was high. However a substantial fraction of ROs reported burnout feelings. Perceptions about supply and demand balance were mixed. ROs top concerns reflect areas of attention for the healthcare sector as a whole.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Vitamin D Deficiency Is Associated With the Severity of Radiation-Induced Proctitis in Cancer Patients

Purpose: Radiation-induced injury to normal tissues is a common complication of radiation therapy in cancer patients. Considering the role of vitamin D in mucosal barrier hemostasis and inflammatory responses, we investigated whether vitamin D deficiency is associated with the severity of radiation-induced acute proctitis in cancer patients. Methods and Materials: This prospective observational study was conducted in cancer patients referred for pelvic radiation therapy. Serum concentration of 25-hydroxyvitamin D was measured before radiation therapy. Vitamin D deficiency was defined as 25-hydroxyvitamin D concentrations of <35 nmol/L and <40 nmol/L in male and female patients, respectively, based on available normative data. Acute proctitis was assessed after 5 weeks of radiation therapy (total received radiation dose of 50 Gy) and graded from 0 to 4 using Radiation Therapy Oncology Group (RTOG) criteria. Results: Ninety-eight patients (57.1% male) with a mean age of 62.8 ± 9.1 years were studied. Vitamin D deficiency was found in 57 patients (58.1%). Symptoms of acute proctitis occurred in 72 patients (73.4%) after radiation therapy. RTOG grade was significantly higher in patients with vitamin D deficiency than in normal cases (median [interquartile range] of 2 [0.5-3] vs 1 [0-2], P=.037). Vitamin D deficiency was associated with RTOG grade of ≥2, independent of possible confounding factors; odds ratio (95% confidence interval) = 3.07 (1.27-7.50), P=.013. Conclusions: Vitamin D deficiency is associated with increased severity of radiation-induced acute proctitis. Investigating the underlying mechanisms of this association and evaluating the effectiveness of vitamin D therapy in preventing radiation-induced acute proctitis is warranted.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Pregnancy and Parenthood in Radiation Oncology, Views and Experiences Survey (PROVES): Results of a Blinded Prospective Trainee Parenting and Career Development Assessment

Purpose: Medical training spans nearly a decade, during which many physicians traditionally begin families. Although childrearing responsibilities are shared by men and women in the modern era, differences in time allocated to child care by sex and its potential impact on residency experience merit discussion. Methods and Materials: An anonymous, voluntary, 102-item survey was distributed to 540 current radiation oncology residents and 2014 graduates that asked about marital and parental status, pregnancy during residency, publication productivity, career aspirations, and experiences working with pregnant co-residents. Respondents with children were asked about childcare arrangements, and women who were pregnant during residency were asked about radiation safety, maternity leave, and breastfeeding experiences. Results: A total of 190 respondents completed the survey, 107 men (56.3%) and 84 women (43.7%). Ninety-seven respondents (51.1%) were parents, and 84 (44.2%) reported a pregnancy during residency. Respondents with children more often were male (65% vs 47.3%; P=.014), in a higher level of training (79.3% vs 54.8% were PGY4 or higher; P=.001), were older (median age of 32, interquartile range [IQR]:31-35] vs age 30 [IQR: 29-33]; P<.001), had a PhD (33% vs 19.3%, respectively; P=.033), were married (99% vs 43%, respectively; P<.001), and had a partner who did not work (24.7% vs 1.9%, respectively; <.001). There were no differences in the number of manuscripts published or the number of residents who expressed likelihood of pursing an academic career by parental status. Among parents, men more frequently had partners who did not work (38.1% vs 0%, respectively; P<.001) and reported that their partner performed a greater percentage of childcare duties (70% [IQR: 60%-80%] vs 35% [IQR: 20%-50%], respectively; P<.001). Conclusions: Pregnancy and parenthood are common during residency. Female residents are frequently responsible for more childcare duties than males but have similar research productivity and career aspirations. Further investigation is critical to elucidate gender disparities in parenthood and career development.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Importance of Local Control in Early-Stage Prostate Cancer: Outcomes of Patients With Positive Post-Radiation Therapy Biopsy Results Treated in RTOG 9408

Purpose: The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. Methods and Materials: Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b-T2b and prostate-specific antigen concentrations of ≤20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. Results: A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3-2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease-specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score ≥7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). Conclusions: Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors.

62 RADIOLOGY AND NUCLEAR MEDICINE↗