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Nano-aerosols composed of large agglomerates (LA) (100nm) are more likely to promote pulmonary clearance via macrophages phagocytosis. Small agglomerates (SA) (100nm) seem to escape this first defense mechanism and are more likely to interact directly with biological material. These different mechanisms can influence pulmonary toxicity. This hypothesis was evaluated by comparing the relative pulmonary toxicity induced by aerosolized nano-TiO(2) showing two different agglomeration states: SA (100nm) and LA (100nm) at mass concentrations of 2 or 7mg/m(3). Groups of Fisher 344 male rats were nose-only exposed for 6h. The median number aerodynamic diameters were 30 and 185nm at 2mg/m(3), and 31 and 194nm at 7mg/m(3). We found in rat's bronchoalveolar lavage fluids (BALF) a significant 2.1-fold increase in the number of neutrophils (p0.05) in the group exposed to the 7mg/m(3) LA nano-aerosol suggesting a mild inflammatory response. Rats exposed to the 7mg/m(3) SA nano-aerosol showed a 1.8-fold increase in LDH activity and 8-isoprostane concentration in BALF, providing evidence for cytotoxic and oxidative stress effects. Our results indicate that biological responses to nanoparticles (NP) might depend on the dimension and concentration of NP agglomerates.

Abstract Background There is increasing evidence suggesting that Bisphenol A (BPA), one of the highest volume chemicals produced worldwide, can interfere with the body’s natural weight control mechanisms to promote obesity. However, epidemiological studies for this are limited, especially for children. Methods A cross-sectional study was conducted to investigate the association between BPA exposure and body mass index (BMI) in school children. Three primary and three middle schools were randomly selected from 26 primary and 30 middle candidate schools in Changning District of Shanghai City in China. According to the BMI-based criteria by age and sex for screening of overweight or obese children, we randomly chose 20 obese, 10 overweight, and 30 normal weight children aged 8-15 years of age from each selected school. First morning urine was collected and total urine BPA concentrations were determined by ultra-performance liquid chromatography tandem mass spectrometry. Multiple linear regression analysis was conducted to examine the association of urine BPA concentrations and daily intake estimates with BMI. Results BPA was detected in 84.9% of urine samples with a geometric mean of 0.45 ng/mL. The daily intake estimates ranged from 0.03 μg/day to 1.96 μg/day with a geometric mean of 0.37 μg/day. The average urine BPA concentrations and daily intake estimates were similar for boys and girls, but significantly higher in older children than younger ones, and showed an increasing trend with BMI. Multiple linear regression analyses showed that urine BPA concentrations were significantly associated with increasing BMI values in all subjects after adjustment for age and sex and the results were similar before and after corrected by urine specific gravity. When stratified by age or sex, the associations remained significant in females and in those 8-11 years of age before corrected by specific gravity. Similar results were shown for the association between BMI and daily intake estimates. Conclusions There is a possibility that BPA exposure increases BMI in school children. Given the cross-sectional nature of this study, longitudinal studies are warranted to confirm BPA exposure as a contributor to increased BMI in children.

Ethanol used as an antidote is said to have various adverse effects, particularly in children. The rate of these adverse effects is not known.Twenty-one-year retrospective chart review (1980-2000) from suspected methanol poisoning patients treated with ethanol in two large pediatric tertiary care centers.A total of 60 children (median age of 24 months) received ethanol for suspected methanol poisoning: 39 orally and 21 intravenously. Median initial methanol level was 4.16 mmol/L (13.3 mg/dL) (range 0 to 87.5 mmol/L or 0 to 280 mg/dL). Median duration of ethanol treatment was 16 hours (range 1.5 to 72 hours). None [0% (95% CI 0-5%)] of the 60 patients developed symptomatic hypoglycemia. Of the 50 patients that had a glucose level measured, none [(0% [95% CI 0-6%)] had a serum glucose concentration2.78 mmol/L (50 mg/dL). Eight patients [16% (95% CI 8-30%)] had at least one serum glucose concentration between 2.78-3.61 mmol/L (50-65 mg/dL), but none of those had symptoms compatible with hypoglycemia. A total of 42 patients [84% (95% CI 70-92%)] had all their serum glucose concentrations3.61mmol/L (65 mg/dL). There was no identifiable difference in the glucose intake between the serum glucose concentration groups. Six out of the 60 patients [10% (95% CI 4-21%)] were described as more drowsy after ethanol but none was comatose or needed intubation. No child showed signs of hypothermia [0/40 (95% CI 0-8%)] (rectal temperature35 degrees C), hepatotoxicity (0/12) (AST or ALT100 U/L) or even thrombophlebitis (0/21). None of the 22 patients with toxic levels of methanol (or = 26.2 mmol/L-or = 20 mg/dL) died or had ethanol-induced morbidity despite wide variation in ethanol levels.The rate of clinically important adverse effects related to ethanol used as an antidote to treat methanol poisoning in children was either absent or low in a tertiary care pediatric hospital setting. There was no morbidity or mortality associated with ethanol when it was used despite wide variation in ethanol levels. These results suggest that with appropriate monitoring and intravenous glucose intake in a controlled environment such as a pediatric intensive care unit, ethanol therapy does not carry as many risks as currently believed.

Glucagon is usually accepted as part of the standard treatment in the management of patients with beta-blocker and calcium channel blocker overdoses.A systematic review was done in order to evaluate the evidence supporting glucagon use in beta-blocker and calcium channel blocker overdoses. Studies evaluating glucagon for those uses were identified using the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, MedLine, ToxLine, and EMBASE searches, as well as reviewing medical toxicology textbooks and references of identified articles. Only controlled studies of human or animal studies were included, the latter only when it was an in vivo model of acute poisoning. The quality of the included studies was assessed.The search found no study in humans but identified 30 in animals. In the five studies of animal models of beta-blocker overdose included, glucagon appeared to consistently increase the heart rate at least transiently but appeared to have no effect on mean arterial pressure even though it possibly increased cardiac output. Its effect on the survival rate in animal models of beta-blocker overdose was unclear. In the six studies of animal models of calcium channel blocker overdose included, glucagon appeared to increase heart rate and cardiac output and reverse second and third degree AV blocks, all at least transiently. There appeared to be no effect of glucagon on mean arterial pressure although it did increase in one model. Glucagon appeared to have no effect on survival rate. The included studies for both overdoses were not blinded, had limited numbers of animals, and some had inadequate glucagon regime.The evidence supporting the use of glucagon in the management of patients with beta-blocker and calcium channel blocker overdoses is limited to animal studies.

Abstract Background While the effects of daily fine particulate exposure (PM) have been well reviewed, the epidemiological and physiological evidence of cardiovascular effects associated to sub-daily exposures has not. We performed a theoretical model-driven systematic non-meta-analytical literature review to document the association between PM sub-daily exposures (≤6 hours) and arrhythmia, ischemia and myocardial infarction (MI) as well as the likely mechanisms by which sub-daily PM exposures might induce these acute cardiovascular effects. This review was motivated by the assessment of the risk of exposure to elevated sub-daily levels of PM during fireworks displays. Methods Medline and Elsevier's EMBase were consulted for the years 1996-2008. Search keywords covered potential cardiovascular effects, the pollutant of interest and the short duration of the exposure. Only epidemiological and experimental studies of adult humans (age > 18 yrs) published in English were reviewed. Information on design, population and PM exposure characteristics, and presence of an association with selected cardiovascular effects or physiological assessments was extracted from retrieved articles. Results Of 231 articles identified, 49 were reviewed. Of these, 17 addressed the relationship between sub-daily exposures to PM and cardiovascular effects: five assessed ST-segment depression indicating ischemia, eight assessed arrhythmia or fibrillation and five considered MI. Epidemiologic studies suggest that exposure to sub-daily levels of PM is associated with MI and ischemic events in the elderly. Epidemiological studies of sub-daily exposures suggest a plausible biological mechanism involving the autonomic nervous system while experimental studies suggest that vasomotor dysfunction may also relate to the occurrence of MI and ischemic events. Conclusions Future studies should clarify associations between cardiovascular effects of sub-daily PM exposure with PM size fraction and concurrent gaseous pollutant exposures. Experimental studies appear more promising for elucidating the physiological mechanisms, time courses and causes than epidemiological studies which employ central pollution monitors for measuring effects and for assessing their time course. Although further studies are needed to strengthen the evidence, given that exposure to sub-daily high levels of PM (for a few hours) is frequent and given the suggestive evidence that sub-daily PM exposures are associated with the occurrence of cardiovascular effects, we recommend that persons with cardiovascular diseases avoid such situations.

Background Exposure to traffic-related air pollution (TRAP) can adversely impact health but epidemiologic studies are limited in their abilities to assess long-term exposures and incorporate variability in indoor pollutant infiltration. Methods In order to examine settled house dust levels of hopanes, engine lubricating oil byproducts found in vehicle exhaust, as a novel TRAP exposure measure, dust samples were collected from 171 homes in five Canadian cities and analyzed by gas chromatography–mass spectrometry. To evaluate source contributions, the relative abundance of the highest concentration hopane monomer in house dust was compared to that in outdoor air. Geographic variables related to TRAP emissions and outdoor NO2 concentrations from city-specific TRAP land use regression (LUR) models were calculated at each georeferenced residence location and assessed as predictors of variability in dust hopanes. Results Hopanes relative abundance in house dust and ambient air were significantly correlated (Pearson’s r=0.48, p<0.05), suggesting that dust hopanes likely result from traffic emissions. The proportion of variance in dust hopanes concentrations explained by LUR NO2 was less than 10% in Vancouver, Winnipeg and Toronto while the correlations in Edmonton and Windsor explained 20 to 40% of the variance. Modeling with household factors such as air conditioning and shoe removal along with geographic predictors related to TRAP generally increased the proportion of explained variability (10-80%) in measured indoor hopanes dust levels. Conclusions Hopanes can consistently be detected in house dust and may be a useful tracer of TRAP exposure if determinants of their spatiotemporal variability are well-characterized, and when home-specific factors are considered.

Abstract Background Environmental exposure to organophosphorus pesticides has been characterized in various populations, but interpretation of these data from a health risk perspective remains an issue. The current paper proposes biological reference values to help interpret biomonitoring data related to an exposure to organophosphorus pesticides in children for which measurements of alkylphosphate metabolites are available. Methods Published models describing the kinetics of malathion and chlorpyrifos in humans were used to determine no-observed effect level – biomarker equivalents for methylphosphates and ethylphosphates, respectively. These were expressed in the form of cumulative urinary amounts of alkylphosphates over specified time periods corresponding to an absorbed no-observed effect level dose (derived from a published human exposure dose) and assuming various plausible exposure scenarios. Cumulative amounts of methylphosphate and ethylphosphate metabolites measured in the urine of a group of Quebec children were then compared to the proposed biological reference values. Results From a published no-observed effect level dose for malathion and chlorpyrifos, the model predicts corresponding oral biological reference values for methylphosphate and ethylphosphate derivatives of 106 and 52 nmol/kg of body weight, respectively, in 12-h nighttime urine collections, and dermal biological reference values of 40 and 32 nmol/kg of body weight. Out of the 442 available urine samples, only one presented a methylphosphate excretion exceeding the biological reference value established on the basis of a dermal exposure scenario and none of the methylphosphate and ethylphosphate excretion values were above the obtained oral biological reference values, which reflect the main exposure route in children. Conclusion This study is a first step towards the development of biological guidelines for organophophorus pesticides using a toxicokinetic modeling approach, which can be used to provide a health-based interpretation of biomonitoring data in the general population.

AbstractOur recent studies revealed a dose‐dependent proinflammatory response to copper oxide nanoparticles (CuO NPs) in rats following short‐term inhalation exposure for five consecutive days. Here transcriptomics approaches were applied using the same model to assess global gene expression in lung tissues obtained 1 day post‐exposure and after a recovery period of 22 days from rats exposed to clean air or 6 hour equivalent doses of 3.3 mg m−3 (low dose) and 13.2 mg m−3 (high dose). Microarray analyses yielded about 1000 differentially expressed genes in the high‐dose group and 200 in low‐dose compared to the clean air control group, and less than 20 after the recovery period. Pathway analysis indicated cell proliferation/survival and inflammation as the main processes triggered by exposure to CuO NPs. We did not find significant perturbations of pathways related to oxidative stress. Upregulation of epithelial cell transforming protein 2 (Ect2), a known oncogene, was noted and ECT2 protein was upregulated in the lungs of exposed animals. Proliferation of alveolar epithelial cells was demonstrated based on Ki67 expression. The gene encoding monocyte chemoattractant protein 1 (or CCL2) was also upregulated and this was confirmed by immunohistochemistry. However, no aberrant DNA methylation of inflammation‐associated genes was observed. In conclusion, we have found that inhalation of CuO NPs in rats causes upregulation of the oncoprotein ECT2 and the chemokine CCL2 and other proinflammatory markers as well as proliferation in bronchoalveolar epithelium after a short‐term inhalation exposure. Thus, pathways known to be associated with neoplastic processes and inflammation were affected in this model.