Within-city spatial variations in PM2.5 magnetite nanoparticles and brain cancer incidence in Toronto and Montreal, Canada.

Magnetite nanoparticles are small, strongly magnetic iron oxide particles which are produced during high-temperature combustion and friction processes and form part of the outdoor air pollution mixture. These particles can translocate to the brain and have been found in human brain tissue. In this study, we estimated associations between within-city spatial variations in concentrations of magnetite nanoparticles in outdoor fine particulate matter (PM2.5) and brain cancer incidence. We performed a cohort study of 1.29 million participants in four cycles of the Canadian Census Health and Environment Cohort in Montreal and Toronto, Canada who were followed for malignant brain tumour (glioma) incidence. As a proxy for magnetite nanoparticle content, we measured the susceptibility of anhysteretic remanent magnetization (χARM) in PM2.5 samples (N = 124 in Montreal, N = 110 in Toronto), and values were assigned to residential locations. Stratified Cox proportional hazards models were used to estimate hazard ratios (per IQR change in volume-normalized χARM). ARM was not associated with brain tumour incidence (HR = 0.998, 95% CI 0.988, 1.009) after adjusting for relevant potential confounders. Although we found no evidence of an important relationship between within-city spatial variations in airborne magnetite nanoparticles and brain tumour incidence, further research is needed to evaluate this understudied exposure, and other measures of exposure to magnetite nanoparticles should be considered.

Identifying patients with multidrug-resistant tuberculosis who may benefit from shorter durations of treatment.

OBJECTIVE: Studying treatment duration for rifampicin-resistant and multidrug-resistant tuberculosis (MDR/RR-TB) using observational data is methodologically challenging. We aim to present a hypothesis generating approach to identify factors associated with shorter duration of treatment. STUDY DESIGN AND SETTING: We conducted an individual patient data meta-analysis among MDR/RR-TB patients restricted to only those with successful treatment outcomes. Using multivariable linear regression, we estimated associations and their 95% confidence intervals (CI) between the outcome of individual deviation in treatment duration (in months) from the mean duration of their treatment site and patient characteristics, drug resistance, and treatments used. RESULTS: Overall, 6702 patients with successful treatment outcomes from 84 treatment sites were included. We found that factors commonly associated with poor treatment outcomes were also associated with longer treatment durations, relative to the site mean duration. Use of bedaquiline was associated with a 0.51 (95% CI: 0.15, 0.87) month decrease in duration of treatment, which was consistent across subgroups, while MDR/RR-TB with fluoroquinolone resistance was associated with 0.78 (95% CI: 0.36, 1.21) months increase. CONCLUSION: We describe a method to assess associations between clinical factors and treatment duration in observational studies of MDR/RR-TB patients, that may help identify patients who can benefit from shorter treatment.

Within-city spatial variations in long-term average outdoor oxidant gas concentrations and cardiovascular mortality: Effect modification by oxidative potential in the Canadian Census Health and Environment Cohort.

Health effects of oxidant gases may be enhanced by components of particulate air pollution that contribute to oxidative stress. Our aim was to examine if within-city spatial variations in the oxidative potential of outdoor fine particulate air pollution (PM2.5) modify relationships between oxidant gases and cardiovascular mortality. Methods: We conducted a retrospective cohort study of participants in the Canadian Census Health and Environment Cohort who lived in Toronto or Montreal, Canada, from 2002 to 2015. Cox proportional hazards models were used to estimate associations between outdoor concentrations of oxidant gases (Ox, a redox-weighted average of nitrogen dioxide and ozone) and cardiovascular deaths. Analyses were performed across strata of two measures of PM2.5 oxidative potential and reactive oxygen species concentrations (ROS) adjusting for relevant confounding factors. Results: PM2.5 mass concentration showed little within-city variability, but PM2.5 oxidative potential and ROS were more variable. Spatial variations in outdoor Ox were associated with an increased risk of cardiovascular mortality [HR per 5 ppb = 1.028, 95% confidence interval (CI): 1.001, 1.055]. The effect of Ox on cardiovascular mortality was stronger above the median of each measure of PM2.5 oxidative potential and ROS (e.g., above the median of glutathione-based oxidative potential: HR = 1.045, 95% CI: 1.009, 1.081; below median: HR = 1.000, 95% CI: 0.960, 1.043). Conclusion: Within-city spatial variations in PM2.5 oxidative potential may modify long-term cardiovascular health impacts of Ox. Regions with elevated Ox and PM2.5 oxidative potential may be priority areas for interventions to decrease the population health impacts of outdoor air pollution.

Fine Particulate Air Pollution and the "No-Multiple-Versions-of-Treatment" Assumption: Does Particle Composition Matter for Causal Inference?

Here we discuss possible violations of the "no-multiple-versions-of-treatment" assumption in studies of outdoor fine particulate air pollution (particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5)) owing to differences in particle composition, which in turn influence health. This assumption is part of the potential outcomes framework for causal inference, and it is needed for well-defined potential outcomes, as multiple versions of the same treatment could lead to different health risks for the same level of treatment. Since 2 locations can have the same outdoor PM2.5 mass concentration (i.e., treatment) but different chemical compositions (i.e., versions of treatment), violations of the "no-multiple-versions-of-treatment" assumption seem likely. Importantly, violations of this assumption will not bias health risk estimates for PM2.5 mass concentrations if there are no unmeasured confounders of the "version of treatment"-outcome relationship. However, confounding can occur if these factors are not identified and controlled for in the analysis. We describe situations in which this may occur and provide simulations to estimate the magnitude and direction of this possible bias. In general, violations of the "no-multiple-versions-of-treatment" assumption could be an underappreciated source of bias in studies of outdoor PM2.5. Analysis of the health impacts of outdoor PM2.5 mass concentrations across spatial domains with similar composition could help to address this issue.

Long-term Exposure to Oxidant Gases and Mortality: Effect Modification by PM 2.5 Transition Metals and Oxidative Potential.

BACKGROUND: Populations are simultaneously exposed to outdoor concentrations of oxidant gases (i.e., O 3 and NO 2 ) and fine particulate air pollution (PM 2.5 ). Since oxidative stress is thought to be an important mechanism explaining air pollution health effects, the adverse health impacts of oxidant gases may be greater in locations where PM 2.5 is more capable of causing oxidative stress. METHODS: We conducted a cohort study of 2 million adults in Canada between 2001 and 2016 living within 10 km of ground-level monitoring sites for outdoor PM 2.5 components and oxidative potential. O x exposures (i.e., the redox-weighted average of O 3 and NO 2 ) were estimated using a combination of chemical transport models, land use regression models, and ground-level data. Cox proportional hazards models were used to estimate associations between 3-year moving average O x and mortality outcomes across strata of transition metals and sulfur in PM 2.5 and three measures of PM 2.5 oxidative potential adjusting for possible confounding factors. RESULTS: Associations between O x and mortality were consistently stronger in regions with elevated PM 2.5 transition metal/sulfur content and oxidative potential. For example, each interquartile increase (6.27 ppb) in O x was associated with a 14.9% (95% CI = 13.0, 16.9) increased risk of nonaccidental mortality in locations with glutathione-related oxidative potential (OP GSH ) above the median whereas a 2.50% (95% CI = 0.600, 4.40) increase was observed in regions with OP GSH levels below the median (interaction P value <0.001). CONCLUSION: Spatial variations in PM 2.5 composition and oxidative potential may contribute to heterogeneity in the observed health impacts of long-term exposures to oxidant gases.

Predicting Spatial Variations in Multiple Measures of PM2.5 Oxidative Potential and Magnetite Nanoparticles in Toronto and Montreal, Canada.

There is growing interest to move beyond fine particle mass concentrations (PM2.5) when evaluating the population health impacts of outdoor air pollution. However, few exposure models are currently available to support such analyses. In this study, we conducted large-scale monitoring campaigns across Montreal and Toronto, Canada during summer 2018 and winter 2019 and developed models to predict spatial variations in (1) the ability of PM2.5 to generate reactive oxygen species in the lung fluid (ROS), (2) PM2.5 oxidative potential based on the depletion of ascorbate (OPAA) and glutathione (OPGSH) in a cell-free assay, and (3) anhysteretic magnetic remanence (XARM) as an indicator of magnetite nanoparticles. We also examined how exposure to PM oxidative capacity metrics (ROS/OP) varied by socioeconomic status within each city. In Montreal, areas with higher material deprivation, indicating lower area-level average household income and employment, were exposed to PM2.5 characterized by higher ROS and OP. This relationship was not observed in Toronto. The developed models will be used in epidemiologic studies to assess the health effects of exposure to PM2.5 and iron-rich magnetic nanoparticles in Toronto and Montreal.

Ambient particulate matter oxidative potential: Chemical determinants, associated health effects, and strategies for risk management.

Exposure to ambient air pollution has an adverse influence on human health. There is increasing evidence that oxidative potential (OP), the capacity of airborne pollutants to oxidize target molecules by generating redox oxidizing species, is a plausible metric for particulate matter (PM) toxicity. Here we describe the commonly used acellular techniques for measuring OP (respiratory tract lining fluid, dithiothreitol, ascorbic acid, and electron paramagnetic resonance assays) and review the PM chemical constituents that have been identified to drive the OP response. We further perform a review of the epidemiologic literature to identify studies that reported an association between exposure to ambient PM and a health outcome in a human population, and in which exposure was measured by both PM mass concentration and OP. Laboratory studies have shown that specific redox-active metals and quinones are able to contribute OP directly. However, interactions among PM species may alter the redox properties of PM components. In ambient PM measurements, all OP assays were found to be correlated with metals (Fe, Cu) and organic species (photochemically aged organics). Across the epidemiological studies reviewed, associations between fine PM (PM2.5) mass and cardio-respiratory outcomes were found to be stronger at elevated OP levels but findings varied across the different OP measurement techniques. Future work should aim to identify specific situations in which PM OP can improve air pollution exposure assessment and/or risk management. This may be particularly useful in countries with low PM2.5 mass concentrations over broad spatial scales where such information may greatly improve the efficiency of risk management activities.

Blood and hair mercury concentrations among Cree First Nations of Eeyou Istchee (Quebec, Canada): time trends, prenatal exposure and links to local fish consumption.

To describe exposure to methylmercury among Cree, focusing on women of childbearing age, we used data from 2 studies. Multiple regression was employed to examine associations between blood and hair mercury concentrations and consumption of locally harvested fish. Approximately 9.9% of non-pregnant women aged 15-44 y and 3.9% of pregnant women required follow-up according to Health Canada's blood mercury guidance value of 40 nmol/L. 8% of hair mercury observations in the non-pregnant women and 2.5% among pregnant women exceeded the equivalent threshold of 10 nmol/g. The geometric mean blood mercury concentration was 12.7 nmol/L in 1,429 persons aged 8 and over, and 17.7 nmol/L in adults aged 18 and older. The proportion of hair mercury concentrations greater than 12.5 nmol/g decreased in all age-sex groups when comparing the 2002-2009 data to published values for 1993-1994. Among women of childbearing age, local fish consumption was associated with increased blood and hair mercury concentrations. While over 90% of women of childbearing age in this population have acceptable levels of mercury, ongoing intake of mercury suggests that their consumption of fish with known high mercury content be minimised. Reducing consumption of fish known to be high in mercury content needs to be balanced with promoting ongoing connection to Cree culture and land-based activities that are also important determinants of health.