Disease assimilation: The mortality impacts of fine particulate matter on immigrants to Canada.

BACKGROUND: Immigrants make up 20% of the Canadian population; however, little is known about the mortality impacts of fine particulate matter (PM2.5) air pollution on immigrants compared with non-immigrants, or about how impacts may change with duration in Canada. DATA AND METHODS: This study used the 2001 Canadian Census Health and Environment Cohort, a longitudinal cohort of 3.5 million individuals, of which 764,000 were classified as immigrants (foreign-born). Postal codes from annual income tax files were used to account for mobility among respondents and to assign annual PM2.5 concentrations from 1998 to 2016. Exposures were estimated as a three-year moving average prior to the follow-up year. Cox survival models were used to determine hazard ratios (HRs) for cause-specific mortality, comparing the Canadian and foreign-born populations, with further stratification by year of immigration grouped into 10-year cohorts. RESULTS: Differences in urban-rural settlement patterns resulted in greater exposure to PM2.5 for immigrants compared with non-immigrants (mean = 9.3 vs. 7.5 µg/m3), with higher exposures among more recent immigrants. In fully adjusted models, immigrants had higher HRs per 10 µg/m3 increase in PM2.5 concentration compared with Canadian-born individuals for cardiovascular mortality (HR [95% confidence interval] = 1.22 [1.12 to 1.34] vs. 1.12 [1.07 to 1.18]) and cerebrovascular mortality (HR = 1.25 [1.03 to 1.52] vs. 1.03 [0.93 to 1.15]), respectively. However, tests for differences between the two groups were not significant when Cochran's Q test was used. No significant associations were found for respiratory outcomes, except for lung cancer in non-immigrants (HR = 1.10 [1.02 to 1.18]). When stratified by year of immigration, differences in HRs across varied by cause of death. DISCUSSION: In Canada, PM2.5 is an equal-opportunity risk factor, with immigrants experiencing similar if not higher mortality risks compared with non-immigrants for cardiovascular-related causes of death. Some notable differences also existed with cerebrovascular and lung cancer deaths. Continued reductions in air pollution, particularly in urban areas, will improve the health of the Canadian population as a whole.

Low concentrations of fine particle air pollution and mortality in the Canadian Community Health Survey cohort.

BACKGROUND: Approximately 2.9 million deaths are attributed to ambient fine particle air pollution around the world each year (PM2.5). In general, cohort studies of mortality and outdoor PM2.5 concentrations have limited information on individuals exposed to low levels of PM2.5 as well as covariates such as smoking behaviours, alcohol consumption, and diet which may confound relationships with mortality. This study provides an updated and extended analysis of the Canadian Community Health Survey-Mortality cohort: a population-based cohort with detailed PM2.5 exposure data and information on a number of important individual-level behavioural risk factors. We also used this rich dataset to provide insight into the shape of the concentration-response curve for mortality at low levels of PM2.5. METHODS: Respondents to the Canadian Community Health Survey from 2000 to 2012 were linked by postal code history from 1981 to 2016 to high resolution PM2.5 exposure estimates, and mortality incidence to 2016. Cox proportional hazard models were used to estimate the relationship between non-accidental mortality and ambient PM2.5 concentrations (measured as a three-year average with a one-year lag) adjusted for socio-economic, behavioural, and time-varying contextual covariates. RESULTS: In total, 50,700 deaths from non-accidental causes occurred in the cohort over the follow-up period. Annual average ambient PM2.5 concentrations were low (i.e. 5.9 µg/m3, s.d. 2.0) and each 10 µg/m3 increase in exposure was associated with an increase in non-accidental mortality (HR = 1.11; 95% CI 1.04-1.18). Adjustment for behavioural covariates did not materially change this relationship. We estimated a supra-linear concentration-response curve extending to concentrations below 2 µg/m3 using a shape constrained health impact function. Mortality risks associated with exposure to PM2.5 were increased for males, those under age 65, and non-immigrants. Hazard ratios for PM2.5 and mortality were attenuated when gaseous pollutants were included in models. CONCLUSIONS: Outdoor PM2.5 concentrations were associated with non-accidental mortality and adjusting for individual-level behavioural covariates did not materially change this relationship. The concentration-response curve was supra-linear with increased mortality risks extending to low outdoor PM2.5 concentrations.

Evaluation of a method to indirectly adjust for unmeasured covariates in the association between fine particulate matter and mortality.

BACKGROUND: Indirect adjustment via partitioned regression is a promising technique to control for unmeasured confounding in large epidemiological studies. The method uses a representative ancillary dataset to estimate the association between variables missing in a primary dataset with the complete set of variables of the ancillary dataset to produce an adjusted risk estimate for the variable in question. The objective of this paper is threefold: 1) evaluate the method for non-linear survival models, 2) formalize an empirical process to evaluate the suitability of the required ancillary matching dataset, and 3) test modifications to the method to incorporate time-varying exposure data, and proportional weighting of datasets. METHODS: We used the association between fine particle air pollution (PM2.5) with mortality in the 2001 Canadian Census Health and Environment Cohort (CanCHEC, N = 2.4 million, 10-years follow-up) as our primary dataset, and the 2001 cycle of the Canadian Community Health Survey (CCHS, N = 80,630) as the ancillary matching dataset that contained confounding risk factor information not available in CanCHEC (e.g., smoking). The main evaluation process used a gold-standard approach wherein two variables (education and income) available in both datasets were excluded, indirectly adjusted for, and compared to true models with education and income included to assess the amount of bias correction. An internal validation for objective 1 used only CanCHEC data, whereas an external validation for objective 2 replaced CanCHEC with the CCHS. The two proposed modifications were applied as part of the validation tests, as well as in a final indirect adjustment of four missing risk factor variables (smoking, alcohol use, diet, and exercise) in which adjustment direction and magnitude was compared to models using an equivalent longitudinal cohort with direct adjustment for the same variables. RESULTS: At baseline (2001) both cohorts had very similar PM2.5 distributions across population characteristics, although levels for CCHS participants were consistently 1.8-2.0 µg/m3 lower. Applying sample-weighting largely corrected for this discrepancy. The internal validation tests showed minimal downward bias in PM2.5 mortality hazard ratios of 0.4-0.6% using a static exposure, and 1.7-3% when a time-varying exposure was used. The external validation of the CCHS as the ancillary dataset showed slight upward bias of -0.7 to -1.1% and downward bias of 1.3-2.3% using the static and time-varying approaches respectively. CONCLUSIONS: The CCHS was found to be fairly well representative of CanCHEC and its use in Canada for indirect adjustment is warranted. Indirect adjustment methods can be used with survival models to correct hazard ratio point estimates and standard errors in models missing key covariates when a representative matching dataset is available. The results of this formal evaluation should encourage other cohorts to assess the suitability of ancillary datasets for the application of the indirect adjustment methodology to address potential residual confounding.

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Associations between fine particulate matter and mortality in the 2001 Canadian Census Health and Environment Cohort.

BACKGROUND: Large cohort studies have been used to characterise the association between long-term exposure to fine particulate matter (PM2.5) air pollution with non-accidental, and cause-specific mortality. However, there has been no consensus as to the shape of the association between concentration and response. METHODS: To examine the shape of this association, we developed a new cohort based on respondents to the 2001 Canadian census long-form. We applied new annual PM2.5 concentration estimates based on remote sensing and ground measurements for Canada at a 1km spatial scale from 1998 to 2011. We followed 2.4 million respondents who were non-immigrants aged 25-90 years and did not reside in an institution over a 10 year period for mortality. Exposures were assigned as a 3-year mean prior to the follow-up year. Income tax files were used to account for residential mobility among respondents using postal codes, with probabilistic imputation used for missing postal codes in the tax data. We used Cox survival models to determine hazard ratios (HRs) for cause-specific mortality. We also estimated Shape Constrained Health Impact Functions (a concentration-response function) for selected causes of death. RESULTS: In models stratified by age, sex, airshed, and population centre size, and adjusted for individual and neighbourhood socioeconomic variables, HR estimates for non-accidental mortality were HR = 1.18 (95% CI: 1.15-1.21) per 10µg/m3 increase in concentration. We observed higher HRs for cardiovascular disease (HR=1.25; 95% CI: 1.19-1.31), cardio-metabolic disease (HR = 1.27; 95% CI: 1.21-1.33), ischemic heart disease (HR = 1.36; 95% CI: 1.28-1.44) and chronic obstructive pulmonary disease (COPD) mortality (HR = 1.24; 95% CI: 1.11-1.39) compared to HR for all non-accidental causes of death. For non-accidental, cardio-metabolic, ischemic heart disease, respiratory and COPD mortality, the shape of the concentration-response curve was supra-linear, with larger differences in relative risk for lower concentrations. For both pneumonia and lung cancer, there was some suggestion that the curves were sub-linear. CONCLUSIONS: Associations between ambient concentrations of fine particulate matter and several causes of death were non-linear for each cause of death examined.

The association between the incidence of postmenopausal breast cancer and concentrations at street-level of nitrogen dioxide and ultrafine particles.

BACKGROUND: There is scant information as to whether traffic-related air pollution is associated with the incidence of breast cancer. Nitrogen dioxide (NO2) and ultrafine particles (UFPs, <0.1µm), are two pollutants that capture intra-urban variations in traffic-related air pollution and may also be associated with incidence. METHODS: We conducted a population-based, case-control study of street-level concentrations of NO2 and UFPs and incident postmenopausal breast cancer in Montreal, Canada. Incident cases were identified between 2008 and 2011 from all but one hospital that treated breast cancer in the Montreal area. Population controls were identified from provincial electoral lists of Montreal residents and frequency-matched to cases using 5-year age groups. Concentrations of NO2 and UFPs were estimated using two separate land-use regression models. Exposures were assigned to residential locations at the time of recruitment, and we identified residential histories of women who had lived in these residences for 10 years or more. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusting for individual-level and ecological covariates. We assessed the functional form of NO2 and UFP exposures using natural cubic splines. RESULTS: We found that the functional form of the response functions between incident postmenopausal breast cancer and concentrations of NO2 and UFPs were consistent with linearity. For NO2, we found increasing risks of breast cancer for all subjects combined and stronger associations when analyses were restricted to those women who had lived at their current address for 10 years or more. Specifically, the OR, adjusted for personal covariates, per increase in the interquartile range (IQR=3.75 ppb) of NO2 was 1.08 (95%CI: 0.92-1.27). For women living in their homes for 10 years or more, the adjusted OR was 1.17 (95%CI: 0.93-1.46; IQR=3.84 ppb); for those not living at that home 10 years before the study, it was 0.93 (95%CI: 0.64, 1.36; IQR=3.65 ppb). For UFPs, the ORs were lower than for NO2, with little evidence of association in any of the models or sub-analyses and little variability in the ORs (about 1.02 for an IQR of ~3500cm-3). On the other hand, we found higher ORs amongst cases with positive oestrogen and progesterone receptor status; namely for NO2, the OR was 1.13 (95%CI: 0.94-1.35) and for UFPs it was 1.05 (95%CI: 0.96-1.14). CONCLUSIONS: Our findings suggest that exposure to ambient NO2 and UFPs may increase the risk of incident postmenopausal breast cancer especially amongst cases with positive oestrogen and progesterone receptor status.

Maternal exposure to ambient air pollution and risk of early childhood cancers: A population-based study in Ontario, Canada.

BACKGROUND: There are increasing concerns regarding the role of exposure to ambient air pollution during pregnancy in the development of early childhood cancers. OBJECTIVE: This population based study examined whether prenatal and early life (<1year of age) exposures to ambient air pollutants, including nitrogen dioxide (NO2) and particulate matter with aerodynamic diameters ≤2.5µm (PM2.5), were associated with selected common early childhood cancers in Canada. METHODS: 2,350,898 singleton live births occurring between 1988 and 2012 were identified in the province of Ontario, Canada. We assigned temporally varying satellite-derived estimates of PM2.5 and land-use regression model estimates of NO2 to maternal residences during pregnancy. Incident cases of 13 subtypes of pediatric cancers among children up to age 6 until 2013 were ascertained through administrative health data linkages. Associations of trimester-specific, overall pregnancy and first year of life exposures were evaluated using Cox proportional hazards models, adjusting for potential confounders. RESULTS: A total of 2044 childhood cancers were identified. Exposure to PM2.5, per interquartile range increase, over the entire pregnancy, and during the first trimester was associated with an increased risk of astrocytoma (hazard ratio (HR) per 3.9µg/m3=1.38 (95% CI: 1.01, 1.88) and, HR per 4.0µg/m3=1.40 (95% CI: 1.05-1.86), respectively). We also found a positive association between first trimester NO2 and acute lymphoblastic leukemia (ALL) (HR=1.20 (95% CI: 1.02-1.41) per IQR (13.3ppb)). CONCLUSIONS: In this population-based study in the largest province of Canada, results suggest an association between exposure to ambient air pollution during pregnancy, especially in the first trimester and an increased risk of astrocytoma and ALL. Further studies are required to replicate the findings of this study with adjustment for important individual-level confounders.

A class of non-linear exposure-response models suitable for health impact assessment applicable to large cohort studies of ambient air pollution.

The effectiveness of regulatory actions designed to improve air quality is often assessed by predicting changes in public health resulting from their implementation. Risk of premature mortality from long-term exposure to ambient air pollution is the single most important contributor to such assessments and is estimated from observational studies generally assuming a log-linear, no-threshold association between ambient concentrations and death. There has been only limited assessment of this assumption in part because of a lack of methods to estimate the shape of the exposure-response function in very large study populations. In this paper, we propose a new class of variable coefficient risk functions capable of capturing a variety of potentially non-linear associations which are suitable for health impact assessment. We construct the class by defining transformations of concentration as the product of either a linear or log-linear function of concentration multiplied by a logistic weighting function. These risk functions can be estimated using hazard regression survival models with currently available computer software and can accommodate large population-based cohorts which are increasingly being used for this purpose. We illustrate our modeling approach with two large cohort studies of long-term concentrations of ambient air pollution and mortality: the American Cancer Society Cancer Prevention Study II (CPS II) cohort and the Canadian Census Health and Environment Cohort (CanCHEC). We then estimate the number of deaths attributable to changes in fine particulate matter concentrations over the 2000 to 2010 time period in both Canada and the USA using both linear and non-linear hazard function models.

Risk estimates of mortality attributed to low concentrations of ambient fine particulate matter in the Canadian community health survey cohort.

BACKGROUND: Understanding the shape of the relationship between long-term exposure to ambient fine particulate matter (PM2.5) concentrations and health risks is critical for health impact and risk assessment. Studies evaluating the health risks of exposure to low concentrations of PM2.5 are limited. Further, many existing studies lack individual-level information on potentially important behavioural confounding factors. METHODS: A prospective cohort study was conducted among a subset of participants in a cohort that linked respondents of the Canadian Community Health Survey to mortality (n = 299,500) with satellite-derived ambient PM2.5 estimates. Participants enrolled between 2000 and 2008 were followed to date of death or December 31, 2011. Cox proportional hazards models were used to estimate hazard ratios (HRs) for mortality attributed to PM2.5 exposure, adjusted for individual-level and contextual covariates, including smoking behaviour and body mass index (BMI). RESULTS: Approximately 26,300 non-accidental deaths, of which 32.5 % were due to circulatory disease and 9.1 % were due to respiratory disease, occurred during the follow-up period. Ambient PM2.5 exposures were relatively low (mean = 6.3 µg/m(3)), yet each 10 µg/m(3) increase in exposure was associated with increased risks of non-accidental (HR = 1.26; 95 % CI: 1.19-1.34), circulatory disease (HR = 1.19; 95 % CI: 1.07-1.31), and respiratory disease mortality (HR = 1.52; 95 % CI: 1.26-1.84) in fully adjusted models. Higher hazard ratios were observed for respiratory mortality among respondents who never smoked (HR = 1.97; 95 % CI: 1.24-3.13 vs. HR = 1.45; 95 % CI: 1.17-1.79 for ever smokers), and among obese (BMI ≥ 30) respondents (HR = 1.76; 95 % CI: 1.15-2.69 vs. HR = 1.41; 95 % CI: 1.04-1.91 for normal weight respondents), though differences between groups were not statistically significant. A threshold analysis for non-accidental mortality estimated a threshold concentration of 0 µg/m(3) (+95 % CI = 4.5 µg/m(3)). CONCLUSIONS: Increased risks of non-accidental, circulatory, and respiratory mortality were observed even at very low concentrations of ambient PM2.5. HRs were generally greater than most literature values, and adjusting for behavioural covariates served to reduce HR estimates slightly.

Oxidative burden of fine particulate air pollution and risk of cause-specific mortality in the Canadian Census Health and Environment Cohort (CanCHEC).

BACKROUND: Fine particulate air pollution (PM2.5) is known to contribute to cardiorespiratory mortality but it is not clear how PM2.5 oxidative burden (i.e. the ability of PM2.5 to cause oxidative stress) may influence long-term mortality risk. METHODS: We examined the relationship between PM2.5 oxidative burden and cause-specific mortality in Ontario, Canada. Integrated PM2.5 samples were collected from 30 provincial monitoring sites between 2012 and 2013. The oxidative potential (% depletion/µg) of regional PM2.5 was measured as the ability of filter extracts to deplete antioxidants (glutathione and ascorbate) in a synthetic respiratory tract lining fluid. PM2.5oxidative burden was calculated as the product of PM2.5 mass concentrations and regional estimates of oxidative potential. In total, this study included 193,300 people who completed the Canadian long-form census in 1991 and who lived within 5km of a site where oxidative potential was measured. Deaths occurring between 1991 and 2009 were identified through record linkages and Cox proportional hazard models were used to estimate hazard ratios (and 95% confidence intervals) for interquartile changes in exposure adjusting for individual-level covariates and indirect-adjustment for smoking and obesity. RESULTS: Glutathione-related oxidative burden was associated with cause-specific mortality. For lung cancer specifically, this metric was associated with a 12% (95% CI: 5.0-19) increased risk of mortality whereas a 5.0% (95% CI: 0.1, 10) increase was observed for PM2.5. Indirect adjustment for smoking and obesity decreased the lung cancer hazard ratio for glutathione-related oxidative burden but it remained significantly elevated (HR=1.07, 95% CI: 1.005, 1.146). Ascorbate-related oxidative burden was not associated with mortality. CONCLUSIONS: Our findings suggest that glutathione-related oxidative burden may be more strongly associated with lung cancer mortality than PM2.5 mass concentrations.

Long-Term Ozone Exposure and Mortality in a Large Prospective Study.

RATIONALE: Tropospheric ozone (O3) is potentially associated with cardiovascular disease risk and premature death. Results from long-term epidemiological studies on O3 are scarce and inconclusive. OBJECTIVES: In this study, we examined associations between chronic ambient O3 exposure and all-cause and cause-specific mortality in a large cohort of U.S. adults. METHODS: Cancer Prevention Study II participants were enrolled in 1982. A total of 669,046 participants were analyzed, among whom 237,201 deaths occurred through 2004. We obtained estimates of O3 concentrations at the participant's residence from a hierarchical Bayesian space-time model. Estimates of fine particulate matter (particulate matter with an aerodynamic diameter of up to 2.5 µm [PM2.5]) and NO2 concentrations were obtained from land use regression. Cox proportional hazards regression models were used to examine mortality associations adjusted for individual- and ecological-level covariates. MEASUREMENTS AND MAIN RESULTS: In single-pollutant models, we observed significant positive associations between O3, PM2.5, and NO2 concentrations and all-cause and cause-specific mortality. In two-pollutant models adjusted for PM2.5, significant positive associations remained between O3 and all-cause (hazard ratio [HR] per 10 ppb, 1.02; 95% confidence interval [CI], 1.01-1.04), circulatory (HR, 1.03; 95% CI, 1.01-1.05), and respiratory mortality (HR, 1.12; 95% CI, 1.08-1.16) that were unchanged with further adjustment for NO2. We also observed positive mortality associations with both PM2.5 (both near source and regional) and NO2 in multipollutant models. CONCLUSIONS: Findings derived from this large-scale prospective study suggest that long-term ambient O3 contributes to risk of respiratory and circulatory mortality. Substantial health and environmental benefits may be achieved by implementing further measures aimed at controlling O3 concentrations.

Long-term Exposure to Fine Particulate Matter Air Pollution and Mortality Among Canadian Women.

BACKGROUND: Long-term exposure to fine particulate matter (PM2.5) has been associated with increased mortality, especially from cardiovascular disease. There are, however, uncertainties about the nature of the exposure-response relation at lower concentrations. In Canada, where ambient air pollution levels are substantially lower than in most other countries, there have been few attempts to study associations between long-term exposure to PM2.5 and mortality. METHODS: We present a prospective cohort analysis of 89,248 women who enrolled in the Canadian National Breast Screening Study between 1980 and 1985, and for whom residential measures of PM2.5 could be assigned. We derived individual-level estimates of long-term exposure to PM2.5 from satellite observations. We linked cohort records to national mortality data to ascertain mortality between 1980 and 2005. We used Cox proportional hazards models to characterize associations between PM2.5 and several causes of death. The hazard ratios (HRs) and 95% confidence intervals (CIs) computed from these models were adjusted for several individual and neighborhood-level characteristics. RESULTS: The cohort was composed predominantly of Canadian-born (82%) and married (80%) women. The median residential concentration of PM2.5 was 9.1 µg/m(3) (standard deviation = 3.4). In fully adjusted models, a 10 µg/m(3) increase in PM2.5 exposure was associated with elevated risks of nonaccidental (HR: 1.12; 95% CI = 1.04, 1.19), and ischemic heart disease mortality (HR: 1.34; 95% CI = 1.09, 1.66). CONCLUSIONS: The findings from this study provide additional support for the hypothesis that exposure to very low levels of ambient PM2.5 increases the risk of cardiovascular mortality.

Data resource profile: 1991 Canadian Census Cohort.

The 1991 Canadian Census Cohort is the largest population-based cohort in Canada (N=2,734,835). Prior to the creation of this Cohort, no national population-based Canadian cohort was available to examine mortality by socioeconomic indicators. The 1991 Canadian Census Cohort was created via the linkage of a sub-sample of respondents from the mandatory 1991 Canadian Census long-form to historical tax summary files, Canadian Mortality Database, Canadian Cancer Database, 1991 Health and Activity Limitation Survey and a sub-sample of the Longitudinal Worker File. Overall ascertainment of mortality and cancer is anticipated to be nearly complete and the Cohort is broadly representative of most groups in the Canadian population. The Cohort has been used to examine mortality outcomes by different indicators of socioeconomic status, occupational categories, ethnic groups, educational attainment, and for exposure to ambient air pollution. Results have shown that the estimated remaining years of life at age 25 differed substantially by income adequacy quintile, educational attainment, housing type and Aboriginal ancestry.