Systematic review and meta-analysis of cohort studies of long term outdoor nitrogen dioxide exposure and mortality.

OBJECTIVE: To determine whether long term exposure to outdoor nitrogen dioxide (NO2) is associated with all-cause or cause-specific mortality. METHODS: MEDLINE, Embase, CENTRAL, Global Health and Toxline databases were searched using terms developed by a librarian. Screening, data extraction and risk of bias assessment were completed independently by two reviewers. Conflicts were resolved through consensus and/or involvement of a third reviewer. Pooling of results across studies was conducted using random effects models, heterogeneity among included studies was assessed using Cochran's Q and I2 measures, and sources of heterogeneity were evaluated using meta-regression. Sensitivity of pooled estimates to individual studies was examined and publication bias was evaluated using Funnel plots, Begg's and Egger's tests, and trim and fill. RESULTS: Seventy-nine studies based on 47 cohorts, plus one set of pooled analyses of multiple European cohorts, met inclusion criteria. There was a consistently high degree of heterogeneity. After excluding studies with probably high or high risk of bias in the confounding domain (n = 12), pooled hazard ratios (HR) indicated that long term exposure to NO2 was significantly associated with mortality from all/ natural causes (pooled HR 1.047, 95% confidence interval (CI), 1.023-1.072 per 10 ppb), cardiovascular disease (pooled HR 1.058, 95%CI 1.026-1.091), lung cancer (pooled HR 1.083, 95%CI 1.041-1.126), respiratory disease (pooled HR 1.062, 95%CI1.035-1.089), and ischemic heart disease (pooled HR 1.111, 95%CI 1.079-1.144). Pooled estimates based on multi-pollutant models were consistently smaller than those from single pollutant models and mostly non-significant. CONCLUSIONS: For all causes of death other than cerebrovascular disease, the overall quality of the evidence is moderate, and the strength of evidence is limited, while for cerebrovascular disease, overall quality is low and strength of evidence is inadequate. Important uncertainties remain, including potential confounding by co-pollutants or other concomitant exposures, and limited supporting mechanistic evidence. (PROSPERO registration number CRD42018084497).

Correction to: Systematic review and meta-analysis of case-crossover and time-series studies of short term outdoor nitrogen dioxide exposure and ischemic heart disease morbidity.

An amendment to this paper has been published and can be accessed via the original article.

Systematic review and meta-analysis of case-crossover and time-series studies of short term outdoor nitrogen dioxide exposure and ischemic heart disease morbidity.

BACKGROUND: Nitrogen dioxide (NO2) is a pervasive urban pollutant originating primarily from vehicle emissions. Ischemic heart disease (IHD) is associated with a considerable public health burden worldwide, but whether NO2 exposure is causally related to IHD morbidity remains in question. Our objective was to determine whether short term exposure to outdoor NO2 is causally associated with IHD-related morbidity based on a synthesis of findings from case-crossover and time-series studies. METHODS: MEDLINE, Embase, CENTRAL, Global Health and Toxline databases were searched using terms developed by a librarian. Screening, data extraction and risk of bias assessment were completed independently by two reviewers. Conflicts between reviewers were resolved through consensus and/or involvement of a third reviewer. Pooling of results across studies was conducted using random effects models, heterogeneity among included studies was assessed using Cochran's Q and I2 measures, and sources of heterogeneity were evaluated using meta-regression. Sensitivity of pooled estimates to individual studies was examined using Leave One Out analysis and publication bias was evaluated using Funnel plots, Begg's and Egger's tests, and trim and fill. RESULTS: Thirty-eight case-crossover studies and 48 time-series studies were included in our analysis. NO2 was significantly associated with IHD morbidity (pooled odds ratio from case-crossover studies: 1.074 95% CI 1.052-1.097; pooled relative risk from time-series studies: 1.022 95% CI 1.016-1.029 per 10 ppb). Pooled estimates for case-crossover studies from Europe and North America were significantly lower than for studies conducted elsewhere. The high degree of heterogeneity among studies was only partially accounted for in meta-regression. There was evidence of publication bias, particularly for case-crossover studies. For both case-crossover and time-series studies, pooled estimates based on multi-pollutant models were smaller than those from single pollutant models, and those based on older populations were larger than those based on younger populations, but these differences were not statistically significant. CONCLUSIONS: We concluded that there is a likely causal relationship between short term NO2 exposure and IHD-related morbidity, but important uncertainties remain, particularly related to the contribution of co-pollutants or other concomitant exposures, and the lack of supporting evidence from toxicological and controlled human studies.

Health impact analysis of PM2.5 from wildfire smoke in Canada (2013-2015, 2017-2018).

Smoke from wildfires contains many air pollutants of concern and epidemiological studies have identified associations between exposure to wildfire smoke PM2.5 and mortality and respiratory morbidity, and a possible association with cardiovascular morbidity. For this study, a retrospective analysis of air quality modelling was performed to quantify the exposure to wildfire-PM2.5 across the Canadian population. The model included wildfire emissions from across North America for a 5-month period from May to September (i.e. wildfire season), between 2013 and 2015 and 2017-2018. Large variations in wildfire-PM2.5 were noted year-to-year, geospatially, and within fire season. The model results were then used to estimate the national population health impacts attributable to wildfire-PM2.5 and the associated economic valuation. The analysis estimated annual premature mortalities ranging from 54-240 premature mortalities attributable to short-term exposure and 570-2500 premature mortalities attributable to long-term exposure, as well as many non-fatal cardiorespiratory health outcomes. The economic valuation of the population health impacts was estimated per year at $410M-$1.8B for acute health impacts and $4.3B-$19B for chronic health impacts for the study period. The health impacts were greatest in the provinces with populations in close proximity to wildfire activity, though health impacts were also noted across many provinces indicating the long-range transport of wildfire-PM2.5. Understanding the population health impacts of wildfire smoke is important as climate change is anticipated to increase wildfire activity in Canada and abroad.

Human health effects of traffic-related air pollution (TRAP): a scoping review protocol.

BACKGROUND: Traffic-related air pollution (TRAP) is one of the major sources of exposure in urban areas and has been associated with a wide range of adverse human health effects. Much of the Canadian population is regularly exposed to TRAP as a result of daily activities (e.g., commuting) and a significant portion of the population resides in close proximity to major roadways. The objective of this scoping review is to develop an evidence map of the epidemiological literature of the human health effects of exposure to TRAP, to support future reviews and assessments by Health Canada. METHODS: Literature searches will be conducted in Ovid EMBASE and Ovid MEDLINE database. DistillerSR will be used to manage the review process. Two reviewers will independently screen the studies in a two-part process (title and abstract; full text) for eligibility. Epidemiological studies and reviews will be included if they report on the human health effects of exposure to TRAP. Data collection will include study design parameters and human health outcomes evaluated in the study. A descriptive analysis will be used to provide a high-level summary of the number of studies evaluating the different types of health effects and cross-tabulations by study design parameters. DISCUSSION: The scoping review will be used to identify subject areas for more detailed review and evaluation of the human health effects of TRAP by the Air Health Effects Assessment Division of Health Canada.

Evaluation of daily time spent in transportation and traffic-influenced microenvironments by urban Canadians.

Exposure to traffic and traffic-related air pollution is associated with a wide array of health effects. Time spent in a vehicle, in active transportation, along roadsides, and in close proximity to traffic can substantially contribute to daily exposure to air pollutants. For this study, we evaluated daily time spent in transportation and traffic-influenced microenvironments by urban Canadians using the Canadian Human Activity Pattern Survey (CHAPS) 2 results. Approximately 4-7% of daily time was spent in on- or near-road locations, mainly associated with being in a vehicle and smaller contributions from active transportation. Indoor microenvironments can be impacted by traffic emissions, especially when located near major roadways. Over 60% of the target population reported living within one block of a roadway with moderate to heavy traffic, which was variable with income level and city, and confirmed based on elevated NO2 exposure estimated using land use regression. Furthermore, over 55% of the target population ≤ 18 years reported attending a school or daycare in close proximity to moderate to heavy traffic, and little variation was observed based on income or city. The results underline the importance of traffic emissions as a major source of exposure in Canadian urban centers, given the time spent in traffic-influenced microenvironments.

Urban-rural differences in daily time-activity patterns, occupational activity and housing characteristics.

BACKGROUND: There is evidence that rural residents experience a health disadvantage compared to urban residents, associated with a greater prevalence of health risk factors and socioeconomic differences. We examined differences between urban and rural Canadians using data from the Canadian Human Activity Pattern Survey (CHAPS) 2. METHODS: Data were collected from 1460 respondents in two rural areas (Haldimand-Norfolk, Ontario and Annapolis Valley-Kings County, Nova Scotia) and 3551 respondents in five urban areas (Vancouver, Edmonton, Toronto, Montreal, and Halifax) using a 24-h recall diary and supplementary questionnaires administered using computer-assisted telephone interviews. We evaluated differences in time-activity patterns, occupational activity, and housing characteristics between rural and urban populations using multivariable linear and logistic regression models adjusted for design as well as demographic and socioeconomic covariates. Taylor linearization method and design-adjusted Wald tests were used to test statistical significance. RESULTS: After adjustment for demographic and socioeconomic covariates, rural children, adults and seniors spent on average 0.7 (p < 0.05), 1.2 (p < 0.001), and 0.9 (p < 0.001) more hours outdoors per day respectively than urban counterparts. 23.1% (95% CI: 19.0-27.2%) of urban and 37.8% (95% CI: 31.2-44.4%) of rural employed populations reported working outdoors and the distributions of job skill level and industry differed significantly (p < 0.001) between urban and rural residents. In particular, 11.4% of rural residents vs. 4.9% of urban residents were employed in unskilled jobs, and 11.5% of rural residents vs. <0.5% of urban residents were employ in primary industry. Rural residents were also more likely than urban residents to report spending time near gas or diesel powered equipment other than vehicles (16.9% vs. 5.2%, p < 0.001), more likely to report wood as a heating fuel (9.8% vs. <0.1%; p < 0.001 for difference in distribution of heating fuels), less likely to have an air conditioner (43.0% vs. 57.2%, p < 0.001), and more likely to smoke (29.1% vs. 19.0 %, p < 0.001). Private wells were the main water source in rural areas (68.6%) in contrast to public water systems (97.6%) in urban areas (p < 0.001). Despite these differences, no differences in self-reported health status were observed between urban and rural residents. CONCLUSIONS: We identified a number of differences between urban and rural residents, which provide evidence pertinent to the urban-rural health disparity.

Effects of age, season, gender and urban-rural status on time-activity: CanadianHuman Activity Pattern Survey 2 (CHAPS 2).

Estimation of population exposure is a main component of human health risk assessment for environmental contaminants. Population-level exposure assessments require time-activity pattern distributions in relation to microenvironments where people spend their time. Societal trends may have influenced time-activity patterns since previous Canadian data were collected 15 years ago. The Canadian Human Activity Pattern Survey 2 (CHAPS 2) was a national survey conducted in 2010-2011 to collect time-activity information from Canadians of all ages. Five urban and two rural locations were sampled using telephone surveys. Infants and children, key groups in risk assessment activities, were over-sampled. Survey participants (n = 5,011) provided time-activity information in 24-hour recall diaries and responded to supplemental questionnaires concerning potential exposures to specific pollutants, dwelling characteristics, and socio-economic factors. Results indicated that a majority of the time was spent indoors (88.9%), most of which was indoors at home, with limited time spent outdoors (5.8%) or in a vehicle (5.3%). Season, age, gender and rurality were significant predictors of time activity patterns. Compared to earlier data, adults reported spending more time indoors at home and adolescents reported spending less time outdoors, which could be indicative of broader societal trends. These findings have potentially important implications for assessment of exposure and risk. The CHAPS 2 data also provide much larger sample sizes to allow for improved precision and are more representative of infants, children and rural residents.

Cell death, stress-responsive transgene activation, and deficits in the olfactory system of larval zebrafish following cadmium exposure.

Cadmium (Cd) is a well-described environmental pollutant known to have adverse effects in fish, including behavioral deficits. We have previously reported the development of an in vivo system that utilizes hsp70 gene activation as a measure of acute 3 h cadmium toxicity in whole living transgenic zebrafish larvae carrying a stably integrated hsp70-enhanced green fluorescent protein (eGFP) reporter gene. Here, we report that activation of this transgene in olfactory epithelium of zebrafish larvae during 96 h sublethal Cd exposure is predictive of cadmium-induced cell death, altered histological and surface organization of the epithelium, and changes in olfactory dependent behavior. The transgene is first activated in the olfactory epithelium at concentrations below those giving rise to significant defects, but exhibits a more robust response following exposure to Cd at concentrations that begin to cause significant cell death, morphological alterations, and behavioral deficits. Further, the data show that Cd-induced olfactory deficits reported previously in juvenile and adult fish can also occur during larval stages of fish development, and that such behavioral deficits are closely associated with cell death and structural alterations in the olfactory epithelium.

Brief embryonic cadmium exposure induces a stress response and cell death in the developing olfactory system followed by long-term olfactory deficits in juvenile zebrafish.

The toxic effects of cadmium and other metals have been well established. A primary target of these metals is known to be the olfactory system, and fish exposed to a number of different waterborne metals display deficiencies in olfaction. Importantly, exposure over embryonic/larval development periods can cause deficits in chemosensory function in juvenile fish, but the specific cell types affected are unknown. We have previously characterized a transgenic zebrafish strain expressing the green fluorescent protein (eGFP) gene linked to the hsp70 gene promoter, and shown it to be a useful tool for examining cell-specific toxicity in living embryos and larvae. Here we show that the hsp70/eGFP transgene is strongly and specifically upregulated within the olfactory sensory neurons (OSNs) of transgenic zebrafish larvae following a brief 3-h exposure to water-borne cadmium. This molecular response was closely correlated to an endpoint for tissue damage within the olfactory placode, namely cell death. Furthermore, cadmium-induced olfactory cytotoxicity in zebrafish larvae gives rise to more permanent effects. Juvenile zebrafish briefly exposed to cadmium during early larval development display deficits in olfactory-dependent predator avoidance behaviors 4-6 weeks after a return to clean water. Lateral line neuromasts of exposed zebrafish larvae also activate both the endogenous hsp70 gene and the hsp70/eGFP transgene. The data reveal that even a very brief exposure period that gives rise to cell death within the developing olfactory placode results in long-term deficits in olfaction, and that hsp70/eGFP may serve as an effective indicator of sublethal cadmium exposure in sensory cells.

Accumulation and elimination of cadmium in larval stage zebrafish following acute exposure.

A number of recent studies have examined the impact of acute cadmium exposure on early zebrafish development at the morphological, cellular, and molecular levels. However, no information on the accumulation and elimination of cadmium during early life stages of zebrafish development has been available. Here we have quantified cadmium accumulation in larval zebrafish (Danio rerio) by graphite furnace atomic absorption spectroscopy following short-term acute exposure and recovery periods. Zebrafish (80 h postfertilization) were exposed to various concentrations of cadmium (0.2, 1.0, 5.0, 25, 125 microM) for 3 h. Cadmium accumulation in larvae increased with exposure concentration. After exposure at 5.0, 25, and 125 microM cadmium, the fish were allowed to recover in freshwater for 0, 12, or 24 h. Cadmium content did not show a statistically significant decrease over the recovery period when exposed to 5.0 or 25 microM cadmium, whereas significant losses over the recovery period were observed following 125 microM exposure. These results suggest that the larval zebrafish decrease total cadmium body burden only following relatively high short-term acutely toxic exposures.