Daniel Krewski

Cardiovascular Mortality and Long-Term Exposure to Particulate Air Pollution Epidemiological Evidence of General Pathophysiological Pathways of Disease

Background—Epidemiologic studies have linked long-term exposure to fine particulate matter air pollution (PM) to broad cause-of-death mortality. Associations with specific cardiopulmonary diseases might be useful in exploring potential mechanistic pathways linking exposure and mortality. Methods and Results—General pathophysiological pathways linking long-term PM exposure with mortality and expected patterns of PM mortality with specific causes of death were proposed a priori. Vital status, risk factor, and cause-of-death data, collected by the American Cancer Society as part of the Cancer Prevention II study, were linked with air pollution data from United States metropolitan areas. Cox Proportional Hazard regression models were used to estimate PM-mortality associations with specific causes of death. Long-term PM exposures were most strongly associated with mortality attributable to ischemic heart disease, dysrhythmias, heart failure, and cardiac arrest. For these cardiovascular causes of death, a 10-&mgr;g/m3 elevation in fine PM was associated with 8% to 18% increases in mortality risk, with comparable or larger risks being observed for smokers relative to nonsmokers. Mortality attributable to respiratory disease had relatively weak associations. Conclusions—Fine particulate air pollution is a risk factor for cause-specific cardiovascular disease mortality via mechanisms that likely include pulmonary and systemic inflammation, accelerated atherosclerosis, and altered cardiac autonomic function. Although smoking is a much larger risk factor for cardiovascular disease mortality, exposure to fine PM imposes additional effects that seem to be at least additive to if not synergistic with smoking.

TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

Spatial analysis of air pollution and mortality in Los Angeles.

Background: The assessment of air pollution exposure using only community average concentrations may lead to measurement error that lowers estimates of the health burden attributable to poor air quality. To test this hypothesis, we modeled the association between air pollution and mortality using small-area exposure measures in Los Angeles, California. Methods: Data on 22,905 subjects were extracted from the American Cancer Society cohort for the period 1982–2000 (5,856 deaths). Pollution exposures were interpolated from 23 fine particle (PM2.5) and 42 ozone (O3) fixed-site monitors. Proximity to expressways was tested as a measure of traffic pollution. We assessed associations in standard and spatial multilevel Cox regression models. Results: After controlling for 44 individual covariates, all-cause mortality had a relative risk (RR) of 1.17 (95% confidence interval = 1.05–1.30) for an increase of 10 &mgr;g/m3 PM2.5 and a RR of 1.11 (0.99–1.25) with maximal control for both individual and contextual confounders. The RRs for mortality resulting from ischemic heart disease and lung cancer deaths were elevated, in the range of 1.24–1.6, depending on the model used. These PM results were robust to adjustments for O3 and expressway exposure. Conclusion: Our results suggest the chronic health effects associated with within-city gradients in exposure to PM2.5 may be even larger than previously reported across metropolitan areas. We observed effects nearly 3 times greater than in models relying on comparisons between communities. We also found specificity in cause of death, with PM2.5 associated more strongly with ischemic heart disease than with cardiopulmonary or all-cause mortality.

Cardiovascular Mortality and Exposure to Airborne Fine Particulate Matter and Cigarette Smoke Shape of the Exposure-Response Relationship

Background— Fine particulate matter exposure from both ambient air pollution and secondhand cigarette smoke has been associated with larger risks of cardiovascular mortality than would be expected on the basis of linear extrapolations of the relative risks from active smoking. This study directly assessed the shape of the exposure-response relationship between cardiovascular mortality and fine particulates from cigarette smoke and ambient air pollution. Methods and Results— Prospective cohort data for >1 million adults were collected by the American Cancer Society as part of the Cancer Prevention Study II in 1982. Cox proportional hazards regression models that included variables for increments of cigarette smoking and variables to control for education, marital status, body mass, alcohol consumption, occupational exposures, and diet were used to describe the mortality experience of the cohort. Adjusted relative risks of mortality were plotted against estimated average daily dose of fine particulate matter from cigarette smoke along with comparison estimates for secondhand cigarette smoke and air pollution. There were substantially increased cardiovascular mortality risks at very low levels of active cigarette smoking and smaller but significant excess risks even at the much lower exposure levels associated with secondhand cigarette smoke and ambient air pollution. Conclusions— Relatively low levels of fine particulate exposure from either air pollution or secondhand cigarette smoke are sufficient to induce adverse biological responses increasing the risk of cardiovascular disease mortality. The exposure-response relationship between cardiovascular disease mortality and fine particulate matter is relatively steep at low levels of exposure and flattens out at higher exposures.

Residential radon and risk of lung cancer : A combined analysis of 7 north american case-control studies

Background: Underground miners exposed to high levels of radon have an excess risk of lung cancer. Residential exposure to radon is at much lower levels, and the risk of lung cancer with residential exposure is less clear. We conducted a systematic analysis of pooled data from all North American residential radon studies. Methods: The pooling project included original data from 7 North American case–control studies, all of which used long-term α-track detectors to assess residential radon concentrations. A total of 3662 cases and 4966 controls were retained for the analysis. We used conditional likelihood regression to estimate the excess risk of lung cancer. Results: Odds ratios (ORs) for lung cancer increased with residential radon concentration. The estimated OR after exposure to radon at a concentration of 100 Bq/m3 in the exposure time window 5 to 30 years before the index date was 1.11 (95% confidence interval = 1.00–1.28). This estimate is compatible with the estimate of 1.12 (1.02–1.25) predicted by downward extrapolation of the miner data. There was no evidence of heterogeneity of radon effects across studies. There was no apparent heterogeneity in the association by sex, educational level, type of respondent (proxy or self), or cigarette smoking, although there was some evidence of a decreasing radon-associated lung cancer risk with age. Analyses restricted to subsets of the data with presumed more accurate radon dosimetry resulted in increased estimates of risk. Conclusions: These results provide direct evidence of an association between residential radon and lung cancer risk, a finding predicted using miner data and consistent with results from animal and in vitro studies.

Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide.

Note: This article was originally published with an incorrect version of the Acknowledgments, which appeared on p. 218 of the print version. The correct version of the Acknowledgments appeared on pp. 1–2. The corrected article is available below.

Overview of the Reanalysis of the Harvard Six Cities Study and American Cancer Society Study of Particulate Air Pollution and Mortality

This article provides an overview of the Reanalysis Study of the Harvard Six Cities and the American Cancer Society (ACS) studies of particulate air pollution and mortality. The previous findings of the studies have been subject to debate. In response, a reanalysis team, comprised of Canadian and Amercian researchers, was invited to participate in an independent reanalysis project to address the concerns. Phase I of the reanalysis involved the design of data audits to determine whether each study conformed to the consistency and accuracy of their data. Phase II of the reanalysis involved conducting a series of comprehensive analyses using alternative statistical methods. Alternative models were also used to identify covariates that may confound or modify the association of particulate air pollution as well as identify sensitive population subgroups. The audit demonstrated that the data in the original analyses were of high quality, as were the risk estimates reported by the original investigators. The sensitivity analysis illustrated that the mortality risk estimates reported in both studies were found to be robust against alternative Cox models. Detailed investigation of the covariate effects found a significant modifying effect of education and a relative risk of mortality associated with fine particles and declining education levels. The study team applied spatial analytic methods to the ACS data, resulting in various levels of spatial autocorrelations supporting the reported association for fine particles mortality of the original investigators as well as demonstrating a significant association between sulfur dioxide and mortality. Collectively, our reanalysis suggest that mortality may be attributable to more than one component of the complex mixture of ambient air pollutants for U.S. urban areas.

Lung Cancer and Cardiovascular Disease Mortality Associated with Ambient Air Pollution and Cigarette Smoke: Shape of the Exposure–Response Relationships

Background: Lung cancer and cardiovascular disease (CVD) mortality risks increase with smoking, secondhand smoke (SHS), and exposure to fine particulate matter < 2.5 μm in diameter (PM2.5) from ambient air pollution. Recent research indicates that the exposure–response relationship for CVD is nonlinear, with a steep increase in risk at low exposures and flattening out at higher exposures. Comparable estimates of the exposure–response relationship for lung cancer are required for disease burden estimates and related public health policy assessments. Objectives: We compared exposure–response relationships of PM2.5 with lung cancer and cardiovascular mortality and considered the implications of the observed differences for efforts to estimate the disease burden of PM2.5. Methods: Prospective cohort data for 1.2 million adults were collected by the American Cancer Society as part of the Cancer Prevention Study II. We estimated relative risks (RRs) for increments of cigarette smoking, adjusting for various individual risk factors. RRs were plotted against estimated daily dose of PM2.5 from smoking along with comparison estimates for ambient air pollution and SHS. Results: For lung cancer mortality, excess risk rose nearly linearly, reaching maximum RRs > 40 among long-term heavy smokers. Excess risks for CVD mortality increased steeply at low exposure levels and leveled off at higher exposures, reaching RRs of approximately 2–3 for cigarette smoking. Conclusions: The exposure–response relationship associated with PM2.5 is qualitatively different for lung cancer versus cardiovascular mortality. At low exposure levels, cardiovascular deaths are projected to account for most of the burden of disease, whereas at high levels of PM2.5, lung cancer becomes proportionately more important.

Epidemiologic Evidence of Relationships Between Reproductive and Child Health Outcomes and Environmental Chemical Contaminants

This review summarizes the level of epidemiologic evidence for relationships between prenatal and/or early life exposure to environmental chemical contaminants and fetal, child, and adult health. Discussion focuses on fetal loss, intrauterine growth restriction, preterm birth, birth defects, respiratory and other childhood diseases, neuropsychological deficits, premature or delayed sexual maturation, and certain adult cancers linked to fetal or childhood exposures. Environmental exposures considered here include chemical toxicants in air, water, soil/house dust and foods (including human breast milk), and consumer products. Reports reviewed here included original epidemiologic studies (with at least basic descriptions of methods and results), literature reviews, expert group reports, meta-analyses, and pooled analyses. Levels of evidence for causal relationships were categorized as sufficient, limited, or inadequate according to predefined criteria. There was sufficient epidemiological evidence for causal relationships between several adverse pregnancy or child health outcomes and prenatal or childhood exposure to environmental chemical contaminants. These included prenatal high-level methylmercury (CH3Hg) exposure (delayed developmental milestones and cognitive, motor, auditory, and visual deficits), high-level prenatal exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and related toxicants (neonatal tooth abnormalities, cognitive and motor deficits), maternal active smoking (delayed conception, preterm birth, fetal growth deficit [FGD] and sudden infant death syndrome [SIDS]) and prenatal environmental tobacco smoke (ETS) exposure (preterm birth), low-level childhood lead exposure (cognitive deficits and renal tubular damage), high-level childhood CH3Hg exposure (visual deficits), high-level childhood exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (chloracne), childhood ETS exposure (SIDS, new-onset asthma, increased asthma severity, lung and middle ear infections, and adult breast and lung cancer), childhood exposure to biomass smoke (lung infections), and childhood exposure to outdoor air pollutants (increased asthma severity). Evidence for some proven relationships came from investigation of relatively small numbers of children with high-dose prenatal or early childhood exposures, e.g., CH3Hg poisoning episodes in Japan and Iraq. In contrast, consensus on a causal relationship between incident asthma and ETS exposure came only recently after many studies and prolonged debate. There were many relationships supported by limited epidemiologic evidence, ranging from several studies with fairly consistent findings and evidence of dose-response relationships to those where 20 or more studies provided inconsistent or otherwise less than convincing evidence of an association. The latter included childhood cancer and parental or childhood exposures to pesticides. In most cases, relationships supported by inadequate epidemiologic evidence reflect scarcity of evidence as opposed to strong evidence of no effect. This summary points to three main needs: (1) Where relationships between child health and environmental exposures are supported by sufficient evidence of causal relationships, there is a need for (a) policies and programs to minimize population exposures and (b) population-based biomonitoring to track exposure levels, i.e., through ongoing or periodic surveys with measurements of contaminant levels in blood, urine and other samples. (2) For relationships supported by limited evidence, there is a need for targeted research and policy options ranging from ongoing evaluation of evidence to proactive actions. (3) There is a great need for population-based, multidisciplinary and collaborative research on the many relationships supported by inadequate evidence, as these represent major knowledge gaps. Expert groups faced with evaluating epidemiologic evidence of potential causal relationships repeatedly encounter problems in summarizing the available data. A major driver for undertaking such summaries is the need to compensate for the limited sample sizes of individual epidemiologic studies. Sample size limitations are major obstacles to exploration of prenatal, paternal, and childhood exposures during specific time windows, exposure intensity, exposure–exposure or exposure–gene interactions, and relatively rare health outcomes such as childhood cancer. Such research needs call for investments in research infrastructure, including human resources and methods development (standardized protocols, biomarker research, validated exposure metrics, reference analytic laboratories). These are needed to generate research findings that can be compared and subjected to pooled analyses aimed at knowledge synthesis.

ASSOCIATION BETWEEN PARTICULATE- AND GAS-PHASE COMPONENTS OF URBAN AIR POLLUTION AND DAILY MORTALITY IN EIGHT CANADIAN CITIES

Although some consensus has emerged among the scientific and regulatory communities that the urban ambient atmospheric mix of combustion related pollutants is a determinant of population health, the relative toxicity of the chemical and physical components of this complex mixture remains unclear. Daily mortality rates and concurrent data on sizefractionated particulate mass and gaseous pollutants were obtained in eight of Canadas largest cities from 1986 to 1996 inclusive in order to examine the relative toxicity of the components of the mixture of ambient air pollutants to which Canadians are exposed. Positive and statistically significant associations were observed between daily variations in both gas- and particulate-phase pollution and daily fluctuations in mortality rates. The association between air pollution and mortality could not be explained by temporalvariation in either mortality rates or weather factors. Fine particulate mass (less than 2.5 μm in average aerometric diameter) was a stronger predictor of mortality than coarse mass (between 2.5 and 10 μm). Size-fractionated particulate mass explained 28% of the total health effect of the mixture, with the remaining effects accounted for by the gases. Forty-seven elemental concentrations were obtained for the fine and coarse fraction using nondestructive x-ray fluorescence techniques. Sulfate concentrations were obtained by ion chromatography. Sulfate ion, iron, nickel, and zinc from the fine fraction were most strongly associated with mortality. The total effect of these four components was greater than that for fine mass alone, suggesting that the characteristics of the complex chemical mixture in the fine fraction maybe a better predictor of mortality than mass alone. However,the variation in the effects of the constituents of the fine fraction between cities was greater than the variation in the mass effect, implying that there are additional toxic components of fine particulate matter not examined in this study whose concentrations and effects vary between locations. One of these components, carbon, represents half the mass of fine particulate matter. We recommend that measurements of elemental and organiccarbon be undertaken in Canadian urban environments to examine their potential effects on human health.