Journal of Occupational & Environmental Medicine:
Background: Original Article
Lessons From Air Pollution Epidemiology for Studies of Engineered Nanomaterials
Peters, Annette PhD; Rückerl, Regina PhD; Cyrys, Josef PhD
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology II, Neuherberg, Germany (Drs Peters, Rückerl, and Cyrys); Harvard School of Public Health, Department of Environmental Health, Boston, MA (Dr Peters); and University of Augsburg, Environment Science Center, Augsburg, Germany (Dr Cyrys).
Address correspondence to: Annette Peters, PhD, Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology II, Ingolstädter Landstr 1, 87564 Neuherberg, Germany; firstname.lastname@example.org.
Objectives: This article discusses evidence from epidemiological studies on air pollution for assessing engineered nano-sized particles in workplace environments.
Methods: Results from epidemiological studies on health effects of fine and ultrafine particles are summarized. These findings are applied to workplaces exposed to engineered nanoparticles.
Results: Ultrafine or nano-sized particles smaller than 100 nm represent potential health hazards. Because of their short half-lives in ambient air and their large spatial variability, individual exposures in population-based studies are likely to be misclassified.
Conclusions: Studies of health effects of nanoparticles in occupational settings seem mandated for adequate worker protection but face several challenges, including exposure quantification and adequate confounder characterization. Inclusion of personal measurements of ultrafine particles in future studies will allow exploiting the full scale of temporal-spatial variation of both ambient and engineered nanoparticles.
Ambient particulate matter has been a long-standing concern to induce short-term as well as long-term health effects.1–3 The size, shape, and density of the particles determine their behavior in the gas phase of the aerosols. As the airways are the major surfaces of interaction, particles with a diameter of less than 10 μm (PM10) entering the airways and with a diameter less than 2.5 μm (fine particles, PM2.5) entering the lungs are of primary concern. Nano-sized particles, also called ultrafine particles (UFP), with a diameter less than 100 nm have different properties than larger particles.
1. They deposit with high efficiency in the alveolar region and to a lesser extent in the larger airways.4
2. Their motion is defined by diffusion rather than their aerodynamic properties.4
3. They have little mass but high number and surface area concentrations.5
4. They are not well recognized and are cleared by macrophages in the alveolar space.6
5. They potentially translocate into cells through diffusion mechanisms.7
In addition to these physical and toxicological properties, the UFP may have a different composition than larger particles in urban atmospheres.8 In particular, their major sources are local combustion sources, while other sources such as secondary aerosol formation through regional transport or resuspension of dusts do not generally contribute substantially to the fraction of UFP in ambient air.9 Therefore, UFP have a higher content of soot and organic carbon, while sulfates and nitrates are predominantly found in the accumulation mode range.
Because of the different properties of ultrafine or nano-sized particles, they are often characterized by number concentration, whereas fine particles are most frequently characterized by the measurements of mass concentration. The measurement of number concentrations for ambient UFP captures their underlying mechanism, which is surface activity based rather then mass based.10 Also, there is usually too little mass of UFP in ambient air to be measured on an hourly or a 24-hour basis. Toxicological studies often choose to use both metrics, the number and the mass concentrations, to be able to compare the effects.
While a lot of information is available on the health effects of the mass of PM2.5 or PM10, substantially fewer studies have assessed the health effects of UFP. In this article, we will briefly summarize the evidence available on health effects of fine particles, highlight findings from studies that have assessed health effects of UFP, and provide an outlook on the potential of applying these findings to workplace settings, where employees may be exposed to engineered nanoparticles.
HEALTH EFFECTS OF FINE PARTICLES
Air pollution not only affects the lungs, as one may intuitively expect, but can have negative impacts on several parts of the human body, as shown in Fig. 1. Mortality is the most studied health endpoint in association with air pollution due to the widespread availability of mortality data for large populations and the importance of mortality in estimating health impacts.
Long-term studies compare mortality rates across populations that vary in their long-term exposure to air pollution, usually using a cohort design. The Harvard Six Cities study11,12 and the American Cancer Society study,13,14 first published in the mid 1990s, show a clear increase in all-cause mortality, especially in cardiovascular or cardiopulmonary mortality in association with PM2.5. The extended reanalysis of the Harvard Six Cities study by Laden et al11 showed that a reduction in PM2.5 levels resulted in a reduced long-term risk of cardiovascular and respiratory disease mortality over the 16-year period of the study. These associations are mostly attributable to cardiovascular disease mortality.15 Detailed analyses by Pope et al15 showed that the largest specific cause of death was ischemic heart disease, which represented almost 25% of all deaths. Myocardial infarction accounted for about half of this category. In addition, statistically significant associations were found for the combined category of dysrhythmias, heart failure, and cardiac arrest.
Short-term studies, usually time-series and case-crossover studies, explore associations between short-term changes in air pollution exposure and daily mortality rates. There are a large number of time-series studies on the association between daily mortality rates and PM10 or PM2.5 published. In the United States, for example, the “National Morbidity, Mortality and Air Pollution Study,” originally conducted in 20 and later in 90 of the largest cities and metropolitan areas in the United States from 1987 to 1994, reported small but constant positive associations between PM10 and death.16 These findings were confirmed in several reanalyses.17–19 With a comparable approach, hospital admission data have also been analyzed, indicating that on days with elevated PM concentrations, hospital admissions for cardiovascular and respiratory diseases are more frequent.20–23
To further establish these associations, small cohort studies, so called panel studies, employing repeated measurements of intermediate phenotypes, for example, measurements of lung function, blood biomarkers, or electrocardiograms, were conducted. These studies provide consistent evidence that on days with high ambient particulate matter exposures or after cumulative exposures over several days, a deterioration of pulmonary24,25 and cardiovascular function26 can be observed. In particular, susceptible subgroups are affected, including children and individuals with pulmonary or cardiovascular disease and diabetes or individuals of old age. These findings have been interpreted as being coherent with the both the short-term exacerbation and the long-term effects observed in association with particulate matter exposures.27 Overall, the growing evidence on the cardiovascular effects of ambient fine particles in urban areas has provided the basis for an update of the global air-quality guidelines and a call for more stringent standards still to be met all over the world.28
HEALTH EFFECTS OF ULTRAFINE PARTICLES
Considerations Regarding Exposure Assessment
Studying health effects of UFP pose several challenges. First, the concentrations of UFP are generally not being monitored for regulatory purposes, so that additional air-monitoring efforts are needed to characterize outdoor concentrations of UFP for epidemiological studies. An often used, proxy for UFP is the (total) particle number concentration (PNC). Measurement of UFP requires additional equipment, exposure assessment expertise, and quality assurance measures. Second, the spatial distribution of UFP is substantially more heterogeneous than for fine particles, as shown in the schematic drawing of Fig. 2. In particular, major roads are hot spots for UFP exposures as well as other traffic-related pollutants, such as carbon monoxide, nitrogen oxides, or organic hydrocarbons, originating from incomplete combustion. Therefore, thoughtful selection of the measurement site(s) and multiple measurement sites may be needed under the consideration of a particular epidemiological study design.
Despite high variability within an urban area, reasonable correlations over time have been observed for UFP when measured at urban background stations.29–32
Associations Between Mortality and Ultrafine Particles
Long-term health effects of UFP have not been published to date. Nevertheless, studies assessing the role of major roads on long-term health have indicated that effects of fine particles are larger in these settings,33,34 suggesting that potentially also the UFP contribute to this strengthened association.
Short-term studies on UFP and mortality are still rare (Table 1). One of the first short-term studies on UFP and mortality was published by Wichmann et al35 in 2000. They analyzed all-cause, cardiovascular, and respiratory mortality in Erfurt, Germany, and found independent effects of both fine and ultrafine particles. Results suggested a more delayed association for UFP than for fine particles, and the overall association was slightly stronger for respiratory diseases than for cardiovascular diseases. When Stölzel and colleagues36 reanalyzed the data by using an extended data set (September 1995 to August 2001) as well as an alternative modeling approach similar to the Air Pollution and Health: A European Approach (APHEA) 2 study,37 they also found a small increase in total and cardiopulmonary mortality in association with different size ranges of UFP for a lag of 4 days. In contrast to the first study in Erfurt, they did not see associations for fine particle mass with total or cause-specific mortality. A recent reanalysis by Breitner et al,38 moreover, evaluated changes in the association between daily mortality and UFP, as air quality substantially improved during the study period. Overall, relative risk estimates were consistent but somewhat smaller than in the previous analyses. Results further suggested that the relative risks for short-term associations of UFP decreased as pollution control measures were implemented in Eastern Germany. In addition to the German study, results from a case-crossover study in Rome indicate an association between fatal coronary events and PNC, PM10, and CO, which appeared strongest for the age group greater than 65 years.39 A group of experts estimated that a reduction of 1000 particles cm−3 would result in a 0.3% reduced risk of mortality, with a 95% confidence interval ranging from 0.1% to 0.9%.40
A big European multicity study found positive associations for black smoke and all-cause, cardiovascular, and respiratory mortality.41
The few studies considering the associations between mortality and elemental carbon (EC) and organic carbon indicate a positive association, especially for low-educated people.42,43
Associations Between Respiratory Disease Exacerbation and Ultrafine Particles
One of the first studies examining the association between UFP and respiratory health in a group of adults with asthma was published by Peters et al.44 Participants kept a symptom diary and measured peak expiratory flow (PEF) daily for a period of 6 months. The authors found small but consistent associations between elevated fine particles and UFP and a decrease in PEF, an increase in cough, and feeling ill during the day. Associations for PEF were more pronounced for the ultrafine fraction. Analogue results for PEF were seen in a similar Finnish study,45 however, no associations were observed with respiratory symptoms or medication use. Another panel study on adult asthma patients in Germany, on the contrary, showed that an increase in UFP was associated with the use of corticosteroids and β2-agonists.46
A more recent study in London, England, compared lung function parameters in adults with mild or moderate asthma, walking along Oxford Street, a busy shopping street with a lot of diesel-powered bus traffic, and walking in a nearby park. The authors found that reductions in the forced expiratory volume in 1 second, forced vital capacity, forced expiratory flow at 25% to 75% of vital capacity, and exhaled breath condensate pH were associated with UFP exposure at most measured time points. Results were similar for EC, while there were no consistent associations for PM2.5. This fact may indicate that the carbon core of the particles is responsible for the health effects. The authors concluded that UFP and EC might only be sensitive proxy for roadside diesel exposure, a complex mixture of diesel exhaust and resuspended particles.47 Nevertheless, other studies found no or only small associations between ambient air pollutants and lung function.48–50 Up to now, only one study on hospital admission for respiratory diseases has been carried out.51 This study, conducted in Copenhagen, Denmark, extracted daily counts of hospital admissions for respiratory diseases in the elderly (≥65 years) and asthmatic children (5 to 18 years) for 3.5 years and associated the daily counts with air pollution data from a central monitoring site. The authors found significant associations between hospital admission for respiratory diseases and total number concentrations; however, associations diminished after additional adjustment for PM10 or PM2.5. Taken together, the few epidemiological studies conducted on effects of UFP indicate an adverse relationship on respiratory outcomes; however, results are not consistent.
A study by Heinrich et al52 used traffic intensity estimated from residential street type as a proxy for combustion-related particle exposure in a cross-sectional study in almost 7000 German adults. They found that living at extremely or considerably busy roads was associated with chronic bronchitis. Positive but not statistically significant associations were seen for nocturnal coughing attacks, wheeze during the past 12 months, and hay fever, while no increases were seen for asthma.
Additional studies in Sweden,53 Switzerland,54 and California,55 demonstrated associations between living close to a major road and symptoms and diagnosis of asthma, chronic bronchitis, and hospital encounters in asthmatic children. Recent analyses of The California Children's Health Study also showed that new-onset asthma is associated with traffic-related pollution near homes and schools.56
Associations Between Cardiovascular Disease Exacerbation and Ultrafine Particles
Several studies have examined the association between hospital admission due to cardiovascular disease and indicators of UFP. A multicenter cohort study on myocardial infarction (MI) survivors showed an increased risk of cardiac readmission to hospital during days with elevated concentrations of urban air pollution, including PNC.57 In addition, an association was found between exposure to traffic and the onset of MI within 1 hour in a study in Augsburg, Germany.58 While traveling in a car was the most common source of exposure, associations did not differ much for people who had used public transport. The overall effect estimate also did not change in multivariate analyses adjusting for stress (anger), strenuous activity, or getting up in the morning—factors that are also considered to transiently increase the risk of MI. Results from the APHEA study also indicate an association between black smoke and hospital admission for cardiac events, especially in people older than 65 years.23
In addition to comparatively rare severe events such as myocardial infarction or death, more and more studies use parameters, which reflect subclinical physiological responses possibly related to the risk of cardiovascular disease to examine the impact of air pollution. Studies on these more subtle responses support the credibility of the observed associations and provide insight into possible mechanisms that link the inhalation of particles with adverse health outcomes. Air pollution may influence different elements of heart function.59 An imbalance in the autonomic nervous system is, for example, reflected by changes in heart rate variability (HRV). Regarding HRV, a recent study reported an association between being in traffic in the previous 2 hours and a decrease in the high-frequency component of HRV.60 Timonen et al61 found an association between PNC and the ratio of low frequency to high frequency during a period of paced breathing up to 3 days after exposure in a panel of cardiac patients in three European cities. Park et al,62 on the contrary, did not see any association for HRV with PNC 4, 24, or 48 hours after exposure. In a small study on ten and five participants, respectively, an association between personal PM2.5 as well as PNC measurements and HRV parameters was found.63 Associations were more delayed but more pronounced for PNC despite the smaller number of observations.
In 2002, Pekkanen et al64 reported an increased risk of exercise-induced ST-segment depression, a marker for myocardial ischemia, in association with fine particles and UFP two days before the clinical visit among subjects with coronary heart disease in Helsinki, Finland. Since then, several studies on ST-segment depression have been conducted (Table 2). Other examined parameters include QT interval prolongation as well as T-wave amplitude and T-wave complexity,65 both repolarization parameters that play a critical role in arrhythmogenesis, and the number of ventricular and supraventricular runs66 reflecting an increased risk of arrhythmia by traffic. Zanobetti et al67 detected an association between being in traffic in the previous 2 hours and T-wave alternans, a marker of cardiac electrical instability in a panel of patients with documented coronary artery disease. Ibald-Mulli68 found no association between UFP and blood pressure. More recent results from Delfino et al69 showed an association only during periods of high exertion.
Concerns for Other Outcomes
Recent evidence suggested that also in utero growth may be impaired by ambient particulate matter.70–73 Ultrafine particles may be of concern for their potential to transgress the placenta.74
In addition, there is growing concern that systemic effects of ambient particles may also involve the central nervous system.75,76 Again, the potential of the UFP to translocate77 may provide a mechanism that could present an additional risk for disease development as inflammatory processes in the central nervous system are crucial in neurodegenerative diseases such as Alzheimer disease and Parkinson disease, the two most prevalent neurodegenerative diseases.78
LESSONS LEARNED FROM AIR POLLUTION EPIDEMIOLOGY FOR NANOPARTICLE RESEARCH IN OCCUPATIONAL SETTINGS
Overall, epidemiological studies that have assessed health effects of UFP provide evidence that early transient effects may be induced by elevated exposures. While the picture is not entirely consistent, it warrants sufficient concern about UFP in various settings through the inherent difficulties of estimating population average or individual exposures. It is important to note that in ambient settings, a fraction of the UFP may be present as droplets rather than solid particles.79 Nevertheless, only the findings that are considered to be attributable to the nonvolatile portion of the UFP are directly transferable to occupational exposures of engineered solid particles. Therefore, the additional consistency between studies of UFP and carbonaceous particles, which are predominately ultrafine, is an important observation.
Epidemiological long-term studies on fine particulate air pollution are mainly cohort studies, which follow a well-defined cohort of participants for several years. Because of the long follow-up time and repeated examinations of the participants, cohort studies are expensive to conduct and take a long time. On the contrary, they yield reliable data and make it possible to study a wide range of exposure-disease associations. For UFP, long-term health effects have not been systematically studied and the difficulties in occupational settings are even larger than in environmental settings. Besides the challenge of estimating the cumulative exposure to either ambient or engineered nanoparticles, the occupational setting is also highly demanding when assembling cohorts, adequately characterizing confounding exposures and avoiding loss of follow-up.
Short-term associations are usually examined by using time series studies, which associate time-varying exposure to time-varying event counts such as mortality or hospital admission. Time series studies are a type of ecologic study, because they analyze population-averaged health outcomes and exposure levels. Nevertheless, due to the temporal nature of the design, confounding concerns that usually come up with ecological studies such as reverse causation fallacy are avoided in time-series studies. In an occupational setting, routinely collected data are often not readily available and a panel study might therefore be the better design. A panel study is a small prospective cohort study consisting of individual time-series of repeated measurements.
Panel studies provide the advantage of examining individuals repeatedly over a time period of several weeks or months. In addition, each individual is his or her own control. A potentially important conclusion of the expanded work on exposure assessment is to include personal measurements of UFP as epidemiological studies of ambient traffic-related pollution are starting to do. With personal measurements, the full scale of temporal spatial variation can be exploited and associations can be observed, which otherwise may have been overlooked.47 These studies may consider respiratory as well as cardiovascular function as health outcomes. It is important to note that changes in respiratory function may require underlying disease or bronchial hyperresponsiveness44,47 to be observable in response to moderate changes of PNC. Similarly, induction of electrocardiogram signs of ischemia in response to elevated UFP require underlying coronary artery disease and may be even an exercise challenge to be observable.64 This might be a challenge, as people with the respective underlying diseases might be less likely to be working in an occupational setting that involves a high exposure to nanomaterials. In addition, changes in cardiac function or systemic blood markers may be a consequence of a large number of intermediate steps for which not only the particles themselves but also their composition or surface activity may be important. Lastly, it is important to establish whether one is conducting a study for monitoring a highly likely association or for initiating novel research in the face of uncertainty. In the first case, health-monitoring programs might be of the largest benefit for the employees and might indeed be warranted for workers exposed to nanotubes in their occupational setting. In the second case, when an extrapolation from toxicological or epidemiological research carries great uncertainty, well-designed panel studies may be able to quantify the potential for health effects associated with specific and potentially unique occupational exposure scenarios.
This work was funded by BMU grant F&E 370743200 (title: “Physikalische und chemische Charakterisierung von Fein- und Ultrafeinstaubpartikeln in der Außenluft”).
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