Effects of nitrogen dioxide on human health: Systematic review of experimental and epidemiological studies conducted between 2002 and 2006

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Int. J. Hyg. Environ. Health 212 (2009) 271–287 www.elsevier.de/ijheh

Effects of nitrogen dioxide on human health: Systematic review of experimental and epidemiological studies conducted between 2002 and 2006$ Ute Latza, Silke Gerdes, Xaver Baur Institute for Occupational Medicine and Maritime Medicine (ZfAM), University of Hamburg, Hamburg State Department for Social Affairs, Family, Health, and Consumer Protection, Hamburg, Germany Received 15 January 2008; received in revised form 19 June 2008; accepted 24 June 2008

Abstract In order to assess health effects in humans caused by environmental nitrogen dioxide (NO2) a systematic review of studies in humans was conducted. MEDLINE database was searched for epidemiological studies and experiments on adverse effects of NO2 published between 2002 and 2006. The evidence with regard to NO2 exposure limits was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) grading system and the modified three star system. Of the 214 articles retrieved 112 fulfilled the inclusion criteria. There was limited evidence that short-term exposure to a 1-h mean value below 200 mg NO2/m3 is associated with adverse health effects provided by only one study on mortality in patients with severe asthma (*2+). The effect remained after adjusting for other air pollutants. There was moderate evidence that short-term exposure below a 24-h mean value of 50 mg NO2/m3 at monitor stations increases hospital admissions and mortality (**2+). Evidence was also moderate when the search was restricted to susceptible populations (children, adolescents, elderly, and asthmatics). There was moderate evidence that long-term exposure to an annual mean below 40 mg NO2/m3 was associated with adverse health effects (respiratory symptoms/ diseases, hospital admissions, mortality, and otitis media) provided by generally consistent findings in five wellconducted cohort and case-control studies with some shortcomings in the study quality (**2+). Evidence was also moderate when the search was restricted to studies in susceptible populations (children and adolescents) and for the combination with other air pollutants. The most frequent reasons for decreased study quality were potential misclassification of exposure and selection bias. None of the high-quality observational studies evaluated was informative for the key questions due to the choice of the dose parameter (e.g., 1-week mean) and exposure levels above the limit values. Inclusion of study designs unlisted in the SIGN grading system did not bring additional evidence regarding exposures below the current air quality limit values for NO2. As several recent studies reported adverse health effects below the current exposure limits for NO2 particularly among susceptible populations regarding long-term exposure further research is needed. Apart from high-quality epidemiological studies on causality and the

$ The study was funded by the German Association for Research on Automobile-Technique (Forschungsvereinigung Automobiltechnik e.V., FAT), Frankfurt/Main, Germany. Corresponding author at: Alice Salomon Hochschule Berlin/University of Applied Sciences, Alice-Salomon-Platz 5, D-12627 Berlin, Germany. Tel.: +49 30 99245 513; fax: +49 30 99245 555. E-mail address: [email protected] (U. Latza).

1438-4639/$ - see front matter r 2008 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijheh.2008.06.003

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interaction of NO2 with other air pollutants there is a need for double-blinded randomized cross-over studies among susceptible populations for further evaluation of the short-term exposure limits. r 2008 Elsevier GmbH. All rights reserved. Keywords: Nitrogen dioxide; Adverse effects; Air pollutants; Review; Evidence-based; Exposure limits

Introduction In response to the revision of EU Directive 1999/30/ EG (Council Directive, 1999) the World Health Organisation (WHO, 2003) assessed the health effects of nitrogen dioxide (NO2) on the basis of epidemiological studies and experimental studies conducted in humans. The European Union (EU) used the WHO guideline values as a basis to set binding air quality limit values. Presently a 1-h value of 200 mg NO2/m3 and an annual mean of 40 mg NO2/m3 exist. In Germany, the Commission on Air Pollution Prevention (Kommission Reinhaltung der Luft, KRdL) commissioned by the Federal Ministry in charge evaluated the health effects of NO2 (KRdL, 2003). Kraft et al. (2005) provided an updated summary report (KRdL, 2003) in English. Based on the ratio of daily mean value to the maximum hourly value of NO2 the working group of the KRdL (2003) proposed a health-related 24-h value of 50 mg NO2/m3 (Kraft et al., 2005). The WHO (2003, 2005) gave no 24-h value. The study group of the WHO (2003) provided information on the literature search strategy, but the selection of articles was not reproducible. Out of a total of 115 references on NO2 health effects in humans quoted (WHO, 2003; KRdL, 2003), 22 publications were cited in both reports, 64 publications only by the KRdL (2003), and 29 publications only by the WHO (2003) (Latza and Baur, 2006). In their updated air quality guidelines, the study group of the WHO (2005) quoted 16 novel articles regarding particulate matter (PM), ozone (O3), NO2, and sulfur dioxide (SO2). No reference to the cited publications was given in the text and no search string provided. The WHO (2005) noted that ‘‘Epidemiological evidence has emerged, however, that increases the concern over health effects associated with outdoor air pollution mixtures that include NO2’’ and ‘‘The WHO AQG 2000 annual average NO2 guideline value of 40 mg/m3 is within the exposure ranges reported in these investigations’’. In this study the authors wanted to assess the novel publications since the reports of the WHO (2003) and the KRdL (2003) regarding effects of NO2 on human health. For this purpose 4 key questions were formulated regarding the existing limit values. The first question was on health effects at exposure levels below the short-term limit value of 200 mg NO2/m3 for the 1-h mean (WHO, 2003, 2005), the second question at levels

below the short-term limit value of 50 mg NO2/m3 for the 24-h mean (KRdL, 2003), and the third question on effects at levels below the long-term limit value of 40 mg NO2/m3 for the annual mean (WHO, 2003, 2005). The fourth question was related to enhanced health effects of NO2 during simultaneous exposure to other stimuli in experimental studies. In addition, 6 subquestions concerning susceptible populations and the effects in combination with other air pollutants were posed. This paper evaluates the evidence from the respective systematic literature search for the years 2002–2006.

Materials and methods Search strategy The search strings were developed based on recapture of the literature from 1986 to 2002 cited by the WHO (2003) and the KRdL (2003). All articles on the effects of NO2 on human health as the main study question were retrieved with a string that later was adapted for the time period from 2002 to 2006: (‘‘Nitrogen Dioxide’’[MeSH] OR ‘‘Nitrogen Dioxide’’ [All Fields] OR ‘‘NO2’’[All Fields]) AND ‘‘Humans’’ [MeSH] AND (‘‘Epidemiologic Studies’’[MeSH] OR ‘‘Case-Control Studies’’[All Fields] OR ‘‘Cohort Studies’’ [All Fields] OR ‘‘Longitudinal Studies’’[All Fields] OR ‘‘Cross-Sectional Studies’’[All Fields] OR ‘‘Comparative Study’’[Publication Type] OR ‘‘Comparative Study’’ [All Fields] OR ‘‘Epidemiologic Studies’’[All Fields] OR ‘‘Meta-Analysis’’[MeSH] OR ‘‘Meta-Analysis’’[All Fields] OR ‘‘time series’’[All Fields] OR ‘‘ecological study’’[All Fields] OR ‘‘panel studies’’[All Fields] OR ‘‘experimental study’’[All Fields] OR ‘‘chamber study’’ [All Fields] OR ‘‘inhalation challenge’’[All Fields] OR ‘‘Randomized Controlled Trials’’[MeSH] OR ‘‘Randomized Controlled Trials’’[All Fields] OR ‘‘Cross-Over Studies’’[All fields] OR ‘‘Cross-Over Study’’[all fields]) AND (‘‘adverse effects’’[Subheading] OR ‘‘analysis’’[Subheading]) AND (‘‘2002’’[PDAT]: ‘‘2006’’[PDAT]). Publications on other primary study questions (mainly on other air pollutants) with information on NO2-related health effects exclusively in the main body of the publication were missed. These publications were considered not relevant. The most sensitive string

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included ‘‘NOx’’[All Fields] OR ‘‘Air Pollutants’’ [MeSH] that would yield more than 1000 additional abstracts for the hand-search. Richard Atkinson, St George’s Hospital Medical School, London, United Kingdom who conducted the literature review for the study group of the WHO (2003) kindly provided their search strategy that focussed on specific study types (time series) and outcome measures (mortality, hospital admission, emergency room or visit, and physician consultations). As the focus of this systematic review was broader, the developed search strategy was not altered.

Inclusion and exclusion criteria Studies were included when they met the following inclusion criteria: English or German language, information on health effects of NO2 indoor and outdoor exposure, information on exposure with information on health effects, and quantification of the NO2 exposure. Publications on the following topics were excluded: methodological papers (effects of study design or analytical procedures) and unrelated issues (NO2 as biomarker, effect of kitchen ventilation while cooking, health effects of endotoxin, follow up after accidental very high NO2 exposure, identification of susceptible populations without effect estimates for quantified NO2 exposure, identification of biomarkers for the assessment of NO2 exposure, or NO2 as a confounder). Further details on excluded articles are given by Latza et al. (2007).

Standardized check list The studies were assessed based on a comprehensive checklist of the German National Board for Atomic Safety and Radiation Protection (Strahlenschutzkommission, 2002) with queries on study question, study design, study population, outcome measure, exposure assessment, statistical analysis, study quality and validity (confounding, selection bias, information bias, and chance), results, and discussion. The original list was adjusted (e.g., for NO2 dose parameters), and supplemented (e.g., other study design, specific confounders, and grading of evidence). The following conversion factor for NO2 was used: 1 ppb ¼ 1.877 mg/m3 (Brauer et al., 1997). In order to relate the results from regression of continuous exposure data to limit values, a pragmatic approach was chosen. For this purpose the incremental increase (e.g. changes for one interquartile range) in each study was added to the reported minimum in this study. Only studies in which this value was below the limit value in question were considered for the answers of the respective key question (e.g., a study with a minimum in the annual

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mean of 19.5 mg NO2/m3 that analyses a 8.5 mg/m3 incremental increase was considered informative for the question regarding the long-term limit value of 40 mg NO2/m3). All publications were rated by two persons (SG, UL). In cases of differing ratings consensus was reached. Results were entered into a Microsoft Office Excel spread sheet.

Systems to rate the strength of the scientific evidence The revised Scottish Intercollegiate Guidelines Network (SIGN) grading system (Harbour and Miller, 2001) was used to rate the quality of individual studies predicated on the extent to which bias was minimized. Study designs commonly used in epidemiologic air pollution studies (such as ecologic, time series, crosssectional panel, and chamber studies) are not listed in the SIGN grading system. Therefore these study designs were considered separately. Population-based randomization to different levels of NO2 exposure is unethical. Since no randomised controlled trials were expected on this topic and thus no level 1 evidence as defined by the revised SIGN grading system, the strength of evidence for each statement was graded using both the SIGN system and the Royal College of General Practitioners three star system (Royal College of General Practitioners, 1995) that also considers quantity (number of studies), and consistency (extent to which similar findings are reported). The three star system was used as modified by the British Occupational Health Research Foundation (BOHRF, 1999) where *** refers to strong evidence, ** to moderate evidence, * to limited or contradictory evidence, and no star (–) to no scientific evidence. An a-level of 0.05 was considered statistically significant.

Results and discussion Description of articles selected On January 3, 2007 n ¼ 214 abstracts were retrieved from MEDLINE for the years 2002–2006. All abstracts were hand searched regarding the inclusion and exclusion criteria and n ¼ 134 abstracts selected. After reading the entire publications, another 22 articles had to be excluded, mainly publications on adverse health effects of other indoor and outdoor air pollutants (PM, O3) that took NO2 into account. The systematic review included 112 publications (Barck et al., 2005; Barnett et al., 2006; Belanger et al., 2006; Berger et al., 2006; Biggeri et al., 2005; Boezen et al., 2005; Botter et al.,

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2002; Boutin-Forzano et al., 2004; Brauer et al., 2002, 2006; Burnett et al., 2004; Cakmak et al., 2006; Chan et al., 2005; Chan and Wu, 2005b; Chauhan et al., 2003; Chen et al., 2005, 2006; Dales et al., 2004; de Marco et al., 2002; Delfino et al., 2003, 2004; Desqueyroux et al., 2002; D’Ippoliti et al., 2003; Dockery et al., 2005; Emenius et al., 2003, 2004; Erdei et al., 2003; Farhat et al., 2005; Forastiere et al., 2005; Fung et al., 2006; Galan et al., 2003; Gauderman et al., 2004; Gehring et al., 2002, 2006; Gilboa et al., 2005; Gong et al., 2005; Gouveia et al., 2004; Grazuleviciene et al., 2004; Ha et al., 2003; Hansen et al., 2006; Hinwood et al., 2006; Hoek et al., 2002; Holguı´ n et al., 2003; Hong et al., 2002; Horak et al., 2002; Jaffe et al., 2003; Jalaludin et al., 2004; Jang et al., 2003; Just et al., 2002; Kan and Chen, 2003a, b; Kan et al., 2004, 2005; Karr et al., 2006; Kim et al., 2004; Klonoff-Cohen et al., 2005; Lagorio et al., 2006; Le Tertre et al., 2002; Lee et al., 2002, 2003; Liao et al., 2004; Lin et al., 2003, 2004; Lipfert et al., 2006; Liu et al., 2003; Luginaah et al., 2005; Luttmann-Gibson et al., 2006; Mann et al., 2002; Martins et al., 2002; Metzger et al., 2004; Migliaretti and Cavallo 2004; Migliaretti et al., 2005; Mortimer et al., 2002; Moshammer et al., 2006; Nitschke et al., 2006; Oftedal et al., 2003; Park et al., 2002, 2005; Peel et al., 2005; PenardMorand et al., 2005; Pino et al., 2004; Rich et al., 2006; Ritz et al., 2006; Rosenlund et al., 2006; Ruidavets et al., 2005a, b; Saez et al., 2002; Samoli et al., 2006; Schikowski et al., 2005; Schwartz, 2004; Schwartz et al., 2005; Scoggins et al., 2004; Sekine et al., 2004; Shima et al., 2002; Simoni et al., 2002, 2004; Simpson et al., 2005; Stieb et al., 2002; Sunyer et al., 2002, 2004; Tager et al., 2005; Tenias et al., 2002; Tsai et al., 2003a, b; Venn et al., 2003; von Klot et al., 2002; Wong et al., 2002a, b; Yang et al., 2002, 2003b, 2004a, b, 2006; Zmirou et al., 2002). The most frequently examined outcome was mortality (29 studies), followed by respiratory symptoms/diseases

(27 studies), hospital admissions (22 studies), parameters of lung function (22 studies), and parameters of heart function (9 studies). In most studies NO2 ambient concentrations were estimated using fixed-site monitor stations (93 studies). The NO2 exposure measurement was conducted with passive samplers in 15 studies. Eleven studies exclusively investigated indoor NO2 concentration. Fifty-eight studies assessed the 24-h mean, followed by the annual mean (11 studies), and the 1-h mean (8 studies). Most studies considered at least 3 air pollutants (69 studies), mainly particles (84 studies), O3 (69 studies), SO2 (69 studies) and/or CO (45 studies). The most frequently checked shortcoming of the study quality was misclassification of exposure (53 studies, mainly due to a small number of monitor stations or lack of documentation of the number of monitor stations) followed by selection bias (38 studies), misclassification of the outcome (17 studies, mainly due to exclusively subjective information), and multiple comparisons (18 studies). Table 1 shows the number of selected studies that were used to answer the key questions (Table 1). A total of n ¼ 2 studies were informative for the 1-h mean, n ¼ 31 for the 24-h mean, n ¼ 7 for the annual mean, and n ¼ 2 for the evaluation of enhanced health effect of NO2 during simultaneous exposure to other stimuli from experiments using inhalation chambers. Susceptible populations (e.g. children, heart patients, asthmatics) were included in n ¼ 72 studies. The statistical analyses comprised multivariate models with other air pollutants in n ¼ 45 studies. In n ¼ 8 studies (Belanger et al., 2006; Cakmak et al., 2006; Dales et al., 2004; Lee et al., 2002, 2003; Samoli et al., 2006; Tsai et al., 2003a; Yang et al., 2004b) the NO2 associated adverse health effect remained after adjustment for co-pollutants. The studies with information on the dose parameters relevant for the exposure limits (1-h mean, 24-h mean, and annual mean) in which the incremental increase in

Table 1. Effects of ambient NO2 on human health: number of studies with significant health effects by key question and subquestion (number of studies with designs named by the SIGN grading system in parentheses) Significant health effects

Not applicablea

Yes

No

Inconsistent

Key question regarding 1-h mean o200 NO2 mg/m3 24-h mean o50 NO2 mg/m3 Annual mean o40 NO2 mg/m3 Experimental studies with co-exposure to other stimuli

2 (1) 31 (9) 7 (5b) 0 (0)

0 (0) 14 (9) 1 (1b) 0 (0)

0 0 1 2

(0) (0) (0) (0)

109 (48) 67 (32) 103 (45) 0 (0)

Sub question regarding NO2 effects independent of co-pollutants Susceptible populations

8 (3) 49 (21)

5 (3) 19 (9)

32 (13) 4 (2)

66 (30) 40 (17)

a Either different dose parameter or minimal NO2 exposure level plus incremental increase investigated above the respective limit value (see Materials and methods). b A two-center study showed effects for the entire study population and non-significant effects for the cohort from one center.

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the exposure above the reported mean minimum was below the respective limit value (o200, o50, and o40 mg NO2/m3) were used to answer the key questions.

Short-term exposure One-hour mean There was limited evidence that short-term exposure to a 1-h mean value below 200 mg NO2/m3 has an effect on the human health from one study with some shortcomings in the study quality (misclassification of exposure, high correlation of NO2 and other air pollutants) published between 2002 and 2006 (*2+, Table 2). In this well-conducted case-crossover study of subjects with asthma recruited from emergency room admissions for asthma exacerbations in Spain (Sunyer et al., 2002) a 40.5 mg/m3 increase in the NO2 concentration (minimum 8 mg NO2/m3) was associated with mortality. As the study was conducted among patients with severe asthma, there was limited evidence that short-term exposure to a 1-h mean value below 200 mg NO2/m3 is associated with adverse health effects (mortality) in susceptible populations (*2+). As the effect remained after adjusting for copollutants, there was limited evidence that the observed effect on human health of a short-term exposure to a 1-h mean value below 200 mg NO2/m3 was independent of other air pollutants (*2+).

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When additional study designs unlisted in the SIGN grading system were considered, there was evidence from one more study (Chan et al., 2005). In this prospective panel study of patients from the cardiology section of a Taiwanese hospital heart function (heart rate variability) was decreased for each 18.77 mg NO2/m3 (minimum 1.7 mg/m3). In multivariate models the results remained after adjustment for other air pollutants. Table 2 shows all observational studies retrieved for the years 2002–2006 that were informative for the 1-h mean. Both studies were conducted among susceptible populations with clinical diagnosis if applicable and showed effects below 100 mg NO2/m3. Table 3 provides details on significant health effects and their magnitude of the publication that was related to the short-term exposure and that fulfilled the SIGN criteria. The reports of the WHO (2003, 2005) and the KRdL (2003) cited only three epidemiological studies (Anderson et al., 1997; Morgan et al., 1998; Pershagen et al., 1995) that showed effects below 200 mg NO2/m3. In consequence, the limit values (WHO, 2003; KRdL, 2003) were derived from the chamber studies in humans. 24-h mean There was moderate evidence that short-term exposure below a 24-h mean value of 50 mg NO2/m3 at monitor stations is associated with increased hospital admissions and mortality based on generally consistent

Table 2. Effects of ambient nitrogen dioxide (NO2) on human health: number of studies with short-term exposure to a 1-h mean value below 200 mg NO2/m3 with and without health effects by grading system Grading of evidence

Number of studies with and without health effects (reference) Significant effect(s)

No significant effect(s)

SIGN gradinga

Extended gradingb

SIGN gradinga

Extended gradingb

2++ 2+ 2 3

0 1 (Sunyer et al., 2002) 0 0

0 1 (Sunyer et al., 2002) 1 (Chan et al., 2005a) 0

0 0 0 0

0 0 0 0

Sum

1

2

0

0

a

Harbour and Miller (2001). Study designs listed by SIGN plus ecologic, time series, cross-sectional, panel and chamber studies.

b

Table 3. Effects of ambient nitrogen dioxide (NO2) on human health: summary of significant effects in studies with short-term exposure to an 1-h mean value below 200 mg NO2/m3 and study designs listed in the SIGN grading system by outcome parameter Reference

Outcome parameter(s)

NO2 concentration: range/increase

Significant effect (s)a

Sunyer et al. (2002)b,c

Mortality: all causes

8.0 bis 339.2 mg/m3/ 40.5 mg/m3

Patients (asthma) with more than one emergency room admission for asthma: aOR 1.48 (95%CI 1.03–2.13)

a

Abbreviations: Odds ratio (OR), CI confidence interval (CI), adjusted (a). Publication that included susceptible populations. c Non-significant results reported for patients with only one admission (aOR 1.04; 95%CI 0.86–1.26). b

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findings in five well-conducted case-crossover studies with some shortcomings in the study quality as compared to three well-conducted studies with nonsignificant effects (**2+, Table 4). In the positive studies (Barnett et al., 2006; Sunyer et al., 2002; Tsai et al., 2003b; Yang et al., 2003, 2004b) NO2 was not the main/single study question (but air pollution in general or O3). Other drawbacks were deficits in the exposure assessment (Barnett et al., 2006; Yang et al., 2004b), multiple comparisons (Barnett et al., 2006; Yang et al., 2004b), and confounding (Sunyer et al., 2002). Quality was rated good regarding large sample size, long study period, and good exposure assessment due to a great number of monitor stations (Barnett et al., 2006; Yang et al., 2003), and adjusted for other co-pollutants (Barnett et al., 2006; Migliaretti and Cavallo 2004; Yang et al., 2003). In a multi-centre case-cross-over study (Barnett et al., 2006) a 9.6 mg/m3 increase in the NO2 concentration (minimum 0–4.38 mg/m3 depending on the city) was associated with hospitalizations for cardiovascular disease. Particularly in the elderly, hospital admissions for total cardiovascular disease, cardiac failure, ischemic heart disease, and myocardial infarction were increased. In a population-based casecrossover study of subjects with asthma recruited from

emergency room admissions for asthma exacerbations in Spain (Sunyer et al., 2002) a 22.9 mg/m3 increase in the NO2 concentration (minimum 5.2 mg/m3) was associated with mortality. Tsai et al. (2003a) reported associations between hospital admissions for both primary intracerebral hemorrhage and ischemic stroke and NO2 for a 32 mg/m3 incremental increase (minimum 11.73 mg/m3) at temperatures above 20 1C. In another case-crossover study Yang et al. (2004b) reported associations between hospital admissions for cardiovascular diseases and NO2 for a 32 mg/m3 incremental increase (minimum 11.73 mg/m3). In a case-crossover study (Yang et al., 2003) the odds ratios for hospital admission were elevated for an increase of 10.5 NO2 mg/m3 (5% percentile 35.15 mg/m3) in both children and the elderly. In the elderly, the associations remained significant when the models were adjusted for co-pollutants including O3, CO, SO2, and a coefficient of haze. There was additional evidence from four lower-quality studies (Hinwood et al., 2006; Jalaludin et al., 2004; Mann et al., 2002; Migliaretti and Cavallo 2004) as compared to four lower-quality studies with non-significant effects. Evidence was also moderate when the results were restricted to susceptible populations (children, adolescents, elderly, and asthmatics) (Barnett et al., 2006;

Table 4. Effects of ambient nitrogen dioxide (NO2) on the human health: number of studies with short-term exposure to a 24-h mean value below 50 mg NO2/m3 with and without health effects by grading system Grading of evidence

Number of studies with and without health effects (reference) Significant effect(s) a

2++ 2+

2

SIGN grading

Extended grading

SIGN gradinga

Extended gradingb

0 5 (Barnett et al., 2006; Sunyer et al., 2002; Tsai et al., 2003b; Yang et al., 2003, 2004b) 4 (Hinwood et al., 2006; Jalaludin et al., 2004; Mann et al., 2002; Migliaretti and Cavallo, 2004)

0 6 (Barnett et al., 2006; Sunyer et al., 2002; Tsai et al., 2003b; von Klot et al., 2002; Yang et al., 2003, 2004b)

0 3 (Lin et al., 2003; Ruidavets et al., 2005b; Tsai et al., 2003b)

0 3 (Lin et al., 2003; Ruidavets et al., 2005b; Tsai et al., 2003b)

22 (Berger et al., 2006; Burnett et al., 2004; Dales et al., 2004; Fung et al., 2006; Ha et al., 2003; Hinwood et al., 2006; Hong et al., 2002; Jalaludin et al., 2004; Just et al., 2002; Kan and Chen, 2003b; Kan et al., 2005; Lagorio et al., 2006; Lee et al., 2003; Liao et al., 2004; Mann et al., 2002; Migliaretti and Cavallo, 2004; Oftedal et al., 2003; Ruidavets et al., 2005a; Saez et al., 2002; Simoni et al., 2002; Stieb et al., 2002; Wong et al., 2002a) 2 (Jang et al., 2003; Kan et al., 2004)

5 (Boutin-Forzano et al., 2004; Desqueyroux et al., 2002; Rich et al., 2006; Yang et al., 2004a, 2006)

10 (Boutin-Forzano et al., 2004; Desqueyroux et al., 2002; Holguı´ n et al., 2003; LuttmannGibson et al., 2006; Park et al., 2005; Rich et al., 2006; Schwartz et al., 2005; Tenias et al., 2002; Yang et al., 2004a, 2006)

1 (Lipfert et al., 2006) 9

1 (Lipfert et al., 2006)

3 Sum a

No significant effect(s)

9

b

30

Harbour and Miller (2001). Study designs listed by SIGN plus ecologic, time series, cross-sectional, panel, and chamber studies.

b

14

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Table 5. Effects of ambient nitrogen dioxide (NO2) on human health: summary of significant effects in studies with long-term exposure to a daily mean value below 50 mg NO2/m3 and study designs listed in the SIGN grading system by outcome parameter Reference

Parameter

NO2 concentration range/increase

Significant effect(s)a

Mortality Lipfert et al. (2006)

All causes

5.6–76.6 mg/m3/ 1.877 mg/m3 5.2–141.8 mg/m3/ 22.9 mg/m3

Coefficient: 0.004; SE: 0.004; mean effect: 0.0857

Sunyer et al. (2002)b,c All causes

Hospitalizations Barnett et al. (2006)b Cardiovascular 0–55.4 mg/m3/ diseases 9.6 mg/m3

Hospitalizations Barnett et al. (2006)c Cardiovascular diseases

Hinwood et al. (2006)c

Hospitalizations Lin et al. (2003)c

Mann et al. (2002)

Hospitalizations Mann et al. (2002) Migliaretti and Cavallo (2004)b,c

Age group X65 years Cardiac: PI 3.4 (95%CI 1.9–4.9) Cardiac failure: PI 6.9 (95%CI 2.2–11.8) Ischemic heart disease: PI 2.5 (95%CI 1.0–4.1) Myocardial infarction: PI 4.4 (95%CI 1.0–8.0) Total cardiovascular: PI 3.0 (95%CI 2.1–3.9) Total cardiovascular: PI 1.7 (95%CI 0.6–2.8) Age group 15–64 years Arrhythmia: PI 5.1 (95%CI 2.2–8.1) Cardiac: PI 2.2 (95%CI 0.9–3.4) Cardiac failure: PI 4.6 (95%CI 0.1–9.3)

Respiratory 8.3 bis 32.1 mg/m3/ diseases 1.877 mg/m3 Cardiovascular disease

Respiratory diseases

Patients (asthma) with more than one emergency room admission: aOR 1.58 (95%CI 1.06–2.34)

5.6–153.9 mg/m3/ 20.6 mg/m3

No numerical data presented (n ¼ 91 tests performed): OR and CI estimated from the figures: Lag 1 465 years: OR 1.01 (95%CI 1.00–1.01) Lag 1 all ages: OR 1.0 (95%CI 1.00–1.01) Lag 1 465 years: OR 1.01 (95%CI 1.00–1.01) Lag 2 465 years: OR 1.00 (95%CI 1.00–1.01) Boys: 1–7 days exposure averaging period 6 days: aOR 1.16 (95%CI 1.03–1.31) (similar significant results for 2, 3, 4, 5, and 7 days) Girls: 1–7 days exposure averaging period: 6 days: aOR 1.16 (95%CI 1.00–1.35) (similar significant results for 7 days)

Cardiovascular 6.9–259.0 mg/m3/ diseases 18.77 mg/m3

Ischemic heart disease hospital admissions: With secondary diagnosis of arrhythmia: aPI 1.81 (95%CI 0.78–2.85) With secondary diagnosis of congestive heart failure: aPI 2.32 (95%CI 0.69–3.98)

Cardiovascular diseases

With no secondary diagnosis of of arrhythmiaor congestive heart failure: aPI 1.30 (95%CI 0.51–2.10)

Respiratory diseases

45–280 mg/m3/ 10 mg/m3

o4 years: aPI 2.8 (95%CI 0.03–5.03) Total: aPI 2.8 (95%CI 0.07–4.09)

Tsai et al. (2003a, b)c Cardiovascular 11.7–119.0 mg/m3/ disease 32.1 mg/m3

Temperature 420 1C Primary intracerebral hemorrhage aRR 1.56 (95%CI 1.32–1.84) Ischemic stroke: aRR 1.55 (95%CI 1.40–1.71)

Yang et al. (2004b)c

Temperature X25 1C: aOR 1.38 (95% CI 1.26–1.50) Temperature o25 1C: aOR 2.22 (95% CI 2.01–2.44)

Cardiovascular 11.7–119.0 mg/m3/ disease 32.0 mg/m3

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Table 5. (continued ) Reference Hospitalizations Yang et al. (2003)b

Other outcomes Boutin-Forzano et al. (2004)c

Jalaludin et al. (2004)c

Parameter

NO2 concentration range/increase

Significant effect(s)a

Respiratory diseases

21.3–92.9 mg/m3/ 10.5 mg/m3

o3years: Lag 1 single pollutant model: OR 1.05 (95%CI 1.02–1.09). 465 years: Lag 1 single pollutant model: OR 1.05 (95%CI 1.03–1.07) Lag 1 multi pollutant model: OR 1.05 (95%CI 1.01–1.08)

Visits to the emergency room for asthma attacks Wet cough

3.0–85.0 mg/m3/ 10 mg/m3

Lag 0: OR 1.01 (95%CI 1.00–1.02) Identical results for Lag 1, 2 or 3 days

No information/ 15.4 mg/m3

Same day: aOR 1.05 (95%CI 1.00–1.10)

a Abbreviations: Odds ratio (OR), CI confidence interval (CI), relative risk (RR), percent increase (PI), adjusted (a), lag: days. If the lower confidence interval included 1.00 the study was listed because in most studies it was not reported whether the value was rounded from o0.99 or 41.00. b Publication that included susceptible populations. c Non-significant results reported for other outcomes.

Jalaludin et al., 2004; Migliaretti and Cavallo 2004; Sunyer et al., 2002; Yang et al., 2003) (**2+). Table 5 provides details on significant health effects and their magnitude of the publications that were related to the 24-h mean and that fulfilled the SIGN criteria. Inclusion of study designs unlisted in the SIGN grading system (n ¼ 1 meta-analysis of time series studies, n ¼ 5 panel studies, n ¼ 4 cross-sectional studies, and n ¼ 12 time series) did not bring additional evidence. Table 4 shows all observational studies retrieved for the years 2002–2006 that were informative for the 24-h mean. The 31 articles included one metaanalysis of time series studies on mortality (Stieb et al., 2002). Outcome measures were mortality (Burnett et al., 2004; Dales et al., 2004; Ha et al., 2003; Hong et al., 2002; Kan and Chen, 2003b; Kan et al., 2004, 2005; Saez et al., 2002; Stieb et al., 2002; Sunyer et al., 2002), hospital admissions (Barnett et al., 2006; Fung et al., 2006; Hinwood et al., 2006; Lee et al., 2003; Mann et al., 2002; Migliaretti et al., 2005; Oftedal et al., 2003; Tsai et al., 2003a; Yang et al., 2003, 2004a), respiratory symptoms/diseases (Boezen et al., 2005; Jalaludin et al., 2004; Just et al., 2002; Simoni et al., 2002; von Klot et al., 2002), asthma medication (von Klot et al., 2002), lung function measurements (Boezen et al., 2005; Lagorio et al., 2006; Yang et al., 2003), and parameters of heart function (Berger et al., 2006; Liao et al., 2004; Ruidavets et al., 2005a). Twelve studies (Barnett et al., 2006; Boezen et al., 2005; Jalaludin et al., 2004; Yang et al., 2003; Just et al., 2002; Lagorio et al., 2006; Lee et al., 2003; Migliaretti et al., 2005; Sunyer et al., 2002; von Klot et al., 2002; Berger et al., 2006; Yang et al., 2003) included susceptible populations. Twelve studies

showed no effect. Three of the publications with nonsignificant effects seemed to base on the same ambient monitoring in Taiwan (Tsai et al., 2003b; Yang et al., 2004a, 2006).

Long-term exposure Several recent studies reported adverse health effects below the current exposure limits for NO2 particularly among susceptible populations. There was moderate evidence that long-term exposure to an annual mean below 40 mg NO2/m3 is associated with adverse health effects (respiratory symptoms/diseases, hospital admissions, mortality, and otitis media) provided by generally consistent findings in five well-conducted cohort and case-control studies with some shortcomings in the study quality (**2+, Table 6). In a birth cohort with good exposure assessment due to a large number of fixed-site monitor stations (n ¼ 40) combined with a geographic information system and clinical diagnosis, a 8.5 mg/m3 increase in the NO2 concentration (minimum 19.5 mg/m3) was associated with increased bronchial symptoms in the first year of life (Gehring et al., 2002). In a population-based case-control study among men Grazuleviciene et al. (2004) the risk of myocardial infection of the medium (17–19 mg/m3) and high (o19 mg/m3) exposure dose categories were increased compared to the lowest exposure category (o17 mg NO2/m3) but no dose-effect observed. In a large Dutch birth cohort Brauer et al. (2002) reported a significantly higher incidence of respiratory infections and physician diagnosed flu/serious cold for a 10.3 mg/m3 increase in

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Table 6. Effects of ambient nitrogen dioxide (NO2) on human health: number of studies with long-term exposure to an annual mean value below 40 mg NO2/m3 with and without health effects by grading system Grading of evidence

Number of studies with and without health effects (reference) Effect

No effect

SIGN gradinga

Extended gradingb

SIGN gradinga

Extended gradingb 0 1 (Brauer et al., 2006)c

0

0

3d

0

0 5 (Brauer et al., 2002, 2006c; Gehring et al., 2002, 2006; Grazuleviciene et al., 2004) 2 (Schikowski et al., 2005; Scoggins et al., 2004) 0

0 1 (Brauer et al., 2006)c

2

0 5 (Brauer et al., 2002, 2006c; Gehring et al., 2002, 2006; Grazuleviciene et al., 2004) 0

0

0

Sum

5

7

1

1

2++ 2+

a

Harbour and Miller (2001). Study designs listed by SIGN plus ecologic, time series, cross-sectional, panel and chamber studies. c The two-center study showed effects for the entire study population and non-significant effects for the cohort from one center. d One low-quality cross-sectional study with inconsistent results not listed de Marco et al. (2002). b

the NO2 concentration (minimum 12.6 mg/m3). Exposure assessment was good due to additional passive sampling and a geographic information system. In two birth cohorts from the Netherlands and Munich (Brauer et al., 2006) a 10 mg/m3 increase in the NO2 concentration (minimum 19.6 and 12.6 mg/m3 in Munich and in the Netherland, respectively) was associated with otitis media. In a large follow-up of a series of cross-sectional studies among women (Gehring et al., 2006) a 16 mg/m3 increase in the NO2 concentration (minimum 20 mg/m3) was associated with increased all-cause mortality and cardiopulmonary mortality. There was moderate evidence that long-term exposure to an annual mean below 40 mg NO2/m3 is associated with adverse health effects in susceptible populations as three studies were conducted among children, and adolescents (Brauer et al., 2002, 2006; Gehring et al., 2002) (**2+). As the effect remained after adjusting for copollutants, there was limited evidence from two studies that the observed effect on human health of a long-term exposure to an annual mean below 40 mg NO2/m3 was independent of other air pollutants (*2+). Only the studies of Brauer et al. (2006) and Gehring et al. (2002) adjusted for other air pollutants in the statistical analysis. NO2 correlated with co-pollutants in both studies. In the study of Gehring et al. (2002) confounding by particulate matter could not be excluded. The observed effects of NO2 reported by Brauer et al. (2006) seemed to be independent of the other air pollutants. Table 7 provides details on significant health effects and their magnitude of the publications that were related to the annual mean and that fulfilled the SIGN criteria. Inclusion of study designs unlisted in the SIGN

grading system (two cross-sectional studies; de Marco et al., 2002 and Schikowski et al., 2005), and one time series (Scoggins et al., 2004) did not bring additional evidence. Outcome measures were (specific) mortality (Brauer et al., 2006; Gehring et al., 2006; Schikowski et al., 2005; Scoggins et al., 2004), hospital admissions (Gehring et al., 2002), respiratory symptoms/diseases (Brauer et al., 2002; Gehring et al., 2002; Schikowski et al., 2005), lung function (Schikowski et al., 2005), and otitis media (Brauer et al., 2006). Four studies (Brauer et al., 2002, 2006; Grazuleviciene et al., 2004; Scoggins et al., 2004) showed health effects associated with incremental NO2 concentrations below 20 mg/m3. Most studies were population-based (Brauer et al., 2002, 2006; Gehring et al., 2002; Grazuleviciene et al., 2004; Schikowski et al., 2005; Scoggins et al., 2004). Susceptible populations (children and adolecents) were investigated in three studies (Brauer et al., 2002, 2006; Gehring et al., 2002). Only one analysis showed no effect. The effects of the birth cohort from one centre were not significant whereas the results for the entire study population (birth cohorts from two centers) were positive (Brauer et al., 2006).

Experimental studies Between the years 2002 and 2006 there was no evidence from randomized controlled trails on health effect of NO2 during simultaneous exposure to other stimuli (e.g. methacholine or other air pollutants) (–). When additional study designs unlisted in the SIGN grading system were considered there was contradictory evidence of an enhanced adverse effect of short-term

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Table 7. Effects of ambient nitrogen dioxide (NO2) on human health: summary of significant effects in studies with long-term exposure to an annual mean value below 40 mg NO2/m3 with study designs listed in the SIGN grading system by outcome parameter Reference

Outcome parameter(s)

NO2 concentration: range/ increase

Significant effect(s)a

Brauer et al. (2002)b

Respiratory infections and symptoms

12.6–58.4 mg/m3/10.3 mg/m3

Ear, nose, throat infections: aOR 1.16 (95%CI 1.00–1.34) Doctor-diagnosed flu/serious cold : aOR 1.11 (95%CI 1.00–1.23)

Brauer et al. (2006)b,c

Otitis media

Netherlands: 12.6–58.4 mg/m3/10 mg/m3

1st year of life: aOR 1.17 (95%CI 1.03–1.34) 2nd year of life: aOR 1.14 (95%CI 1.03–1.27)

Gehring et al. (2002)b

Respiratory infections and symptoms

19.5–66.9 mg/m3/8.5 mg/m3

1st year of life: Cough without infection: aOR 1.40 (95%CI 1.12–1.75) Dry cough at night: aOR 1.36 (95%CI 1.07–1.74) 2nd year of life Dry cough at night: aOR 1.24 (95%CI 1.02–1.51)

Gehring et al. (2006)

Mortality: All causes Cardiopulmonary All causes Cardiopulmonary

1-year average: 20–60 mg/m3/16 mg/m3 5-year average: 22–55 mg/m3/16 mg/m3

Hospitalized first-time myocardial infarction

No information on range: mean 20.0 mg/m3 (standard deviation 5.4) Tertiles: low: o17 mg/m3 Medium: 17–19 mg/m3 High: 419 mg/m3

Grazuleviciene et al. (2004)

aRR aRR aRR aRR

1.17 1.57 1.19 1.74

(95%CI (96%CI (95%CI (96%CI

1.02–1.34); 1.23–2.00); 1.02–1.39); 1.29–2.33)

25- to 64-year-old men: Medium: aOR 1.43 (95%CI 1.04–1.96) High: aOR 1.43 (95%CI 1.07–1.92) 55- to 64-year old men: Medium: aOR 1.97 (95%CI 1.20–3.24) High: aOR 2.07 (95%CI 1.28–3.35)

a

Abbreviations: Odds ratio (OR), CI confidence interval (CI), relative risk (RR), adjusted (a). If the lower confidence interval included 1.00 the study was listed because in most studies it was not reported whether the value was rounded from o0.99 or 41.00. b Publication that included susceptible populations. c Non-significant results reported for Munich for an increase of 10 mg NO2/m3 (range: 19.6–64.4 mg/m3): 1st year of life: aOR 1.09 (95%CI 0.78–1.54), 2nd year of life: aOR 1.14 (95%CI 0.87–1.49).

exposure to 4500 mg NO2/m3 during simultaneous exposure to other stimuli (allergens and co-pollutants) from two chamber studies conducted with humans (Barck et al., 2005; Gong et al., 2005). As the exposure levels were above 200 mg NO2/m3 the results from these studies with a high risk of bias are not informative for the short-term exposure limits. Barck et al. (2005) subjected adults (n ¼ 18) with allergic asthma to repeated exposures in a randomized order. Eosinophilic cationic protein in both sputum and blood was higher after allergen plus 500 mg NO2/m3 than after allergen plus air. Results for other inflammatory responses were inconsistent. Pulmonary function and symptoms did not differ. Selection bias was most likely. Gong et al. (2005) exposed elderly with and without chronic obstructive pulmonary disease (COPD) and healthy volunteers (n ¼ 24) to 750.8 NO2 mg/m3 alone and combined with concentrated PM. Of the various mainly respiratory

outcome measures examined only heart rate measurements showed a borderline significant interaction of PM and NO2. Information bias was likely because of high contaminations of the filtered air control (containing 60.1 mg NO2/m3) and of the concentrated PM (containing 78.8 NO2 mg/m3). As asthmatics (Barck et al., 2005), COPD patients (Gong et al., 2005), and elderly individuals (Gong et al., 2005) were included in these studies there was also contradictory evidence of an enhanced health effect of NO2 during simultaneous exposure to other stimuli (allergens, co-pollutants) in susceptible populations. The reports of the WHO (2003, 2005) and the KRdL (2003) presented the results from 20 experimental studies of which 14 studies (Avissar et al., 2000; Devalia et al., 1994; Drechsler-Parks, 1995; Jenkins et al., 1999; Jo¨rres and Magnussen, 1991; Orehek et al., 1976; Roger et al., 1990; Rubinstein et al., 1990; Strand et al., 1996, 1997,

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1998; Svartengren et al., 2000; Tunnicliffe et al., 1994; Yang and Yang, 1994) investigated the effects of NO2 exposure in combination with other stimuli. This included unspecific bronchial provocation tests (Strand et al., 1996; Yang and Yang, 1994), allergen challenges (Avissar et al., 2000; Jenkins et al., 1999; Strand et al., 1997, 1998; Svartengren et al., 2000; Tunnicliffe et al., 1994), light exercise, (Jo¨rres and Magnussen, 1991; Roger et al., 1990), SO2 (Devalia et al., 1994), O3 (Drechsler-Parks, 1995; Jenkins et al., 1999), and air pollutants in tunnel air (Svartengren et al., 2000; Yang and Yang, 1994). The exposure was above 200 mg NO2/m3 in all of these studies.

Limitations There are many systems available to rate the strength of scientific evidence (AHRQ, 2002). Evaluation of the evidence depends on the domains covered by the check lists, and the grading system. The issue whether the risk of confounding, bias, and chance in an individual study is regarded as very low or low can be a question of the individual benchmark. When consensus was reached between the two raters in this review, a conservative approach was chosen leading to a lower grading. As population-based randomization to ambient NO2 exposure is unethical, strong evidence for the answer of the key questions based on the SIGN grading system together with the three star system would require at least three high-quality cohort or case-control studies with exposure below the respective limit value together with the appropriate dose parameter (1-h mean, 24-h mean, or annual mean). Merely three out of the 112 publications evaluated were rated as high quality (SIGN 2++). None of the high-quality observational studies evaluated was informative for the key questions due to the choice of the dose parameters or exposure levels above the limit values (Chauhan et al., 2003; Chen et al., 2005; Gauderman et al., 2004). Chauhan et al. (2003) investigated the 1-week mean, Chen et al. (2005) the 1-month mean. The exposure level was above the annual mean of 40 mg NO2/m3 in the third publication (Gauderman et al., 2004). Lower rating of the study quality of the other cohort studies was mainly due to misclassification of the exposure when NO2 was not the main or solitary study question. With evidence from ‘‘well-conducted’’ studies at most, the best achievable evidence was ‘‘moderate’’ evidence. Evaluation of studies with additional study designs (e.g. panel studies) unlisted in the SIGN grading system (n ¼ 29) did not bring further evidence regarding epidemiological studies. There are some issues regarding the completeness of literature identified. Per definition, studies included in the reports of the study groups of the WHO (2003) and of the KRdL (2003) were not evaluated in this

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systematic review. As a consequence four studies published in 2002 – three of them cited by the WHO (2003) (the chamber study of Barck et al., 2002; the cohort study of Gauderman et al., 2002; and the metaanalysis of times series analyses of Stieb et al., 2002) and one cited by the KRdL (2003) (the cohort study of Hoek et al., 2002) – are missing. Both cohort studies were not relevant for the key questions because they investigated the 4-year mean. As the literature data bank was searched at the beginning of the year 2007 for publications until the end of the year 2006, articles published at the end of 2006 might have been missed because they were not yet entered into the data bank or the search terms (MeSH) were not yet coded. For quality assurance another literature search was performed at the end of the year 2007. Nine additional abstracts from 2006 were identified in November 2007 including four publications (Dales et al., 2006; McConnell et al., 2006; Pattenden et al., 2006; Zanobetti and Schwartz, 2006) that fulfilled the criteria for further review. The studies retrieved in this systematic literature review can be further used for overall evaluation of effects of NO2 on human health or on specific outcomes. In addition, the studies retrieved can be utilized for risk assessment. Exposure limits cannot be directly derived from epidemiological studies with quantitative regression modelling. As a pragmatic approach, only studies were selected to answer the key questions in which the observed mean minimum level of NO2 plus the incremental increase investigated was below the respective exposure limit. More elaborative quantitative risk assessment (Bailar and Bailar, 2001) is needed. The presented systematic review can provide the basis to identify high-quality studies for this purpose. The question whether the relationship between NO2 and the observed health effects is causal or due to confounding by other air pollutants (WHO, 2003, 2005; Kraft et al., 2005) is not solved. Although in this review eight additional studies (Belanger et al., 2006; Cakmak et al., 2006; Dales et al., 2004; Lee et al., 2002, 2003; Samoli et al., 2006; Tsai et al., 2003a, b; Yang et al., 2004b) were identified in which the NO2 associated health effect remained after adjustment for co-pollutants, collinearity of ambient pollutants might have prevented the causal separation. Further research on causality a nd the interaction of NO2 with other air pollutants is warranted. On the one hand further high-quality epidemiological studies regarding all limit values are needed. These studies require good exposure assessment, exposure levels below the respective exposure limits, appropriate dose parameters, low correlation of NO2 and particles, spatial differences in exposure to NO2 and particles, adjustment for other air pollutants, and – if possible – explicit analyses of potential interaction between NO2 and particles. On the other hand there is a need for double-blinded randomized cross-over studies

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for further evaluation of the short-term values among susceptible populations as done for diesel exhaust (Mills et al., 2007).

Acknowledgements We thank Dr. med. Michael F. Spallek, Europa¨ische Forschungsvereinigung fu¨r Umwelt und Gesundheit im Transportsektor e.V., EUGT, Berlin, Germany for his valuable comments on the manuscript.

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