Systematic review and meta-analyses of association between transportation noise and ischaemic heart disease based on studies published between 1994 – 2022 Sophie Hamilton 1,5 Benjamin Fenech 1,2 1 Noise and Public Health Team, Radiation Chemical and Environmental Hazards, Science Group, UK Health Security Agency 2 Centre for Environmental Health and Sustainability, University of Leicester Anna Hansell 2,5 Xiangpu Gong 2 , 2 Centre for Environmental Health and Sustainability, University of Leicester 5 National Institute of Health Research (NIHR) Health Protection Research Unit (HPRU) in Environmental Exposures and Health at the University of Leicester Danielle Vienneau 3,4 3 Swiss Tropical and Public Health Institute, Allschwil, Switzerland 4 University of Basel, Switzerland

ABSTRACT There is a growing body of evidence that exposure to transportation noise can increase the risk for ischemic heart disease (IHD). However, there are significant variations in the pooled exposure- response relationships (ERRs) derived by recent meta-analyses which lead to uncertainties in health impact assessments and public health policy decision-making. We aimed to update recent meta- analyses investigating the effects of road, railway, and aircraft transportation noise exposure on IHD mortality and morbidity. We included relevant studies from two meta-analyses and one literature review covering the years 1994-2020. We conducted a systematic literature review using the WHO search strategy to identify new studies published until February 2022 and assessed risk of bias for each retained study. The pooled exposure-response associations were calculated using a random effects model. We identified nine new studies for IHD incidence and mortality. Across all traffic sources, statistically significant risk estimates were observed for IHD incidence (1.02 [1.00, 1.03]) and mortality (1.02 [1.00, 1.03]) per 10dB L den respectively.

1. INTRODUCTION

Transportation noise from road, railways and aircraft is increasing as a result of urbanization and rising demand for mobility [1, 2]. There is growing epidemiological evidence suggesting that long- term exposure to transportation noise is linked to an increased risk of adverse psychological and

1 sophie.hamilton@phe.gov.uk 2 ah618@leicester.ac.uk

21-24 auGUST Scortsi event Cas La inter.noise | ee 2022

physiological health outcomes, including sleep fragmentation, stress, and cardiovascular outcomes [3, 4]. Mechanistically it is hypothesized that elevated stress hormones and oxidative stress can result in vascular dysfunction which increases the risk for cardiovascular disease [5-9]. Approximately 20% (113 million) of the European population live in areas where transportation noise from road and railway sources exceeds 55dB L den [1]. Resulting health impacts are significant, with long-term exposure contributing to an estimated 48,000 cases of IHD per year [1]. The latest revision of the World Health Organization Environmental Noise Guidelines for the European Region (WHO ENG2018) [45] were informed by a number of systematic reviews and meta- analyses, including one investigating the association between transport noise exposure and IHD mortality and incidence [9]. Increased relative risks (RR) were reported for road traffic noise (1.08 [95% CI (confidence interval) 1.01, 1.15] per 10dB L den ) and aircraft noise (1.09 [1.04, 1.15] per 10dB L den ) [9]. In 2019 a follow-up meta-analysis was conducted for the purposes of informing Swiss regulatory noise limits [7]. Road, aircraft and railway noise on incident IHD was examined, with lower RRs reported (1.02[1.00, 1.04] per 10dB L den road traffic), (1.03[0.98, 1.09] per 10dB L den aircraft) and (1.01[0.98, 1.09] per 10dB L den rail). Discrepancies in exposure-response estimates can contribute to uncertainties in health impact assessments and in public health policy decision-making. Regularly updated meta-analyses incorporating newly published studies contribute towards the strengthening of the body of evidence. Our aim was to conduct a meta-analysis including more recent studies on the relationship between exposure to transportation noise (road, railway, aircraft) and incidence, mortality, and prevalence of IHD. The additional aims were to investigate if newer studies had any material effect on these exposure response relationships. The analysis includes studies identified in published literature reviews [7, 9, 10] and a supplemented new search for the period October 2020 to February 2022.

2. METHODS

For the systematic review and meta-analysis, we followed the WHO ENG2018 protocol [9], using a similar search strategy and similar criteria for evaluating risk of bias for each study.

2.1 Part I – Identification of new studies for period 2020-2022

For the updated search, we conducted a literature search to identify studies using road, rail, or aircraft noise as exposure, and IHD as the outcomes. We included non-fatal and fatal incident and prevalent cases and excluded studies assessing occupational noise exposure. Using search strings adopted by Vienneau which were adapted from the WHO meta-analysis [7, 9] our search was conducted in PubMed, Medline, EMBASE, Web of Science and Scopus for studies published in English between October 1 st 2020 to February 1 st 2022. Our search was also supplemented with one study published in March 2022. Study selection criteria followed the PECO approach (Population, exposure, comparator, outcome), and included:

- Residential exposure to traffic noise from road, rail, and aircraft and incidence, mortality, or prevalence of IHD in adult populations - Measured or modelled noise exposure from individual studies - All study designs accepted – including cohort, case-control, small-area, cross-sectional studies - Risk estimates adjusted for at least age, sex, and a socioeconomic variable - Mortality and incidence and prevalence for Ischemic Heart Disease defined using ICD-10 codes (2015): I20-I25, together with atrial fibrillation (I48) and heart failure (I50). We extracted the following study information: lead author and publication year, study region, study design, sample number, mean age and sex of the study population, follow-up periods, traffic noise and air pollution modelling methods, mean or median and range of traffic noise estimate adjusted

covariates, and health risk estimates. If multiple health risk estimates were reported in a study we selected risk estimates adjusted for age, sex, a minimum of one individual or area-level socioeconomic status variable (e.g. education, household income, area level deprivation), if applicable a lifestyle factor (e.g. smoking, alcohol intake), and air pollution (preference order Nitrogen dioxide (NO 2 ) > Oxides of Nitrogen (NO x ) > Particulate matter with a diameter of 2.5  m or less (PM 2.5 ) > Particulate matter with a diameter of 10  m or less (PM 10 ), as NO 2 generally serves as the best proxy for traffic-related air pollution) [44].

2.2 Part 2 – Data synthesis and meta-analysis of previously and newly-identified studies Retained studies used varying noise metrics to estimate health risk estimates which included L den , L Aeq16h , L Aeq24h , L DN , L day and L night . Before pooling individual studies for the meta-analysis, conversions of different metrics to L den were conducted for road, rail and air traffic separately using conversion terms presented by Brink 2017[11] (e.g. L Aeq24h +3.3dB, L Aeq16h +2.0dB). Studies reporting risk estimates by categorical noise exposures were transformed into a linear exposure-response relationship. The midpoint of each exposure interval was assigned as the median exposure corresponding to the risk estimate [9]. For open-ended noise exposure categories, we imputed midpoint values assuming a linear function and the width of the exposure interval [12, 13]. The median noise level for each category was transformed into a noise increment by assigning zero at the respective reference level for each study, then the linear exposure-response relationship for a 10dB L den increase was calculated [14]. RR estimates per 10 dB L den were either directly extracted or converted from each study before the meta-analysis. Pooled exposure estimates and 95% CI were calculated for each transportation noise source and respective IHD incidence, mortality and prevalence measures using random effects meta-analysis. All analyses were conducted using STATA 15.1 (StataCorp LLC).

2.3 Risk of Bias evaluation We followed the approach from the WHO-commissioned systematic review [9] and Vienneau [7] to evaluate risk of bias (RoB) for exposure-response pairs for each study.

3. RESULTS

31 studies [3, 6, 15-43] were included in the meta-analysis, eight of which were identified via our updated literature search [3, 6, 36-41] and one from a manual subsequent search [43] (Figure 1). See Tables S1 and S2 for study characteristics. With the exception of one aircraft noise exposure study [37], all of the newly identified studies included outcome measures adjusted for air pollution. Across the entire pool of studies included, the conversion of risk estimates from a categorical to a 10dB increment was conducted for 12 studies [3, 15, 16, 23-25, 27, 30, 32, 33, 40, 43]. The risk of bias evaluation for each study is presented in Table S3.

Figure 1: Flowchart for study selection

The overall pooled risk estimate for all transportation noise on IHD incidence, mortality, and prevalence were 1.02 [1.00, 1.03], 1.02 [1.01, 1.03], and 1.08 [0.97, 1.20] per 10dB L den , respectively (Figures 2-4). Assessing the outcomes separately for road, rail and air traffic noise, the pooled RR suggest a 2% (1.02 [1.00, 1.04]), 1% (1.01 [0.98,1.02]) and 3% (1.03 [1.00, 1.07]) increased risk of IHD incidence per 10dB L den , of which road and air outcomes were statistically significant (Figure 2).

PubMed 220 Medline ats EMBASE ngs ‘Wos wn Records after removal of duplicates and tile sereening s Studies from existing eta-analyses and systematic review Full text screening n=8 Additional study from manual search nel | ———_ > ‘Total studles included in updated ‘meta-analysis N= 31 Excluded with reason Biomarkers for CHDTHD nt Foreign language 2-3 >| occupational exposure n-1 Least up-to date results 4 ‘Outcome measured in DALYS a1 ‘Outcome out of scope n=

Figure 2: Forest plot of effect estimates per 10dB increase in traffic noise (L den ) and association with IHD incidence

For road, rail, and air the pooled RR from studies measuring IHD mortality resulted in a respective 3%, 2% and 2% increased risk. Results for road and railway traffic were statically significant (1.03 [1.01, 1.05] and 1.02 [1.00, 1.03] per 10dB L den ) respectively.

Figure 3: Forest plot of effect estimates per 10dB increase in traffic noise (L den ) and association with IHD mortality In the small number of eligible studies for IHD prevalence, the meta-analysis showed no overall statistically significant associations for road, rail, or aircraft noise.

Figure 4: Forest plot of effect estimates per 10dB increase in traffic noise (L den ) and association with IHD prevalence

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4. DISCUSSION

In our updated meta-analysis on traffic noise exposure and IHD incidence and mortality, we included studies identified from two published meta-analyses [7,9], one published systematic literature review [10], and a further updated search from which nine new studies were identified. The majority of the newly-identified studies were conducted across Europe, all but one [37] adjusted for air pollution, all used modelled traffic noise exposures, and some included multiple sources of transportation noise in their analyses [6, 40, 41, 43]. For incident IHD, our risk estimates for road traffic exposure aligned most closely with those reported by Vienneau [7] RR (1.02 [1.00, 1.04] per 10dB L den ). Following the addition of two large Danish cohort studies identified by our updated search [40, 43], we also found a significant effect for aircraft noise exposure RR (1.03 [1.00, 1.07] per 10dB L den ). For mortality, we observed statistically significant effects for road (1.03[1.00, 1.05] per 10 dB L den ) and rail (1.02 [1.00, 1.03] per 10dB L den ). Analyses of the exposure-response relationships should also consider exposure thresholds below which transportation noise is not associated with IHD, as this information is vital for policy and decision makers. This has been explored in previous analysis [14], and we aim to explore thresholds in future work, for example by considering noise models that allow estimation to low levels of exposure with reasonable confidence.

5. CONCLUSION

Our results suggest an increased risk of IHD incidence and mortality of 2% per 10dB increase in long-term average road traffic noise exposure. Our results also suggest a comparable size of effect for aircraft and rail noise. These findings take into account a number of large cohort studies with good control for confounders published after the WHO-commissioned systematic review of noise and cardiovascular disease. We noted that our pooled estimates have high heterogeneity (as measured by I 2 values), with leave one out analyses (not shown in this paper) identifying particular studies as major sources of heterogeneity. Investigation of the sources of heterogeneity in our data is underway using sensitivity analyses, including sub-group analysis considering factors such as sex, age, exposure time periods, exposure noise modelling accuracy and lower exposure cut-off levels.

6. ACKNOWLEDGEMENTS The research was supported by National Institute for Health Research (NIHR) Health Protection Research Unit in Environmental Exposures and Health, a partnership between UK Health Security Agency, the Health and Safety Executive and the University of Leicester. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health and Social Care or UK Health Security Agency.

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APPENDICES Table S1: Characteristics of included studies

Author/location Origin* Study design Sex Baseline

Noise source Noise metric

Linear transformation

Disease outcome

Measure Adjusted for

age

air pollution Beelen 2009/Netherlands M-A 2018 Cohort Both 55-69 Road L den Yes IHD Mortality Black smoke Gan 2012/Canada M-A 2018 Cohort Both 45-85 Road, rail,

L den

Yes - aircraft IHD Mortality NO 2 , PM 2.5 , black carbon Floud 2013/ UK, Netherlands, Sweden

aircraft

M-A 2018 Cross-sectional Both 45-70 Road aircraft

LA eq ,24h

- MI Prevalence NO 2

L night

M-A 2019 Case control Male 41-70 Road L day Yes MI Incidence 

Babisch 1994/Germany

(I)

M-A 2019 Case control Male 31-70 Road L day Yes MI Incidence 

Babisch 1994/Germany

(II)

Babisch 1999/ UK M-A 2019 Cohort Male 45-63 Road L day Yes IHD Incidence 

Babisch 2005/ Germany M-A 2019 Case control Both 20-69 Road L day Yes MI Incidence  Selander 2009/Sweden M-A 2019 Case control Both 45-70 Road LA eq ,24h Yes MI Incidence +

NO 2

mortality

Hansell 2013/UK M-A 2019 Small area Both All ages Aircraft L day Yes IHD Incidence +

PM 10

mortality

Halonen 2015/UK M-A 2019 Small area Both 25+ Road L night Yes IHD Incidence +

PM 2.5

mortality

Correia 2012/USA M-A 2019 Small area Both 65+ Road L dn - IHD Incidence PM 2.5 Bodin 2016/Sweden M-A 2019 Cohort Both 18-80 Road L den - MI Incidence NO x Seidler 2016/Germany M-A 2019 Case control Both 40+ Road, rail,



LA eq ,24h - MI Incidence +

aircraft

mortality

Cai 2018/Norway, UK M-A 2019 Cohort Both 52.9 (10.6)

Road L den - IHD Incidence NO 2

Roswall 2017/Denmark M-A 2019 Cohort Both 57.5 Road, rail L den Yes - rail MI Incidence +

NO 2

mortality

M-A 2019 Cohort Both 58 (9.1) Road, aircraft LA eq ,24h - MI Incidence 

Dimakopolou

2017/Greece



Pyko 2019/Sweden M-A 2019 Cohort Both All adults Road, rail,

L den - IHD Incidence +

aircraft

mortality

Andersson 2020/ Sweden ICBEN

Cohort Males 47-55 Road LA eq ,24h - IHD Incidence NO x

2020

Bai 2020/ Canada ICBEN

Cohort

Both 35+ Road LA eq ,24h - MI Incidence NO 2

2020

Klompmaker 2019/

ICBEN

Cross-sectional Both 19+

Road L den - Heart attack Prevalence PM 10 , PM 2.5 ,

Netherlands

2020

NO 2

Thacher 2020/Denmark ICBEN

Cohort Both 50-64 Road L den - IHD Mortality PM 2.5 , NO 2

2020

Yankoty 2021/Canada ICBEN

Cohort

Both 45+ Road L den - MI Incidence NO 2

2020

Road, rail L den - IHD Prevalence 

Zock 2018/ Netherlands ICBEN

Small area Both 40.5 (mean)

2020

Andersen 2021/Denmark Updated

Cohort Female 44+ Road L den - AF Incidence PM 2.5 , NO 2

search

Klompmaker 2021/

Updated

Cohort Both 30+ Road, rail L den - IHD Mortality PM 2.5 , NO 2

Netherlands

search

Lim & Jorgensen 2021/

Updated

Cohort Female 44+ Road L den - MI Incidence +

PM 2.5 , NO 2

Denmark

search

mortality

Magnoni 2021/ Italy Updated

Cohort Both 35+ Road L den Yes MI Incidence NO 2

search

Small area Both Adults aircraft L den - CHD Mortality 

Roca-Barcelo 2021/

Updated

Brazil

search

Thacher 2021/ Denmark Updated

Cohort Both 35+ Road, rail,

L den Yes - aircraft AF Incidence PM 2.5 , NO 2

search

aircraft

Thacher 2022/ Denmark Updated

Cohort Both 50+ Road, rail,

L den Yes - aircraft IHD Incidence PM 2.5, NO 2

search

aircraft

Vienneau 2022/

Updated

Cohort Both 30+ Road, rail,

L den - IHD Mortality PM 2.5 , NO 2

Switzerland

search

aircraft

Cole Hunter 2022/

Updated

Cohort Female 44+ Road L den - IHD Mortality PM 2.5 , NO 2

Denmark

search

* The origin column describes where the studies included in this updated meta-analysis were first identified. M-A 2018,2019 denote studies used in the meta-analyses conducted by van Kempen et al. (2018) and Vienneau et al. (2019); ICBEN denotes studies identified by the Persson-Waye & van Kempen systematic review (2020) as presented at the ICBEN conference; updated search denotes the 2020-2022 search described in this paper.

Noise metric: For a description of noise metrics please see Brink et al. [11] Disease outcome: IHD – Ischaemic heart disease, MI – Myocardial Infarction, AF – Atrial Fibrillation, CHD – coronary heart disease

Table S2: Overview of identified studies to be included in the meta-analysis which assess transportation noise exposure and IHD outcomes

Vienneau et al. (2019) review Incidence* Prevalence Mortality Road 7 cohort [24, 26-28, 31, 27*, 35*]

6 case control [23, 25, 29*, 30*]

1 small area [33]

Aircraft 2 cohort [31, 35*] 1 case control [29*] 2 small area [32, 34]

Railway 2 cohort [27*, 35*] 1 case control [29*]

Pers s o n Waye & van Kempen (2021) review Incidence Prevalence Mortality Road 3 cohort [17-19]

1 cross sectional [21]

1 cohort [20]

1 small-area [22]

Aircraft - - - Railway - 1 small area [22] - van Kempen et al. (2018) review Incidence Prevalence Mortality Road 1 cross-sectional [42] 2 cohort [15, 16] Aircraft - 1 cross-sectional [42] 1 cohort [16] Railway - - 1 cohort [16] Literature review Incidence Prevalence Mortality Road 5 cohort [3, 38-40, 43] - 3 cohort [6, 36, 41] Aircraft 2 cohort [40, 43] - 1 small area [37]

1 cohort [6] Railway 2 cohort [40, 43] - 2 cohort [6, 41] * indicates the effect estimate includes both non-fatal and fatal incident events

Table S3: Risk of bias ratings for included studies

Bias due to selection of participants

Bias due to health outcome

Bias due to non- blinded outcome

Total risk of

Bias due to exposure

Bias due to confounding

Author Year

assessment

assessment

assessment

bias Babisch, Germany (I) 1994 Low Low Low Low Low Low Babisch, Germany (II) 1994 Low Low Low Low Low Low Babisch, UK 1999 High Low Low Low Low Low Babisch, Germany 2005 Low Low Low Low Low Low Correia, USA 2013 High High Low Low Low High Selander, Sweden 2009 Low Low Low Low Low Low Halonen, UK 2015 High Unclear Low Low Low High Bodin, Sweden 2016 Low Low Low Low Low Low Seidler, Germany 2016 Low Unclear Low Low Low Low Cai, UK, Norway 2018 Low Low Low Low Low Low Roswall, Denmark 2017 Low Low Low Low Low Low Dimakopolou, Greece 2017 Low Low High High High High Pyko, Sweden 2019 Low Low Low Low Low Low Bai, Canada 2020 Low Low Unclear Low Low Low Thatcher, Denmark 2020 Low Low High Low Low Low Yankoty, Canada 2021 High High Low Low Low High Andersen, Denmark 2021 Low High Low Low Low Low Lim, Demark 2021 Low High Low Low Low Low Magnoni, Italy 2021 High Unclear Low Low Low Low Thacher, Denmark 2021 Low High Low Low Low Low Beelen, Netherlands 2009 High Low Low Low Low Low Gan, Canada 2012 High Low Low Low Low Low Klompmaker, Netherlands 2021 Low High Low Low Low Low Klompmaker, Netherlands 2019 Low Low High High Low High Zock, Netherlands 2018 Low High Low Low Low Low Floud Netherlands, UK, Sweden 2013 Low Low High High Low High Vienneau, Switzerland 2022 Low Low Low Low Low Low Cole-Hunter, Denmark 2022 Low Low Unclear Low Low Low Andersson, Sweden 2020 Low Low Unclear Low Low Low Roca-Barcelo, Brazil 2021 High Low High Low High High Thacher, Denmark 2022 Low Low Low Low Low Low