Road traffic noise effects on cardiovascular, respiratory, and metabolic health: An integrative model of biological mechanisms

Environmental Research 146 (2016) 359–370

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Environmental Research journal homepage: www.elsevier.com/locate/envres

Review article

Road traffic noise effects on cardiovascular, respiratory, and metabolic health: An integrative model of biological mechanisms Alberto Recio a,n, Cristina Linares b, José Ramón Banegas a, Julio Díaz b a b

Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid, Madrid, Spain National School of Public Health, Instituto de Salud Carlos III, Madrid, Spain

art ic l e i nf o

a b s t r a c t

Article history: Received 20 September 2015 Received in revised form 30 December 2015 Accepted 31 December 2015

Background: Road traffic noise is a major public health issue, given the documented association with several diseases and the growing number of exposed persons all over the world. The effects widely investigated pertain to cardiovascular health, and to a lesser extent to respiratory and metabolic health. The epidemiological design of most studies has made it possible to ascertain long-term associations of urban noise with a number of cardiovascular, respiratory, and metabolic disorders and diseases; additionally, time series studies have reported short-term associations. Objectives: To review the various biological mechanisms that may account for all long-term as well as short-term associations between road traffic noise and cardiovascular, respiratory, and metabolic health. We also aimed to review the neuroendocrine processes triggered by noise as a stressor and the role of the central nervous system in noise-induced autonomic responses. Methods: Review of the literature on road traffic noise, environmental noise in general, psychosomatics, and diseases of the cardiovascular, respiratory, and metabolic systems. The search was done using PubMed databases. Discussion: We present a comprehensive, integrative stress model with all known connections between the body systems, states, and processes at both the physiological and psychological levels, which allows to establish a variety of biological pathways linking environmental noise exposure with health outcomes. Conclusions: The long- and short-term associations between road traffic noise and health outcomes found in latest noise research may be understood in the light of the integrative model proposed here. & 2016 Elsevier Inc. All rights reserved.

Keywords: Noise Cardiovascular disease Respiratory disease Diabetes Immune system Psychosomatics

1. Introduction Non-auditory health effects of noise have been widely investigated over the past decades. Field studies provide strong evidence for risk associations and causal relationships. The biological plausibility of such associations is reasonably well documented, which leads to the consideration of noise pollution as a true risk factor for disease and, given its frequency in the population, a major public health issue (WHO, 2000). Of interest in urban environments is road traffic noise, given the large exposed population and the long exposure time-periods. Some 20% and 30% of the EU population are exposed to noise Abbreviations: CNS, Central nervous system; ANS, Autonomic nervous system; SNS, Sympathetic nervous system; PNS, Parasympathetic nervous system; SAM, Sympathetic–adrenal–medullar (axis); HPA, Hypothalamic–pituitary–adrenocortical (axis); BP, Blood pressure; HRV, Heart rate variability; REM, Rapid eye movement; SWS, Slow wave sleep n Correspondence to: Treboles 2, 28430 Alpedrete, Madrid, Spain. E-mail address: [email protected] (A. Recio). http://dx.doi.org/10.1016/j.envres.2015.12.036 0013-9351/& 2016 Elsevier Inc. All rights reserved.

levels higher than 65 dBA in the daytime and 55 dBA in the nighttime, respectively (WHO, 2011). For such noise levels, a number of studies have reported significant associations with cardiovascular diseases (Selander et al., 2009), respiratory diseases (Niemann et al., 2006), type 2 diabetes (Sørensen et al., 2013), and adverse birth outcomes (Díaz and Linares, 2015). Moreover, short-term associations with cardiovascular, respiratory, and diabetes-related outcomes including mortality have been found (Tobías et al., 2001, 2014, 2015a, 2015c; Linares et al., 2006). Road traffic noise ranks second – only behind fine particles – among the nine environmental risk factors with highest health impact in European countries, which means a loss of 400–1500 healthy life years due to ischemic heart disease per million people (Hänninen et al., 2014). In the city of Madrid (Spain) a health impact study reported a reduction of nearly 200 and 300 deaths per year due to cardiovascular and respiratory causes, respectively, for a 1 dBA decrease in diurnal noise levels, comparable to the death rate reduction obtained with an equivalent decrease in fine particle concentration (Tobías et al., 2015b).

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First we review the various biological mechanisms whereby exposure to environmental noise is likely to cause or aggravate cardiovascular, respiratory, and metabolic disorders. Second we briefly look at the neuroendocrine processes triggered by noise as a stressor, and their implications for autonomic balance. Third we present an integrative model comprising all reviewed psychological and pathophysiological mechanisms involved in the onset and development of noise-induced adverse effects on cardiovascular, respiratory, and metabolic health.

2. Methods First we searched PubMed databases for articles with combinations of the following keywords in the title: “noise”, “cardiovascular”, “heart disease”, “atherosclerosis”, “infarction”, “stroke”, “hypertension”, “blood pressure”, “heart rate”, “diabetes”, “respiratory”, “annoyance”, and “sleep”, from January 2000 to March 2015. Then we manually searched for appropriate articles – i.e. those dealing with specific physiological or psychological mechanisms – included in the references within the primary articles, of any publication date. Over 300 articles were screened and finally 160 selected, of which 23 were animal studies (Table 1).

3. Noise and cardiovascular health Over the years, evidence has grown for the hypothesis of a long-term association between road traffic noise exposure in large cities and the occurrence of ischemic heart disease and cerebrovascular disease, in the light of the results from a recent metaanalysis of cross-sectional studies (Banerjee et al., 2014) and from longitudinal studies with increasing statistical power (Babisch et al., 2005; Selander et al., 2009; Argalášová-Sobotová et al., 2013; Sørensen et al., 2011a, 2012, 2014). Among the specific health outcomes investigated are myocardial infarction and stroke. Furthermore, time series studies have found short-term associations with both cardiovascular morbidity and mortality. Tobías et al. (2015c) reported a 6.6% increased risk of death in the elderly for a 1 dBA increase in daily noise levels, with no changes after adjusting for air pollutants. Cardiovascular events and diseases arise as a consequence of physiological disorders of the circulatory system, which may be observed through various cardiovascular markers such as (a) blood pressure, (b) blood lipid concentration, (c) inflammatory and blood clotting factors, and (d) heart rate variability. 3.1. Blood pressure and hypertension Animal experiments have revealed associations of high noise Table 1 Number of articles screened for each topic. The database search commands included the expression “(traffic OR transportation OR environmental OR residential OR community OR urban) AND noise” in conjunction with the terms listed below. Topic (keywords) “cardiovascular” OR “heart disease” OR “atherosclerosis” “infarction” OR “stroke” “blood pressure” OR “hypertension” “heart rate” OR “cardiac” OR “autonomic” “diabetes” “respiratory” “annoyance” “sleep” TOTAL

Database search Manual search 24

12

13 31 6 3 2 66 36 181

5 18 21 7 15 20 24 122

levels with significant increases in blood pressure (BP), probably as a result of structural changes in the sympathetic nervous system during the exposure (Fisher and Tucker, 1991). Recently, a laboratory study on humans using recorded road traffic noise reported significant increases in BP of 2–4 mmHg after 10 min of high level exposure (Paunovic et al., 2014); the BP increases were due to vasoconstriction and concurrent reduced cardiac flow during the exposure. Cross-sectional studies have found significant associations of road traffic noise with BP in children and adults (Liu et al., 2014, Belojevic et al., 2008, Sørensen et al., 2011b) and with the prevalence of hypertension in adults (Chang et al., 2014). A metaanalysis concluded that the prevalence of hypertension was some 3% higher per a 5-dBA increase in diurnal noise levels (van Kempen and Babisch, 2012). As regards incidence, some cohort studies have found significant associations between occupational noise exposure and elevated blood pressure and hypertension (Chang et al., 2013). However, the fact that the only prospective study to date dealing with road traffic noise and hypertension did not find any significant association for the incidence (Sørensen et al., 2011b) leaves the question that noise itself might cause hypertension somewhat inconclusive, yet the overall evidence points to the possibility that noise be a component cause, i.e. a cause which works in combination with other factors (whether environmental or not). 3.2. Atherogenic processes and atherosclerosis Atherosclerosis is the main pathological state responsible for cardiovascular disease. Factors associated with noise favouring the progression of subclinical atherosclerosis, or liable to trigger acute cardiovascular events because of their prothrombotic activity, are: (a) excess blood lipids, (b) inflammation of the endothelium and endothelial dysfunction, and (c) blood clotting alteration and platelet aggregation. Atherosclerosis is a degenerative process of the vascular system characterized by thickenings of the innermost layer of arteries (the intima) as a result of a chronic inflammatory disorder. Excess blood lipids, endothelial inflammatory processes, and increased platelets and blood clotting factors interact in the development of atherosclerotic lesions (Hansson, 2005; Libby, 2013). The core of an atheroma contains lipids, activated immune cells, proinflammatory cytokines, and debris; the surrounding cap consists of connective tissue and a collagen-rich matrix, making up the atherosclerotic plaque. Proinflammatory molecules secreted by the immune cells inside the plaque increase oxidative stress and weaken its structure, which turns unstable and vulnerable. Eventually, plaque rupture takes place and causes the release of the thrombogenic core to the blood, which may lead to occlusion of the artery and acute coronary syndrome (e.g. myocardial infarction). The mechanism by which noise might act as a proatherogenic agent has to do with cortisol overproduction – in turn associated with exposure to specific noise levels – as a result of the neuroendocrine system activation during acute or chronic stress. Stressful experiences produce changes in lipid and lipoprotein levels, as shown in human experiments (Qureshi et al., 2009). Moreover, animal studies reveal that acute psychological stress causes lipid peroxidation as a result of oxidative stress in tissues, and then such modified lipids turn into proinflammatory agents (Kovács et al., 1996; Wang et al., 2007). Studies on occupational noise – where bias due to exposure misclassification is less likely – have reported higher blood cholesterol and triglyceride concentration, as well as long-term increased risk of dyslipidemia, in workers exposed to noise levels above 80 dBA (Mehrdad et al.,

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2011). An experiment by Samra et al. (1998) ascertained that acute hypercortisolemia causes an increase in free fatty acids due to increased intravascular lipolysis, favouring net artery accumulation of fat plaques by deposition and, eventually, the development of atherosclerosis, though the precise mechanism remains to be elucidated. As regards environmental noise, studies are scarce, especially over the past two decades; either research has not focused sufficiently on noise effects on atherogenic markers, or studies with non-significant results have not been published. As an exception, a recent cross-sectional study based on a German cohort – the Heinz Nixford Recall Study – reported significant associations between nocturnal road traffic noise and subclinical atherosclerosis, even after adjustment for air pollutants (Kälsch et al., 2014). 3.3. Inflammatory processes and endothelial dysfunction The cytokine cascade that takes place as a consequence of an atherosclerotic lesion induces the secretion of a specific cytokine with proinflammatory and procoagulant systemic effects: the interleukin-6 (IL-6), also known as the “endocrine cytokine”. This biomolecule is also involved in both immunologic and neuroendocrine arousal (Hartman and Frishman, 2014). In animal studies IL-6 is associated with proatherogenic effects (Huber et al., 1999). Studies on healthy persons have shown associations between IL-6 levels and endothelial dysfunction (Esteve et al., 2007). Excess IL-6 promotes systemic inflammatory states, which may cause or accentuate endothelial dysfunction thereby destabilizing the atherosclerotic plaques. Meta-analyses have shown strong associations between endothelial dysfunction and cardiovascular events, emphasizing its systemic nature. Over the past years research has grown considerably on the various functions of endothelial cells, with an emphasis on the repairing, vasodilatory, and antithrombotic ones (Lerman and Zeiher, 2005). Endothelial dysfunction provokes a shortage of endothelial progenitor cells involved in reducing both the wear and the lesions commonly present in vessel walls as a result of vascular activity; indeed, inflammation slows down these repairing processes at a systemic level. Endothelial antithrombotic action works through the secretion of anticoagulants (heparin, proteins C/S) and factors with antiaggregant effects on platelets (nitric oxide (NO) and prostaglandin I2); this is the reason why endothelial dysfunction might promote thrombogenic vascular environments. The vascular response to psychological stress is regulated by the endothelium. Extensive research has been carried out on the association between acute psychological stress and endothelial dysfunction through neuroendocrine system malfunction. Some experimental studies have shown that endothelial dysfunction might take place a few hours after a stressful experience (Poitras and Pyke, 2013). Others have reported vasodilatory function impairments lasting several hours in association with short episodes of stress; such impairments, when chronically repeated, might play a part in the progression of atherogenic processes. The precise mechanism for this still remains unknown (Ghiadoni et al., 2000; Spieker et al., 2002). There is evidence that noise exposure, potential cause of psychological stress, provokes the onset or aggravation of endothelial lesions and dysfunction in the short term. Changes in vascular properties intended to compensate for noise-induced elevated BP might damage vascular structure and promote arteriosclerosis and hypertension. A repeated-measure study designed to assess the transient and sustained effects of environmental noise on vascular parameters (Chang et al., 2012) found significant changes in arterial compliance and resistance after exposure to increased noise

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levels; in particular, the unexpected low arterial compliance and high arterial resistance in the night-time compared with the daytime values suggested impaired vascular structural properties caused by noise-disturbed sleep. A recent experiment (Schmidt et al., 2015) reported that exposure to simulated night-time noise peaks of 47 dBA significantly reduced endothelium-dependent vasodilatation. A previous study (Schmidt et al., 2013) had come to similar conclusions on healthy, low-cardiovascular-risk population; also a positive though nonsignificant dose-response relationship was found. Interestingly, those who were given vitamin C right after the exposure underwent a remarkable recovery of the vasodilatory endothelial function after 2 h. Note that L-ascorbic acid increases the production of glutathione – a regulator present in intracellular redox reactions – which reduces oxidative stress. On the other hand, some reactive oxygen species such as superoxide anion may react with endothelial NO, preventing its vasodilatory action (Gokce et al., 1999). All of the above lends support to the hypothesis that damage caused by intravascular oxidative stress may play an important part in the development of endothelial dysfunction. Oxidative stress occurs when cellular metabolism is unable to neutralize the excess reactive oxygen species produced in metabolic chemical reactions – free radicals, oxygen ions, and peroxides – or when the mechanisms intended to repair the damage caused by such species are insufficient. Noise may contribute to increased systemic oxidative stress through neuroendocrine activation and raised IL-6 secretion. Indeed, both animal and human studies have reported associations of high noise levels with markers of increased oxidative stress (Koc et al., 2015, Yildirim et al., 2007). In a nutshell, noise exposure may exacerbate systemic inflammation and endothelial dysfunction mainly through overactivation of neuroendocrine processes and the subsequent increase in intravascular oxidative stress. 3.4. Cardiac output and heart rate variability Individuals develop emotional and physiological responses that enable adaptation to environmental change. Physiological activation is ruled by the autonomic nervous system (ANS), which in turn splits into the excitatory sympathetic nervous system (SNS) and the inhibitory parasympathetic nervous system (PNS). During either mental or physiological stress, SNS activity predominates over PNS activity in generating the proper physiological response. The ease with which an individual switches from a state of activation to another of relaxation, or vice versa, depends on the ability of the ANS to rapidly vary the heart rate. Therefore heart rate variability (HRV) is a marker of the capacity of an individual to produce a balanced physiological response, i.e. adjusted to a specific emotional challenge (Appelhans and Luecken, 2006). HRV gives a measure of how the SNS and the PNS modulate each other in order to generate the appropriate cardiac output in the presence of a stressor. Low HRV means decreased ANS capacity to generate such a regulated response, i.e. overall inefficient stress management, and is associated with higher risk of death after myocardial infarction (Buccelletti et al., 2009). Vulnerable groups having ANS-regulation problems – observable in markers such as HRV – are more likely to die from a cardiovascular outcome (Gerritsen et al., 2001). Exposure to certain noise levels may affect HRV through activation of the ANS (Lee et al., 2010). Increased sympathetic activity due to diurnal noise is prospectively associated with short-term reductions in HRV (Kraus et al., 2013). A case-crossover study found that exposure to road traffic noise levels above 65.6 dBA increased the short-term effects of air pollution on HRV in healthy young persons (Huang et al., 2013). Normal functioning of the ANS during sleep implies enhanced

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parasympathetic activity (Wolk et al., 2005). In the slow-wavesleep (SWS) stages, PNS activity predominates over SNS activity. When environmental noise interferes with sleep, it causes autonomic arousals which alter the normal functioning of the ANS, giving rise to lowered HRV (Graham et al., 2009). No habituation to noise in the course of the night is observed, which makes this impaired ANS functioning potentially pathogenic, especially if it also provokes cortical awakenings (Griefahn et al., 2008). All studies investigating the association of nocturnal noise with HRV – and cardiac output in general – have reported short-term significant results, i.e. effects observable within a few minutes after the exposure (Graham et al., 2009, Griefahn et al., 2008). Alterations in the ANS functioning may lead to progressive deterioration of sleep quality, which entails impairment of the recovery function of sleep at the cardiovascular level and thus higher risks of both short- and long-term adverse outcomes. 3.5. Diabetes Sørensen et al. (2013) investigated the long-term association between type 2 diabetes and road traffic noise; they obtained up to a 14% increased risk of incident diabetes per a 10 dBA increase in daily noise levels. The short-term association was studied by Tobías et al. (2015a), with significant results for the over-65 age group: increases of 1 dBA in nocturnal noise levels were associated with a 9.4% increased risk of death from diabetes the next day. Raised blood glucose levels provoke the hardening of arteries as well as the elevation of blood pressure and viscosity—with higher risk of clotting. That, interacting with dyslipidemia and other major cardiovascular risk factors, is the reason why diabetes increases the risk of both ischemic heart disease and cerebrovascular disease (Kannel, 2011). The likely mechanism linking noise with type 2 diabetes might be mainly related to the overproduction of glucocorticoids – such as cortisol – due to stressful exposures to high noise levels, which causes inhibition of pancreatic insulin secretion as well as decreased insulin sensitivity in the liver, skeletal muscle, and adipose tissue. In addition, sleep disturbances – which may be partly caused by environmental noise – have been associated with alterations in glucose and appetite regulation (Sørensen et al., 2013, Tasali et al., 2009). Intensive research is growing on the relationship between acute inflammatory processes and insulin resistance mediated by cytokine IL-6 systemic activity. Fernández-Real et al. (2001) and Fernández-Real and Ricart (1999) have proposed the hypothesis of an ancestral adaptive response – thus genetically programmed – with a marked acute phase that predisposes humans to inflammation; under this condition, usual metabolic regulation might be altered in order to face threats such as starvation (e.g. preserving glucose levels necessary for proper brain metabolism). Nowadays, such a response would largely have lost its adaptive role, causing more harm than good for the new lifestyles (e.g. promoting type 2 diabetes and atherosclerosis).

that a 1 dBA increase in diurnal road traffic noise levels was associated with a 6.5% increased risk of death the next day in the elderly, with no changes after adjusting for air pollutants (Tobías et al., 2014). The biological pathways proposed are alterations in the immune system and connective tissue. Note that such alterations escape a straightforward assessment in humans, therefore it is usual to simply suggest associations of noise with excess neuroendocrine activation and oxidative stress, and let animal experiments yield evidence for the rest of the mechanisms involved in the hypothetical causal chain. 4.1. Alterations in the immune system The association of psychological stress with the occurrence or exacerbation of respiratory disease has been widely investigated (Aich et al. (2009) and references therein). Given similar environmental risk conditions relative to infectious agents, the fact that some persons fall ill while others do not, or that recovery processes differ considerably, is largely due to the state of their immune system. The causal pathways are hypothesized on the basis of the observed communication between the central nervous system (CNS), the autonomic nervous system (ANS), the endocrine system, and the immune system, in a way that neurochemical processes end up affecting the immunological. In the light of evidence (Aich et al., 2009), the processes involved in the development of a respiratory disease work not only locally but also systemically through a cascade of biomolecular interactions involving neurotransmitters, glucocorticoids, cytokines, metabolytes, receptors, etc. Noise is a psychological stressor liable to disturb neuroendocrine states and cause disorders in both the innate and adaptive immune system (Prasher, 2009). Although sympathetic arousal under acute stress is associated with a prompt activation of lymphoid cells, after a few hours the immune activity becomes suppressed. Glucocorticoids might be responsible for a reduction in circulating lymphocyte count, while catecholamines appear to reduce migration and adhesion of lymphocytes to tissues (Flint et al., 2011). Both field and laboratory studies have revealed that acute as well as long-lasting psychological stress is best associated with NK-cell activity, which is always reduced or even suppressed (Witek-Janusek et al., 2007; Boscolo et al., 2009). Acute stress due to noise exposure affects individuals differently depending on their capacity to exert control over the noise source. Those who feel that do not have control undergo significant reductions in the innate immune activity that lasts up to 3 h after the acute exposure to noise (Sieber et al., 1992). Overall there is evidence that road traffic noise, as a source of acute stress present in everyday life over which individuals cannot exert control, produces states of transient suppression of NK- and lymphoid-cell activity in humans, making it plausible to hypothesize increased toxicity and predisposition to new or aggravated infections, i.e. greater vulnerability to respiratory system outcomes.

4. Noise and respiratory health 4.2. Sleep disturbances Unlike the case of cardiovascular disease, research on respiratory morbidity associated with environmental noise is rather scarce. Some time ago, a few pioneering studies reported longterm significant associations with respiratory outcomes such as bronchitis and asthma (Ising et al., 2003, 2004; Niemann et al., 2006). Regarding short-term associations, a time series study found that 4.7% of hospital admissions due to pneumonia in children could be attributed to a 1 dBA increase in daily noise levels (Linares et al., 2006). Another study on respiratory mortality found

Animal and human studies have revealed links between the daily sleep-wake cycle and the neuroendocrine, immune, and thermal systems (Moldofsky, 1995; Majde and Krueger, 2005). The immune system undergoes circadian variations (e.g. T-cell activation is maximum at dawn). Infections elicit the secretion of proinflammatory cytokines which induce longer SWS phases and defensive responses such as fever; disturbances of this state may result in aggravated infectious processes and higher risk of

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opportunistic infections (Toth, 1995; Prather et al., 2012). Processes of hippocampus-induced immune activation such as division and differentiation of T and B cells take place during SWS stages, since they demand metabolic resources more efficiently mobilized at night. In addition, norepinephrine discharge to tissues after SNS activation caused by sleep disruptions suppresses antiviral immune responses and increases systemic inflammation, compromising respiratory health in the short-term (Irwin, 2012). Therefore sleep plays an important part in infectious processes; it works synergistically with the immune system, proinflammatory cytokine secretion, and other defensive or repairing responses. Since infections are states of systemic inflammation, sleep disorders may spoil this synergy and aggravate tissue inflammation, affecting the course of respiratory disease during its acute phases. In light of the above, sleep disturbances caused by nocturnal road traffic noise may disrupt recovery processes during infectious states and result in exacerbation of respiratory diseases such as bronchitis, pneumonia, and COPD. 4.3. Oxidative stress Oxidative stress due to oxidant-antioxidant imbalance leads to biological alteration linked with a variety of diseases, including respiratory (Santus et al., 2014). In chronic obstructive pulmonary disease (COPD), markers of elevated oxidative stress are detected not only in the respiratory tract and pulmonary tissue, but also in plasma. Indeed, reactive oxygen species together with local recruitment of proinflammatory cells such as neutrophils and macrophages characterize pulmonary inflammation, and therefore play an essential part in the development of COPD and other respiratory diseases such as severe pneumonia (Chen et al., 2014). Apart from air pollutants, smoking, viruses, bacteria and innate immune system activity, another source of oxidative stress to be considered are inflammatory processes associated with psychological stress (as that caused by factors such as road traffic noise), which may lead to a systemic increase in reactive oxygen species (Koc et al., 2015; Yildirim et al., 2007). In addition, increased oxidative stress due to the factors noted above may enhance the effects of the reduction in antioxidants such as glutathione during the immune response—which has been observed, for example, in communitary bacterian pneumonia (Trefler et al., 2014). Furthermore, a proposed mechanism involved in the aggravation of respiratory disease is the degradation of the extracellular matrix in connective tissue (Niemann et al., 2006), what prevents innate immune cells adhesion. There is growing evidence that proliferation and overactivation of fibroblasts may be due to excess apoptosis in alveolar epithelial cells because of damage caused by elevated oxidative stress. Sclerosis of connective tissue as a result of fibrosis may be behind chronic respiratory disorders such as interstitial lung disease, as well as other respiratory diseases with acute phases (Bagnato and Harari, 2015).

5. Noise as a source of stress All proposed mechanisms whereby noise exposure may cause cardiovascular, respiratory, and metabolic alterations rest on the assumption that noise is primarily a psychological stressor (Prasher, 2009). Noise, like any other psychological stimulus, activates the CNS structures of emotional processing and may be a threat for homeostasis. According to the stress model described by McEwen (1998), an individual achieves stability through “allostasis”, which denotes adaptation to environmental challenge through changes in the activity of regulatory systems in order to preserve homeostasis. Allostatic load is the price of adaptation, i.e.

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the physiological wear due to overactivation or underactivation of such regulatory systems. Elevated allostatic load may result in deterioration of allostasis itself, and thus inability to respond efficiently to stress. In mammals, the main allostatic regulatory system is the hypothalamic–pituitary–adrenocortical (HPA) axis, in coordination with the sympathetic–adrenal–medullar (SAM) axis. The prompt response to acute stress is generated by the SAM with the secretion of catecholamines, whereas the HPA prolongs the defensive physiological response with the secretion of glucocorticoids such as cortisol (Aich et al., 2009). The locus coeruleus, a noradrenergic nucleus located in the brainstem, controls both SAM and HPA regulation; the latter through the parvocellular neurons of the hypothalamus (Samuels and Szabadi, 2008). The response to acute stress depends largely on the individual's coping ability (Lundberg, 1999). One of the two following strategies may be used in general: (a) active: for the purpose of controlling and neutralizing the stressor, the individual takes a “fight or flight” action involving SAM activation and catecholamine release; (b) repressed: the feeling that control over the stressor is not possible generates the “defeat” response – associated with inhibition, hopelessness, distress, anxiety, etc. – involving HPA activation and cortisol release. If, owing to the lack of control over the source of stress (such as the case of road traffic noise), the repressed response is the only choice, then repeated environmental conditions may give rise to the so-called “learned helplessness”, which results in chronicity of the repressed response to acute stress. The subsequent overproduction of cortisol may cause damage to both the hippocampus, thus affecting memory functions, and cortisol receptors in the brain, leading to chronic cortisol secretion even in the absence of stress (Sapolsky et al., 1986). Research has revealed no physiological habituation to road traffic noise, especially with regard to nocturnal noise (Ising and Braun, 2000); however, this does not exclude likely psychological habituation (Lercher et al., 2011). Sensitivity appears to play a key part in the effects of environmental noise on health (Selander et al., 2009; Shepherd et al., 2010). A specific noise level or type of noise may interact with sensitivity and cause some degree of annoyance, which in turn determines the type of physiological response generated. Consequences of severe annoyance include fatigue, anxiety, and depression following periods of elevated stress and allostatic load. Annoyance may therefore be a mediator in the complex biological pathways that link road traffic noise with specific health outcomes (Ndrepepa and Twardella, 2011). Thalamic output may be enhanced by the limbic system. Auditory stimuli can reach the HPA axis more quickly via the lateral amygdala, triggering a primary physiological response before the stimuli are processed by consciousness (Spreng, 2000). On the other hand, when consciousness operates, the CNS response to stimuli adjusts properly to suit the situational demands. This usually occurs when there is a balance between the sympathetic and the parasympathetic activity, according to the attenuation mechanism described by Thayer and Brosschot (2005). Alterations in such a balance may lead to increased vulnerability to disease. The termed “central autonomic network” is an integrated functional unit through which the brain controls the neuroendocrine, visceromotor, and conductual responses to emotional stimuli. It comprises structures from both the prefrontal cortex and the limbic system, such as the anterior cingulate, the central nucleus of the amygdala, and the paraventricular and associated nuclei of the hypothalamus. Through this network, the prefrontal cortex inhibits subcortical primary responses, producing instead more flexible ones. Autonomic imbalance due to decreased parasympathetic tone may spoil this, leading to overreaction to stimuli

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that do not represent real threats – which also implies inefficient use of the energy resources. During sleep, stimuli from the auditory thalamus are blocked, preventing unnecessary ANS activation. Note, though, that certain sound levels and frequencies may slip in and provoke either (a) autonomic and/or cortical awakenings at noise peaks, disturbing the SWS phases, or b) autonomic awakenings due to background noise levels, disturbing the rapid-eye-movement (REM) phase (Pirrera et al., 2010). Higher sensitivity to traffic noise is associated with increased risk of cortical awakenings (Stosić et al., 2009). There appears to be no physiological habituation in the long run (Ouis, 1999). In the absence of stress, the HPA activity is synchronized with the sleep-wake cycle. Cortisol release suppression in the first half of the night is crucial for proper recovery of the body systems (Born and Fehm, 2000).

6. Discussion 6.1. Towards a new integrative model At this point we are ready to propose an up-to-date stress model comprising all the investigated mechanisms that link noise with cardiovascular, respiratory, and metabolic health outcomes. The new model allows for an adaptive mechanism that enables coping with sustained psychological stress; this implies diversion of stress from the prefrontal cortex to the central autonomic network for physical processing, reducing the psychological load at the cost of elevating the allostatic load. By doing so, allostasis attempts to free the psyche from chronic stress, which moves down to the physiological or somatic level. That is what we shall hereafter refer to as “emotional flight”. The “emotional flight” concept may be understood as follows (Fig. 1). An encounter with a stressor provokes the classic “fight or flight” response. If this response is successful, or if it fails but the individual accepts the new situation, the stress comes to an end. Otherwise the stress persists and the “defeat” response takes over. Further exposure to the stressor may lead to new attempts to face or evade the stress. Eventually, the psychological overload due to maintained stress leads to the “emotional flight”, which is actually a non-physical flight response. As a result the stress remains, but away from consciousness, i.e. temporarily isolated from the prefrontal cortex and assumed by the central autonomic network to prevent mental collapse. Thanks to such a mechanism, Stressor

Fight Flight

Success

Failure not accepted

Failure accepted

Defeat

End of stress Fight Flight

Chronicity of stress

Fig. 1. Extended stress model.

Defeat

Emotional flight Somatization

consciousness recovers the capacity of attending effectively to other emotional demands. Also, whether this mechanism takes place or not largely depends on the individual's ability to cope with environmental challenge. The absence of physiological habituation reported in some studies on nocturnal noise (Eberhardt, 1988; Ouis, 1999) may be due to consciousness inhibition, since only through consciousness can an individual modify the influence of a stressor. Recall that, within the central autonomic network (Thayer and Brosschot, 2005), attenuation of the SAM activity derives from the prefrontal cortex by means of parasympathetic feedback. Therefore, the short-term effects of nocturnal noise may be mainly due to subcortical arousal via the thalamus-amygdala connection (Spreng, 2000). Being consciousness inhibited, it is likely that sound signals be interpreted as threat, resulting in HPA overactivation and excess cortisol secretion (Ising et al., 2004). These effects, closely associated with low-intensity background noise, are notorious during the REM phase (Vgontzas et al., 2003). The above does not exclude psychological habituation, since some studies indicate greater noise effects on objective sleep quality in persons who report absence of annoyance caused by sleep disturbances (Frei et al., 2014). Similarly, some studies report reductions in cortical – likely conscious – awakenings over time, whereas other effects relative to autonomic regulation such as increased heart rate remain (Ohrström, 2000). Seemingly, the chronicity of certain physiological reactions could be caused by noise levels without mediation of annoyance (i.e. consciousness). To this regard, the adaptive mechanism of “emotional flight” might explain why sometimes chronic exposure to stressors such as road traffic noise entails psychological but not physiological habituation. Even after a reduction in the exposure, the state of “emotional flight” might persist as if the exposure remained unaltered. Neuroendocrine imbalance due to maintained stress would not be such, but rather a defense mechanism controlled by the central autonomic network for the purpose of preserving homeostasis, which at the same time increases the individual's capability of survival in a challenging environment. Energetically, the more inefficient the new balance, the greater the allostatic load. This means that such a new physiological state may increase the individual's vulnerability to environmental change, with higher risk of health outcomes even in the short-term. Noise, though not a physical threat such as infections or air pollutants, may trigger the same defensive body responses, including immune system activation, systemic inflammation, and the creation of oxidant environments. Oxidative stress arises when such a response is excessive. As suggested by Fernández-Real and Ricart (1999), this response might not be the same in all individuals, since for example different cytokine genotypes would make some individuals more prone to inflammation. Acute exposure to a stressor may cause severe adverse effects in the short term. In fact, Maclure (1991) suggested long ago a possible atherosclerotic mechanism whereby myocardial infarction occurred after the induction period following a physiological alteration caused by a surge of stress, namely: a sudden increase in BP provokes the rupture of a coronary plaque, and the resultant clot grows to the point of causing ischemia in the surrounding tissue. Likewise, adverse outcomes may take place after a cascade of events triggered by acute exposure to high noise levels, concurring different short-term biological mechanisms. Such is, for example, the case of a rise in BP due to sympathetic arousal with concurrent vasoconstriction due to accentuated endothelial dysfunction, threatening the stability of coronary plaques (Lerman and Zeiher, 2005). The consequences of acute stress may be more severe when there is also a background of chronic stress, i.e. elevated allostatic load at the moment of the point exposure. Noise may thereby act

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Fig. 2. Integrative model of stress and adverse effects applied to environmental noise. (a) Reduced model for the cardiovascular system. (b) Reduced model for the respiratory system.

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Fig. 2. (continued)

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Fig. 2. (continued)

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at the chronic level increasing the allostatic load, and at the acute level triggering cardiovascular as well as respiratory events. 6.2. Final model In Fig. 2 we present a new integrative stress model built on the results of the present review (reduced versions are provided in Fig. 2a and b for simplicity). Integrative because it includes the psychosomatic approach to the effects of stressor exposure. Also, it suggests a mechanism of acute and chronic stress interaction based on the “emotional flight” concept. Subcortical connections are shown to account for the non-conscious effects of noise as a primary stressor. Given the numerous connections among the CNS structures, only those relevant for noise as a stressor are considered. All relations shown are applicable to acute environmental noise exposure, and to road traffic noise exposure in particular, for which the diagram specifically reflects the major sleep disturbances and their consequences. The model also includes an update of all hypothesized noise effects on cardivascular, respiratory, and metabolic health, as well as the biological mechanisms involved. The diagram shows the two levels of stress processing: (a) the psychological level, beginning with the entry of the sound signal to the auditory thalamic structures and ending with the hypothalamus excitation, and (b) the physiological level, which begins with the allostatic response from the hypothalamus and ends, under certain circumstances, with the onset or exacerbation of one or several adverse effects. If the emotional response is flexible, hypothalamic activation produces a balanced physiological response deprived of adverse effects, which enables to efficiently cope with stress. However, a rigid emotional response results in excess allostatic load – with great energy demands – that increases the risk of adverse outcomes in the cardiovascular, respiratory, and metabolic systems. In order to properly understand the integrative dimension of the noise model, it is essential to highlight the concept of “emotion” as described by Damasio (1998) within the perspective of an integrated nervous system, in which homeostasis is a neurophysiological state closely linked with the emotional. According to this, emotion is no longer a psychological state restricted to the brain, but a collection of responses originated in the brain and directed to the various body systems via neurohumoral routes (neurons and blood stream). The result is a specific emotional state, and relates to changes at both the level of the CNS – prefrontal and somatosensory cortices, brainstem nuclei, etc. – and the peripheral/visceral level. Therefore emotion, as an integrated process, surpasses the boundaries of the limbic system. When consciousness certainly operates – during wakefulness – the auditory cortex stimulates the prefrontal region, where the sound signal is fully processed after prior contact with the limbic system via the thalamus-amygdala connection. As a result an emotion arises from the anterior region of the cingulate cortex, and then the central autonomic network takes over. Again, owing to innervation from the locus coeruleus to the cingulate cortex, certain sounds may excite the prefrontal cortex even under inhibition of the auditory cortex, e.g. during sleep. Immediate effects of nocturnal noise are indicated in Fig. 2 with the label “sleep”. Activation of the amygdala by noise during sleep may cause unconscious autonomic awakening (top-left of Fig. 2). Concurrent activation of the prefrontal cortex may induce cortical awakening through annoyance (top-right of Fig. 2). Sleep inhibits a number of structures of the CNS, ensuring isolation from the outside world. Yet the limbic system is permanently alert, eliciting memory-dependent primary emotions via hippocampal action. During sleep, environmental noise may provoke autonomic awakenings, disturbing either the REM phase in

the case of background noise or the SWS phases in the case of noise events. Autonomic arousals affect the hippocampus and alter the reaction of the amygdala to similar stimuli. Hippocampal dysfunction leads to deterioration of adaptive immunity. If because of the nature and intensity of noise cortical awakenings occur, then SWS stages are certain to be disrupted. Undisturbed SWS ensures adaptive immune system recovery. Moreover, SWS reduces systemic inflammation, preventing the development and destabilization of atherosclerotic plaques. Emotions emerge as a result of cortical and subcortical (limbic system) interaction. A single emotion may cause psychological stress, i.e. annoyance. Whether from sleep or wakefulness, annoyance involves similar emotional responses. Habituation to the stressor – such as environmental noise and more specifically road traffic noise – inhibits the emotion elicited by the point exposure, reducing the risk of annoyance. In the absence of annoyance, a flexible response is generated out of the balanced activation of two brainstem neural structures: the locus coeruleus and the preganglionic nuclei. The former is responsible for the excitatory sympathetic action which predisposes the individual to face the stressor, while the latter produce the inhibitory parasympathetic action for proper balanced response at low energy expense. If the emotion intensity is such that annoyance arises, an emotional overload may be generated in the anterior cingulate, then processed by the central autonomic network, and finally sent to the body systems in the form of allostatic load. The psychological stress that gives rise to this inefficient response may be enhanced by the individual's sensitivity and softened by his/her coping ability, overall determining whether the emotional overload emerges or not. In turn, sensitivity to environmental noise may be influenced by the nature of the activity performed, e.g. when the activity requires intellectual effort (Miki et al., 1998). On the other hand, physical exercise helps lower the allostatic load (Sasse et al., 2013). When annoyance is high and recurrent, the central autonomic network might cope with it and isolate it from consciousness. This is what we have referred to as “emotional flight”, a hypothetical mechanism of psychological habituation that reduces the emotional overload in the prefrontal cortex at the cost of increasing the allostatic load, which implies no physiological habituation. The “emotional flight” works as a defense mechanism that blocks or notably reduces the psychological strain due to chronic/repetitive exposure to a specific source of stress. Indeed, once the mechanism of emotional flight has been activated, a further contact with the stressor may no longer cause annoyance; however, it may perpetuate the allostatic overload. If nonetheless the new state succeeds in maintaining homeostasis without serious physiological alterations, the individual survives, but at the cost of increased risk of adverse health outcomes after exposure to additional stressors. Excessive allostatic response causes SAM and HPA overactivation. Besides affecting HRV and BP, SAM and HPA overactivity promotes the release of proinflammatory cytokines and systemic inflammation, leading to aggravated respiratory infections, increased oxidative stress, accentuated endothelial dysfunction, and aggravation of atherosclerosis. Excessive SAM activity inhibits lymphocyte adhesion and fosters blood clotting. HPA activity reduces lymphocyte count, inhibits the innate immune system, favors fat (LDL) accumulation in arteries, and increases blood glucose. Excess circulating glucose raises BP and favors clot formation owing to increased blood viscosity. Chronic HPA activation – due to repeated SWS disturbances, among other causes – may lead to insuline resistance in the long run, contributing to the development of type 2 diabetes.

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7. Conclusions The possible biological pathways linking road traffic noise with health outcomes are well documented in noise research. However, some small-scale mechanisms need to be investigated in greater detail, such as those relating noise exposure to systemic inflammation, endothelial dysfunction, and alterations in the immune system. Again, further research is needed to elucidate the role of both the central nervous system structures and the neuroendocrine system in noise stress management, provided that many cortical–subcortical connections remain to be discovered. We have proposed an integrative model of psychological and physiological processes in relation to stress in general, and to noise as a stressor in particular, which emphasizes the psychosomatic dimension of stress. We have also suggested the “emotional flight” mechanism as an attempt to explain some elusive aspects of environmental noise habituation. The integrative model accounts for the two types of associations between road traffic noise and various adverse effects and diseases found in latest noise research. First, those in which noise levels are considered constant predictors, i.e. not allowed to vary over time and thus liable to cause chronic stress. Second, those investigated in the latest time series studies, where the results indicate also acute effects of road traffic noise on health.

Acknowledgments We thank Aurelio Tobías for his support and valuable comments.

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