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1 Dept of Epidemiology of Immediate Hypersensitivity, INSERM U472: Epidemiology and Biostatistics, Villejuif, France, 2 Dept of Epidemiology ASL RME, Lazio Region, Rome, Italy, 3 Dept of Clinical Medicine, Catholic University, Rome, Italy, 4 Dept of Public Health, School of Medicine Paris XIII, Bobigny, France
CORRESPONDENCE: I. Annesi-Maesano, Dept of Epidemiology of Immediate Hypersensitivity, INSERM U472: Epidemiology and Biostatistics, 16, Ave PV-Couturier, F94807 Villejuif, France. Fax: 33 145595169. E-mail: annesi@vjf.inserm.fr
Keywords: air pollution, elderly, gender, respiratory diseases, sex, susceptibility
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Abstract |
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From the available studies, there is evidence that both "endogenous" and "exogenous" factors contribute to individual susceptibility. Females and the elderly are at an increased risk of pollution-related diseases. Moreover, some chronic clinical conditions seem to be good candidates for identifying the "frail" populations: chronic obstructive pulmonary disease including asthma, coronary heart diseases, congestive heart failure, and heart rhythm disorders.
It seems clear that epidemiological research on susceptibility in the future should investigate the underlying biological and physiological mechanisms, in addition to the environmental and toxicological effects.
There is increasing evidence that the effect of air toxicants varies from one individual to another because of the variation in the susceptibility level, i.e. the degree of vulnerability, frailty or sensitivity of the individual to exposures, stimuli, and influences. Susceptibility results from the complex interrelationships of various mechanisms. It has been suggested that those who suffer more from exposure to air pollution levels are likely to be individuals, mainly females and/or elderly people, already at risk because of serious cardiovascular or pulmonary diseases 1. Few studies, however, have addressed the question of which specific subpopulations are most sensitive to air pollutants.
In the present paper, the authors will disentangle the complex mechanisms underlying individual susceptibility by investigating the features that predispose individuals to having a greater risk from air pollution. Although partial, this approach seems necessary to better comprehend the phenomenon of individual susceptibility. The paper will briefly present the epidemiological evidence regarding the link between air pollution and 1) sex/"gender", 2) certain clinical conditions, and finally, 3) various other characteristics on which specific hypotheses have been raised. This link will be discussed in the light of the suggested potential biological and physiological mechanisms by which air pollution may cause health effects, with a particular attention to those factors acting on individual susceptibility.
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Epidemiological studies on susceptibility to air pollution |
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). The search for such factors is obviously a research priority, but so far, only a few steps have been undertaken. Appropriate designs are needed to investigate susceptibility. The available time series studies on the acute health effects of air pollution cannot provide detailed descriptions of the populations affected, chiefly because they use routinely collected data (death certificates or hospital admissions). In a time series analysis, the clinical conditions, circumstances and characteristics of those affected (e.g. biological and physiological parameters) are usually not studied. Similarly, studies on long-term effects of air pollution considering individual susceptibility have been scanty so far. Some recent investigations, however, have used novel study designs and/or new approaches to evaluate short-term as well as long-term effects of air pollution among specific population subgroups.
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). Furthermore, young female asthmatics have a higher risk of air pollution effects than young female nonasthmatics. All major pollutants are involved (table 1). However, only one study had a longitudinal design with the assessment of individual exposure.
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). Many studies, however, did not consider sex differences to a great extent. The three large cohort studies on long-term effects of air pollution, conducted in the USA, have examined the relationship between various particle indicators and mortality. Due to the prospective design, these studies are the most appropriate to investigate the causal relationship. There was no significant difference between males and females for all-cause mortality in the Six Cities Study 25, in the American Cancer Society (ACS) study 23 and in the Seventh-day Aventists Health Study on Smog (AHSMOG) 24. However, males had a higher risk of respiratory cancer in the AHSMOG study and females of cardiopulmonary diseases in the ACS study.
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Mechanisms
Differences in the susceptibility to air pollution observed between females and males are the result of the interaction of sex (genetic and biological) and "gender" (sociocultural) factors.
There are recognised sex differences in organ growth and development as well as in the maturation of the immune system. Females have smaller lung and airways calibre, a higher level of bronchial hyperresponsiveness, but suffer less than males from childhood respiratory infections. The heart of a female, relative to her body size, is also smaller (about two-thirds) and typically pulses at a higher rate than a male's. Sex differences generated by genetic and biological factors are responsible, through the production of hormones and enzymes, for the physiological variations observed between females and males. Unfortunately, the role of genetic factors has not yet been studied.
However, an interest in the sex hormones has begun in this last decade, although there are still few population-based data. The most compelling evidence that sex hormones are involved emerges from natural models, i.e. menarche, menstrual cycle, contraception, pregnancy and menopause. In these models, clinical and functional variations can be measured in parallel with well-known fluctuations of the hormonal profile. Although oestrogen has a beneficial impact, which extends beyond sex and reproduction to virtually every part of a female's body (e.g. strengthening bones, fostering the growth of brain cells, blocking platelets that can clog arteries, altering insulin metabolism), it may contribute to a host of medical problems. Oestrogen might act on both the lung/airways and heart. Oestrogen is likely to exert an effect on the constriction of bronchial smooth muscle. Thus, oestrogen may contribute to the rise of asthma incidence in females in adolescence.
Fluctuations in oestrogen during the menstrual cycle may also cause flare-ups in asthma. In the late luteal or premenstrual phase (the 6 days before menstrual bleeding begins), when the corpus luteum disintegrates and oestrogen and progesterone levels begin to fall, some women may experience asthma 27. The effect of the contraceptive pill on the lung can only be hypothesised, but clinical and functional improvement of asthma has been observed after normalisation of the hormonal profile in females.
Regarding pregnancy, it is known that this depends on the type of asthma phenotype. In most asthmatic females, pregnancy is characterised by amelioration of both clinical and functional indices of asthma. Furthermore, asthma attacks in the last period of the pregnancy and during labour are rare in these same females. This might be due to an increased production of progesterone and cortisol, which may exert a protective effect. However, females with severe asthma may present severe exacerbation of the disease, which has not yet been explained.
Finally, it has been shown that menopause can increase either the risk of asthma or the severity of pre-existing asthma in predisposed females. This might be due to an excess of estradiol in these predisposed females, which can enhance both the formation of prostaglandin and arachidonic acid metabolism implicated in asthma inflammation. Furthermore, during menopause, abnormally high levels of oestrogen, because of replacement therapy, can increase the risk of asthma 28, whereas physiologically low levels of oestrogens may have protective effects.
Abundant knowledge also exists in the case of the cardiovascular system. It is well known that, throughout the reproductive years, oestrogen prevents the build-up of atherosclerotic plaque in the arteries, boosts levels of the beneficial form of cholesterol (high-density lipoprotein (HDL)) and lowers heart-harming low-density lipoprotein (LDL), thus protecting females from cardiovascular disease (CVD). However, oral contraceptives, even those with lower oestrogen, raise LDL and lower HDL, which increases CVD risk. As their oestrogen levels fall at midlife, the risk of CVD rises for all females. Like oral contraceptives, the menopause brings a rise in LDL and a small decline in HDL. This explains why the annual risk of CVD is reduced for every year a female continues menstruating.
Unfortunately, in spite of the incipient research on sexual differences in the development of diseases having raised hypotheses on the implicated mechanisms, the precise role played by air pollution on these mechanisms has not yet been examined.
"Gender" is responsible for differences in environmental exposures, which may be crucial in the case of air pollution. Due to sociocultural factors, personal habits and exposure vary between females and males throughout the world 22. Because of differences in activities, occupational and domestic exposures differ between females and males. Females are more exposed than males to some hazards (e.g. nitrogen dioxide 15 and biomass smoke 29 due to cooking, passive smoking at home, hygiene/cosmetic products, indoor exposures, cleaning).
Similarly, "gender" differences exist in diet, which can have repercussions on obesity, related to both asthma and CVD.
However, there are also "gender" differences in perception, reporting and interpretation of risk and health outcomes 22. It is not yet clear, for instance, whether the asthma exacerbations occurring in many females during the premenstrual period are due to objectively measurable intensification of the disease or to the increased perception of symptoms caused by the particular psychological state before menstruation 27.
Regarding health outcomes, there is also a difference between females and males in their management (e.g. diagnosis, treatment, emergency room visits). According to an analysis in the USA 30, females were less likely than males to get clot-dissolving drugs, to limit the damage of a heart attack, or to receive standard medication like aspirin or beta-blockers. This "gender" gap in treatment may be one reason why the death rate for CVD has declined only for males. Similar patterns have been seen in respiratory health.
Differences due to the interactions between sex and "gender" can also exist, but they are difficult to study 22. They concern factors such as, childhood exposures, active smoking, nutrition and diet, exercise, occupational exposure, and air pollution exposure. For instance, diet, tobacco and alcohol consumption differ between females and males, not only because of sociocultural factors, and thus of exposure, but also because of differences in biological resistance.
An example of the complex interactions between sex and "gender" is provided in table 3. Subgroup analysis in a based-population sample of 3,941 adolescents living in a semirural zone of France showed that undiagnosed exercise-induced asthma, as defined by a report of exercise-induced wheezing attacks in the past year in the absence of a physician's diagnosis of asthma (42 out of the 259 with exercise-induced asthma), was independently associated with being a young female, after controlling for potential confounders (table 3). This depends on sexual factors. Compared to young males, young females have a smaller airway calibre in absolute terms (forced expiratory volume in one second (FEV1)), but a higher ratio of airway calibre to lung volume (FEV1/vital capacity), which is partly responsible for their higher level of bronchial hyperresponsiveness. Also, "gender" factors influence the environmental exposures of young females as well as the way they have their diseases managed, fill in the questionnaires, and possibly practice sport.
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Clinical conditions
Various chronic clinical conditions seem to be the best candidates to trace the true "frail" populations susceptible to the effects of air pollution: chronic obstructive pulmonary disease (COPD) including asthma, coronary heart diseases, heart failure, and disorders of the heart rhythm. There is obviously an extreme overlap between these conditions and, especially in the elderly; they all appear in combination as frequent causes of comorbidity.
SUNYER et al. 32 conducted the first study on factors possibly conferring susceptibility to the acute role of air pollution. By using a case-crossover analysis to evaluate mortality in a cohort of patients with COPD, these authors found that older females, patients admitted to intensive care units, and patients with a higher rate of emergency room visits were at greater risk of dying, in association with black smoke.
ZANOBETTI et al. 33 examined whether hospital admissions or secondary diagnoses for heart disease, COPD and pneumonia between 1985–1994 predisposed persons to a greater risk from air pollution. People with asthma, acute respiratory infections, and defects in the electrical control of the heart, conductive heart disorders or dysrhythmias emerged as risk groups for particulate matter effects, in terms of hospital admissions.
Using individual information on decedents of the Quebec Health Insurance Plan database (billing records on medical services, diagnoses coded by physicians, drug prescriptions), GOLDBERG et al. 34 found that daily mortality increased twice, as result of particle pollution among persons who had had acute lower respiratory diseases, chronic coronary artery diseases (especially acute lower respiratory diseases and congestive heart failure) compared to the others.
However, LEVY et al. 35 did not find an association between daily indicators of particulate matter and out-of hospital primary cardiac arrest in Seattle, WA, USA with an analysis of effect modification using a case-crossover. The choice of the sudden deaths series of people with no previous history of CVDs was a limitation of the study.
Time series analyses as well as a case-crossover approach were employed by KWON et al. 36 to specifically test the hypothesis that patients with congestive heart failure are more susceptible to air pollution than the general population. This was done by comparing the air pollution related to mortality among the heart failure cohort members with that of the general population in the same area and the same period. The effects attributable to particles with a 50% cut-off aerodynamic diameter of 10 µm (PM10) among the diseased cohort appeared larger than among the general population (5.8% versus 1.4% increase per 42.1 µg·m–3 PM10).
Mechanisms
Several mechanisms, by which clinical conditions may contribute to increase susceptibility in populations, can be hypothesised.
Acute exacerbations are the most common cause of hospital admissions for COPD. Severe infection-induced exacerbations are associated with a high risk of death up to 40–60% in the following year. The long-term prognostic factors of the patients are related not only to the respiratory parameters (oxygen tension in arterial blood, carbon dioxide tension in arterial blood; forced vital capacity, FEV1) as well as to the onset of respiratory failure, but also to the cardiac status. Electrocardiogram (ECG) signs of right ventricular hypertrophia (chronic cor pulmonale) and ECG signs of ischaemia were strong predictors of mortality among COPD patients studied in Rome 37. On the other hand, a depressed left ventricular diastolic performance is a predictive factor for severe arrhythmias during respiratory failure from COPD.
Both myocardial infarction (MI) and ischaemic stroke are the results of sudden and persistent interruption of regional blood flow from thrombosis, spasm, or small-vessel constriction. Patients hospitalised after a MI are extremely frail and at risk of subsequent death; an overall 30-day mortality rate of 
14–15% and a 1-yr mortality rate of 22–24% have been observed in a population 38. Moreover, such patients are at a high risk of a subsequent MI or hospital re-admission for angina, cardiac failure, cardiac dysrhythmia, and stroke.
Chronic heart failure is a clinical syndrome mainly due to left-ventricular systolic dysfunction associated with a failure of the heart to pump blood at a rate suitable with the demand. Frequent causes of myocardial failure, which has a relatively high prevalence in the general population, especially among the elderly (5–10% for those >65 yrs) 39 and with mortality reaching 50–75% within 5 yrs of the diagnosis 40, are coronary ischaemia and valvular diseases. Several factors of the particular susceptibility of patients with heart failure (e.g. infections, hypertension, MI, pulmonary embolism) may precipitate their conditions to death.
Perspectives
The innovative pilot study of PETERS et al. 41 on the role of air pollution among patients with implanted defibrillators has attracted attention to patients with severe heart rhythm disorders. In fact, all conditions (disorders of sinus node function, atrioventricular conduction disturbances (heart blocks), tachycardias) are sensitive to variation of the autonomic tone, a postulated target of the effects of air pollution. Atrial fibrillation affects a large proportion of elderly people (2.3% in people >40 yrs and 5.9% in those >65 yrs) 42 and is associated with a considerable increase in mortality rates and a four-fold to five-fold increase in the incidence of stroke 43.
Furthermore, there is the attractive hypothesis, according to which oxidants can increase the level of blood coagulability and modify the adhesive properties of red blood cells, thus leading to the increased risk of ischaemic damage in individuals with vulnerable coronary circulation 44.
It is also necessary to mention that breathing pattern (nasal versus oral, especially among COPD patients) may play a role, since there is a more profound deposition of particles in the lower respiratory tract with oral breathing. Patients with COPD, who tend to have oral breathing, seem to have a marked increase in pulmonary particle deposition 45 as well as a reduced clearance 46.
Other factors
There are other factors, either "endogenous" or "exogenous" (to use the terminology introduced for the study of the natural history of COPD 47), intervening in susceptibility that may deserve consideration.
Age, for instance, has been well studied and there is a general consensus, as previously shown, that elderly people are more prone than the nonelderly to the effects of pollution 22, probably because chronic conditions are more frequent late in life. Among the classical risk factors, tobacco smoking, hypertension, diabetes and high cholesterol have been mentioned 49, but no evidence is available.
Furthermore, intense outdoor physical activity should be evaluated not only because it is associated with oral breathing, but also because it is known to carry an elevated risk of MI and sudden death 50.
Socioeconomic status (SES) appears to be of some interest, especially after the surprising findings emerged from the re-analysis of the large American cohort studies on chronic health effects of particulate matter. KREWSKI et al. 51 found that the relative risk estimates for mortality related to average annual particles with a 50% cut-off in aerodynamic diameter of 2.5 µm (PM2.5) were much higher among those with less than a high school education in comparison with those with post high school education. The reasons for such effect modification are not justified by several confounding factors and remain largely unexplained. One hypothesis is that low SES is associated with higher exposure levels.
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Conclusions |
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In conclusion, it is worth underlying that the finding of a stronger association in a subpopulation with a characteristic that predisposes them to adverse effects of exposure to air pollution will provide insights into the specific role of the pollutant as well as the mechanism of the effects. This finding will also provide a basis for public health interventions.
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