39 Environmental Pollution and Atopic Eczema

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39 Environmental Pollution and Atopic Eczema

B. Eberlein-König, J. Huss-Marp, H. Behrendt, J. Ring

39.1 Introduction

The etiology of atopic eczema is multifactorial and its complex pathogenesis is still not fully understood. It is known that many environmental factors are capable of modulating the phenotypic expression of atopic eczema. Among these, the most relevant trigger factors of atopic eczema are inhalant and alimentary allergens.

The role of other environmental factors such as air pollutants (e.g., formaldehyde, nitrogen dioxide, sulfur dioxide, volatile organic compounds, tobacco smoke, particles, ozone) against the background of allergic sensitization and other atopic diseases will be elucidated.

39.2 Formaldehyde

Formaldehyde is a colorless volatile gas with a charac- teristic odor and is highly water soluble. It has many sources in the home: paper products, floor coverings, carpet backings, adhesive binder, permanent-press clothing, tobacco smoking, combustion processes, and resins. Particularly high concentrations may result from the use of urea formaldehyde foam insulations. In homes with these types of insulation, formaldehyde concentrations were from 0.1 to 0.8 ppm; in homes without such insulation they ranged from 0.03 to 0.07 ppm.

The effect of formaldehyde on the production of proinflammatory cytokines (IL-1[ , IL-1 q , TNF [ , IL-8) by normal keratinocytes was investigated. Formalde- hyde (0.25 – 5 µg/ml) alone did not affect the levels of IL-1q and IL-8 production. Formaldehyde significantly increased IL-8 and IL-1q production in cells stimulated with PMA (phorbol 12-myristate 13 acetate), but not

IL-1[ or TNF [ [1]. Furthermore, IL-4 and IL-6 production in A23187-stimulated mouse bone marrow-derived mast cells was significantly increased at 0.5 and 1 µg/ml formaldehyde, but decreased at 5 µg/ml formaldehyde. Antigen-induced IL-4 production also increased significantly in these mast cells treated with 0.5 µg/ml formaldehyde [2]. These in vitro findings suggested that formaldehyde may act as a modulating factor of cutaneous inflammation by affecting the abili- ty of keratinocytes to release pro-inflammatory cytokines and may affect the immune response via the modulation of cytokine production.

Also in animals, exposure to low levels of formaldehyde affected various immune functions. It was reported that exposure to 250 ppb, but not to 130 ppb enhanced sensitization to inhaled ovalbumin in guinea pigs and that exposure to 1,600 ppb formaldehyde for 10 days increased ovalbumin-specific IgE production in mice intranasally sensitized with ovalbumin [3, 4].

Long-term exposure (12 weeks) of low-level formaldehyde (80 – 2,000 ppb) induced differential immunogenic and neurogenic inflammatory responses in an allergic mouse model [5]. Furthermore, in actively sensitized guinea pigs, allergic bronchoconstriction was significantly potentiated by repeated transnasal exposure to formaldehyde in a dose-dependent manner [6].

In humans, a variety of short-term signs and symptoms are commonly accepted as causally related to exposure. Acute mucous membrane and upper airway irritation can occur at levels of 0.01 – 0.1 ppm. It was shown that low-level exposure to indoor formaldehyde may increase the risk of allergic sensitization to common aeroallergens in children [7].

In the skin, formaldehyde is known as a potent con- tact allergen, but patients with atopic eczema have only rarely been assessed under defined conditions at environmental concentrations of formaldehyde.

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35 30 25 20 15 10 5 0

0 2 4 h 0 2 4 h formaldehyde

Transepidermal water loss (g/h.m²)

Controls Patients with AE In our own exposure studies, seven patients with atopic eczema and seven control subjects were exposed to formaldehyde or room air (nonspecific exposure) in a 60 m³climate chamber for 4 h. During the experiments, the temperature in the climate chamber was 22°C and the air humidity was 30 %. Room air without pollutants contained formaldehyde between 0.0044 ppm and 0.0054 ppm. A formaldehyde concentration of 0.08 ± 0.016 ppm was chosen in the exposure experiments. Transepidermal water loss (TEWL) was measured on noninflammed and nonscaling skin of both lower arms not covered by clothing with an evaporimeter before and after 2 and 4 h of exposure. At the same time points, skin roughness was determined by taking replicas with dental impression material of the surface of normal-appearing skin of the volar forearms. Blood was taken at 0, 4 and 24 h to determine eosinophil cationic protein (ECP) and sIL-2R levels in the serum by ELISA.

In patients with atopic eczema, TEWL was significantly increased after exposure to formaldehyde, whereas exposure to room air in the climate chamber reduced significantly the TEWL in patients with atopic eczema. Control subjects showed no changes in TEWL after formaldehyde exposure at the given concentrations (Fig. 39.1). Skin roughness was not influenced by exposure to room air or formaldehyde. ECP levels in

Fig. 39.1. Transepidermal water loss (TEWL) of the same area of the left and right lower arm before (0 h) and after 2 and 4 h of formaldehyde exposure (0.08 ± 0.016 ppm) in patients with atopic eczema (AE) (n = 7) or control subjects (n = 7). (medi- ans; ** p< 0.01)

the serum were not influenced by formaldehyde exposure and observed changes of sIL-2R serum levels seemed to follow a circadian rhythm and were unrelated to pollutant exposure.

This study showed that short-term exposure to low concentrations of formaldehyde can induce skin surface changes, especially a disturbance of the epidermal barrier function in patients with atopic eczema. The known irritant properties of formaldehyde may be the cause of this worsened epidermal barrier function. [8]

39.2.1

Nitrogen Dioxide

Nitrogen dioxide is a poorly water-soluble gas. Com- bustion of gas during cooking and the burning of pilot lights releases nitric oxide, nitric dioxide, CO, CO₂, and water. In homes with gas stoves, 0.025 – 0.075 ppm is a typical range of NO₂ concentrations; peak values in kitchens with gas stoves or kerosene gas heaters range from 0.1 to 0.5 ppm. Furthermore, nitrogen dioxide is discharged during burning of fossil fuels in motor vehicles, and is a common air pollutant of community air in urban areas. During peaks, hourly averages may exceed 0.2 ppm, especially during periods of hot weath- er and stagnant air.

Exposure of human bronchial epithelia cells in vitro to 0.4 – 0.8 ppm NO2induced an increased permeability of the epithelia and a ciliary dyskinesia. This damage was accompanied by the release of inflammatory mediators such as LTC4, GM-CSF, TNF[ , and IL-8 [9]. Pollen pre-exposed to 50 – 200 ppb NO2caused a significant increase of allergen-specific in vitro histamine release from peripheral blood leukocytes compared to histamine release induced by nonexposed pollen [10].

In animals, it was consistently shown that they developed an antigen-specific IgE-immune response only if they had been exposed to nitrogen dioxide alone or in combination prior to allergen application. The anaphylactic reactions of the respiratory system in guinea pigs after allergen inhalation was increased if the animals were exposed to more than 40 ppm nitrogen dioxide for 30 min [11].

A considerable number of studies have investigated the lung function response to nitrogen dioxide in healthy subjects, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). There are indications that asthmatics are more susceptible to increase airway reactivity to NO2than healthy subjects.

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0 2 4 h 0 2 4 h NO2

* *

35 30 25 20 15 10 5 0

Controls Patients with AE

An increase in bronchoconstrictive response to house dust mite has been seen in mild asthmatics after exposure to NO₂[12], although an earlier study showed little response [13]. However, the combination of nitrogen dioxide and another pollutant, such as ozone or sulfur dioxide, has been shown to increase the airway responsiveness of mild IgE-mediated asthmatics to allergen [14]. In patients with a history of allergic rhinitis a 6 h exposure to nitrogen dioxide (400 ppb) did not alter nasal airway resistance, but allergen challenge after exposure to nitrogen dioxide significantly increased levels of ECP in nasal lavage fluid [15].

For atopic eczema, less data on effects of NO₂are available. In epidemiological studies, examination of 1,273 school-aged children in selected areas of East and West Germany in spring 1991 showed that the prevalence of atopic eczema was associated, among other factors, with indoor use of gas without a hood and dis- tance of homes from a busy road, which could be an indication for NO₂ exposure [16]. In another study with 678 5- to 6-year-old children, exposure to NO_x (mean concentrations in four different regions of Ba- varia: indoor NOx: 5.3 – 7.4 µg/m³, outdoor NOx:

4.9 – 17.4 µg/m³) was not positively associated with any manifestation of atopy in children, including atopic eczema [17].

Exposure studies in patients with atopic eczema were conducted as follows. In these experiments including seven patients with atopic eczema and seven control subjects, a concentration of 0.1 ± 0.02 ppm NO2was used. During the experiments, the temperature in the climate chamber was 22°C, and the air humidity was 30 %. Room air without pollutants contained NO2between 0.023 and 0.030 ppm. TEWL and skin roughness was measured on noninflammed and nonscaling skin of both lower arms not covered by clothing with an evaporimeter before and after 2 and 4 h of exposure. Blood was taken at 0, 4 and 24 h for determination of ECP and sIL-2R levels in the serum by ELISA.

In patients with atopic eczema and controls, TEWL was significantly increased after exposure to NO2after 4 h, whereas exposure to room air in the climate chamber significantly reduced TEWL in patients with atopic eczema (Fig. 39.2). Exposure to NO2caused a significant increase in skin roughness in control subjects but not in patients with atopic eczema. ECP levels in the serum were not influenced by NO2 exposure and observed changes in sIL-2R serum levels seemed to fol-

Fig. 39.2. Transepidermal water loss (TEWL) of the same area of the left and right lower arm before (0 h) and after 2 and 4 h of NO2 exposure (0.1 ± 0.02 ppm) in patients with atopic eczema [AE] (n = 7) or control subjects (n = 7). (medians;

* p< 0.05)

low a circadian rhythm and were unrelated to pollutant exposure.

Our results indicate that a short period of exposure to low concentrations of NO2affects the skin of patients with atopic eczema as well as normal skin. It is known that NO2causes oxidative damage resulting in the generation of free radicals that may oxidize amino acids in tissue proteins. NO2also initiates lipid peroxidation of polyunsaturated fatty acid in pulmonary cell membranes. Similar mechanism might be responsible for the effect of NO2on healthy skin, as well as for that on the skin of patients with atopic eczema [8].

39.2.2 Sulfur Dioxide

Sulfur dioxide is a highly water-soluble gas. It is a common air pollutant, produced during combustion of sulfur-rich fossil fuels in, for example, oil refineries, motor vehicles, and for heating and power generation.

Ambient air may contain up to 0.3 – 0.4 ppm in peaks in very polluted urban areas. Kerosene heaters in homes may produce up to 1 – 2 ppm, depending on space and ventilation.

The release of pro-inflammatory eicosanoid-like substances from pollen grains was significantly inhib-

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ited by exposure to sulfur dioxide [18]. Pollen pre- exposed to 900 ppb SO₂caused a significant increase in allergen-specific in vitro histamine release from periph- eral blood leukocytes compared to histamine release induced by nonexposed pollen in one study [10].

Studies in animals showed that an antigen-specific IgE-immune response developed if they had been exposed to sulfur dioxide alone or in combination pri- or to allergen application, e.g., significantly higher antibody titers against ovalbumin were seen in guinea pigs after exposure to sulfur dioxide [19].

Asthmatics respond with airway constriction and asthma symptoms at 0.25 – 0.5 ppm SO₂. Above 5 ppm SO₂, most healthy subjects also seem to develop increased airway resistance. The sensitivity of “atopic”

airways to sulfur dioxide shows great variability. Levels as low as 0.25 ppm SO₂can be reactive in some patients.

Sulfur dioxide alone did not enhance the allergen- induced bronchospasm, but together with other environmental pollutants, it did facilitate the process. It was shown that exposure to 200 ppb SO₂combined with 400 ppb NO₂enhanced the airway response to inhaled allergen [14]. Sulfur dioxide at a concentration of 4 ppm for 10 min did not increase nasal symptoms or nasal resistance in subjects with rhinitis or in subjects with bronchial responsiveness to sulfur dioxide [20].

In an epidemiological study with 678 5- to 6-year- old children, exposure to SO2 (mean concentration in four different regions of Bavaria; indoor SO2: 4.4 – 7.2 µg/m³, outdoor SO2: 5.2 – 37.1 µm/m³) was not positively associated with any manifestation of atopy in children, including atopic eczema [17]. In differently polluted areas of East Germany, where pollution from sulfur dioxide decreased dramatically between 1989 and 1995, cross-sectional studies in about 7-year-old children were conducted. For allergies and related symptoms as well as for eczema, no differences in time trends could be detected and no association with SO2

could be seen in East Germany [21].

For patients with atopic eczema, the following data of exposure experiments are available. In a double- blind study, seven patients with atopic eczema and ten control subjects were exposed to SO2or control air in a 40-m³ climate chamber for 4 h. Before exposure, patients were seated in a smaller chamber at 23 ± 1 °C;

the air humidity was 50 %. Room air without pollutants contained SO2at a concentration of 0.002 ± 0.01 ppm.

Subjects were exposed to SO2at a concentration of 0.38

± 0.05 ppm (1 ± 0.13 mg/m³) and control air for 4 h on

two different days. Transepidermal water loss (TEWL), skin roughness, skin pH, skin hydration, and skin sebum were measured on noninflammed and nonscaling skin of both lower arms not covered by clothing before and after 2 and 4 h of exposure. These skin phys- iology parameters were measured in all subjects at the same time point in order to avoid changes by circadian rhythm. Two investigators measured the same parameters in the same subjects in order to avoid influences by the investigators. Neither in control subjects nor in patients with atopic eczema did the 4 h of exposure of the chosen SO₂concentration influence all skin physi- ology parameters significantly. Thus short-term exposure to environmental sulfur dioxide seems not to influence healthy and atopic skin [22]. Whether the high water solubility of SO₂and a possible absorption by water vapor might be the cause for the lack of effects on the skin can be debated.

39.2.3

Volatile Organic Compounds

Volatile organic compounds (VOCs) make up a large and diverse group of organic substances that share the property of volatizing into the atmosphere at normal room temperature. Numerous sources of VOCs exist in both residences and office buildings, including paints, adhesives, cleansers, cosmetics, building materials, furnishings, dry-cleaned clothes, cigarettes, gasoline, printed material, and other consumer products. Inves- tigations concerning the VOC levels in German house- holds showed concentrations up to 3.3 mg/m³. Mea- surements in 22 new or newly renovated buildings revealed total VOC concentrations up to 35.6 mg/m³, with a median of 9.5 mg/m³.

Pollen grains were incubated in a fluidized bed reac- tor under controlled conditions with VOCs (toluene, m-xylene) at environmentally relevant concentrations.

They induced a significant enhancement of proinflammatory eicosanoid-like substances [18].

The high capacity of VOCs to penetrate through the epidermal barrier was shown in a rat model using 14 VOCs. The absorption of the VOCs was directly correlated with the exposure concentration and decreased with decreased water solubility of the substances [23].

A study of rat skin after dermal exposure to m-xylene for up to 6 h revealed histopathological changes as well as increased IL-1[ and iNOS protein expression after 1 h of exposure [24].

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*

Before exposure

24 h after exposure

48 after exposure

72 h after exposure Time point

2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Relative dermal blood flow [mean difference ±95% CV]

Specific IgE antibodies to food, indoor and outdoor allergens, and cytokine-producing peripheral T cells were measured and correlated with VOC exposure measured over a period of 4 weeks in infants’ bed- rooms. It could be shown that exposure to alkanes and aromatic compounds (toluene, xylenes, chlorobenzene) may contribute to the risk of allergic sensitization to the food allergens milk and egg white (odds ratios between 5.7 and 11.2). Moreover, significantly reduced numbers of CD3+/CD8+ peripheral T cells were found in children exposed to alkanes, naphtha- lene and chlorobenzene. Exposure to benzene, ethyl- benzene and chlorobenzene was associated with higher percentages of IL-4-producing CD3+ T cells. Both an increase in IL-4-producing TH2 cells and a reduction of IFN-* -producing TH1 cells may contribute to a type 2 skewed memory in response to allergens. Therefore, it was suggested that exposure to VOC in association with allergic sensitization could be mediated by a T cell polarization towards the type 2 phenotype [25]. Also, maternal VOC exposure was shown to influence the immune status of the newborn child as an adjuvant for a Th2-polarization [26]. Further epidemiological studies showed that the risk of atopic eczema was significantly increased in 4-year-old children who were exposed to toluene, m-xylene, alpha-pinene, or tetra- chlorothylene during the 3rd year of life (adjusted OR between 6.6 and 25.6). Moreover, restoration during the 3rd year of life may contribute to the risk of atopic eczema in 4-year-old children (adjusted OR 11.3) [27].

The 22 most frequent VOCs have been included in a mixture designed for the use in exposure studies. They induced at concentrations of 25 mg/m³airway obstruc- tions in asthmatics, irritation of eye and throat, head- ache and drowsiness as well as fatigue and mental con- fusion. The effects of these VOC on human skin function with and without allergen exposure were studied in the following exposure experiments.

In a double-blind crossover study, 12 adults with atopic eczema and positive reactions to house dust mites in an atopy patch test and 12 matched healthy volunteers were exposed on their forearms to house dust mite and subsequently to a mixture of 22 VOC at a concentration of 5 mg/m³ in a total body exposure chamber for 4 h. Transepidermal water loss (TEWL) and skin blood flow were measured in all subjects before, during and after exposure.

A significant increase in TEWL was observed after VOC exposure as compared to exposure with filtered

Fig. 39.3. Mean difference of relative dermal blood flow in patients with atopic eczema (n = 12) after exposure to VOCs (5 mg/m³) combined with house dust mite allergen exposure compared to control exposure. (* p< 0.05)

air in all individuals (see Chap. 38). Prior exposure to house dust mites resulted in a significant rise in dermal blood flow after 48 h in patients with atopic eczema but not in controls (Figs. 39.3, 39.4). These results showed that VOC exposure at environmental concentrations can damage the epidermal barrier of healthy and dis- eased human skin and enhance the adverse effect of house dust mites on allergic subjects with atopic eczema (J. Huss-Marp et al., personal communication [28]).

39.2.4

Environmental Tobacco Smoke

Environmental tobacco smoke (ETS) is a potent adjuvant for IgE production in animal models. Sensitized female BALB/c mice showed a long-lasting, increased TH2-lymphocytic immune response after exposure to ETS [5 days, 6 h/day), characterized by elevated IgE and IgG1 concentrations in the serum, an increase in eosinophils and enhanced cytokine levels for IL-4 and IL-10. Additional provocation of animals with allergen aerosol during ETS exposure induced a significantly enhanced total IgE value and an increased allergen- specific IgG1 response compared with exposure to syn- thetic air. It was concluded from these results that exposure to ETS upregulates the IgE-mediated reactions to inhaled allergens [29].

Extensive epidemiological literature documents an association between exposure to ETS and increased lower respiratory illness (bronchitis, bronchiolitis, pneumonia, and their symptoms) in infancy and early

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a b c d

Fig. 39.4a–d. Laser Doppler imaging. Forearms of a patient with atopic eczema before (a) and after exposure (b = 24h, c = 48h, d = 72h) with VOCs (5 mg/m³) combined with house dust with allergen exposure on the left arm and buffer exposure on the right arm. (Red and green areas are areas with a higher dermal blood flow indicating skin inflammation)

childhood. In a quantitative overview of 38 studies on respiratory outcomes, the authors revealed pooled odds ratios (OR) of 1.57 for smoking by either parent and 1.72 for maternal smoking [30]. With respect to asthma, a pooled OR of 1.37 for the risk of asthma was reported [30].

Of 678 5- to 6-year-old children whose mothers had smoked during pregnancy and lactation, 52.2 % exhib- ited manifestation of atopy in contrast to 35.7 % of children of nonsmoking mothers. A history of atopic eczema was the only component of the various manifestations of atopy that were significantly associated with maternal smoking during pregnancy and lactation [17].

In order to further determine the impact of environmental tobacco smoke on atopic eczema, 1,669 school beginners were investigated. Exposure assessment was based on measurement of cotinine in spot urine sam- ples together with questionnaire and interview data on smoking behavior of the parents. In the total study group, prevalence of atopic eczema was significantly associated with urinary CCR (cotinine to creatine ratio) values. This study supported the hypothesis that exposure to ETS has an adjuvant effect on atopic eczema [32].

39.2.5

Particulate Matters

Extracts of atmospheric fine dust collected in heavily polluted areas of western Germany released proinflammatory mediators (prostaglandin E2) and cytokines (IL-8) from polymorphonuclear granulocytes. Togeth- er with the increased production of oxygen species, these results indicate that substances absorbed to particles may lead to tissue inflammation through recruit- ment of inflammatory cells and through tissue damage due to the release of oxygen radicals [33]. Especially for diesel exhaust particulates (DEPs), a potent adjuvant activity in the development of allergies was demon- strated both at the sensitization and at the effector level in animal models and in cell systems. It was shown that polyaromatic hydrocarbon extracts of diesel exhaust particles enhance the IgE-production in purified human B cells from blood or tonsils in presence of costimulatory factors (IL-4, CD40mAb) by 20 % – 360 % [34]. The spontaneous IgE production of the transformed human B cell line 2C4/F3 was also enhanced by diesel exhaust particles [34].

Doses of 25 – 300 µg DEPs enhanced the allergen- induced (ovalbumin, Japanese cedar pollen, ragweed) IgE and IgG1response in mice, independently of the method of application (intraperitoneal, intranasal, intratracheal). The amount of allergen necessary for IgE synthesis was reduced by a factor of 100 when DEP and allergens were given at the same time [35]. Diesel

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exhaust particulates induce the production of the cytokines IL-4, IL-5, IL-10, and IL-13 in the spleen and the local lymph nodes in mice, indicating an Th₂lymphocytic immune response [37]. These results in different species and in vitro studies indicate that particulate matters, especially diesel exhaust particles, may inter- fere with the development of allergic reactions. Howev- er, animal studies, which would allow a clear-cut dose- dependent risk estimation, are lacking.

Although road traffic pollution from automobile exhausts may be a risk factor for atopic sensitization in humans, the evidence in support of this view remains conflictive. Some investigators have reported a clear association between the prevalence of allergy and road traffic-related air pollution, whereas this difference was not observed in other studies. Most discrepancies have been related to important variations in study design and methodology. In addition, in as much as exposure to ambient particles differs substantially in worldwide urban environments, perhaps qualitative rather than quantitative variations in particulate air pollution at different locations account for differences in the prevalence and/or severity of respiratory allergies [38]. For eczema, which was more prevalent in East than in West Germany, a positive association to total suspended particles could not be detected in an epidemiological study [21].

39.2.6 Ozone

Ozone is a secondary pollutant formed through a series of sunlight-driven reactions of atmospheric oxygen with volatile organic compounds and nitrogen oxides, which are produced through combustion.

Pollen pre-exposed to ozone caused a significant increase of allergen-specific in vitro histamine release from peripheral blood leukocytes compared to histamine release induced by nonexposed pollen [10]. Ani- mal studies have shown that exposure to ozone enhanced the allergic response to allergens. Four weeks of ozone exposure led to an increase in immediate cutaneous hypersensitivity and anti-ovalbumin IgG1, with a parallel reduction in anti-ovalbumin IgG2. In the

“high IgE responder” mice, there was also a dose- dependent increase in specific IgE, IL-5, eosinophils, and lymphocytes [39]. In guinea pigs, exposure to ozone increased nasal allergic responses to ovalbumin, as shown by increased nasal responsiveness and eosin-

ophil infiltration, paralleled by an increase in allergen- specific IgG [40].

In human and animal nasal epithelium, the described mechanisms of toxicity included a direct effect of ozone on epithelial lining fluid and cellular membranes and the subsequent release of cytokines and cyclooxygenase and lipoxygenase products. An indirect effect of ozone was indicated by a decreased mucociliary clearance, free radical production inter- acting with a gene promoting factor; and increased DNA synthesis. Studies highlighted the pivotal role of activated neutrophils and mast cells, leading to the release of deleterious enzymes (tryptase, eosinophil cationic protein) and numerous cytokines [41]. How- ever, in asthmatic humans, the effect of ozone on airway allergen responsiveness remains unclear, with some acute exposure studies showing an increase in responsiveness, whereas others found no effect. This may be caused by technical differences or could reflect individual genetic susceptibility [42].

A Japanese study found an association between atopic eczema severity and markers of reactive oxygen species-associated damage in the stratum corneum, adding weight to the hypothesis that environmentally generated reactive oxygen species may induce oxidative protein damage in the stratum corneum, leading to the disruption of barrier function and exacerbation of atopic eczema [43]. But whether ozone directly influences the skin or is associated with atopic eczema seems not to have been investigated.

39.3 Conclusion

Numerous studies on the influence of environmental pollution in allergic sensitization and the development of asthma have been published [44], but the role of environmental factors that are capable of modulating the phenotypic expression of atopic eczema is less clear. The few epidemiological and exposure studies suggest that formaldehyde, nitrogen dioxide, volatile organic compounds, and tobacco smoke at environmental concentrations exert negative effects on atopic eczema, while sulfur dioxide and particulate matters seem to have no influence.

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