Formaldehyde Exposure and Asthma in Children: A Systematic Review

Gerald McGwin Jr.; Jeffrey Lienert; John I. Kennedy Jr.


Environ Health Perspect. 2010;118(3) 

In This Article


Asthma is a disorder characterized by episodic symptoms and a physiology associated with airway hyperresponsiveness, bronchoconstriction, and excessive mucus production. Fundamentally, asthma is a disorder with inflammation of airways that creates a microenvironment capable of reacting to specific and/or nonspecific stimuli with a stereotypic pathogenic response. Although debate on the topic continues, multiple studies have suggested a link between inhalation exposure to formaldehyde and the development of airway hyperresponsiveness and asthma (Thompson et al. 2008). Several mechanisms have been identified that provide plausible connections between formaldehyde exposure and airways disease. Formaldehyde is a well-recognized irritant affecting multiple tissues; it has been demonstrated to provoke transient decline in pulmonary function (Paustenbach et al. 1997). As a small molecule, formaldehyde may associate with larger protein molecules (e.g., albumin) to create newly antigenic moieties. Such exposure presumably would provoke formation of specific IgE antibodies that could bind to mast cells and, upon subsequent exposure, lead to mast cell degranulation and the elaboration of mediators traditionally associated with the asthmatic (early- and late-phase) response. Alternatively, formaldehyde inhalation, through its nonspecific irritant effect, could provoke mucosal inflammation in airways. If the resultant inflammatory response is T helper-2 dominant, cytokine mediators typically associated with asthma [interleukin (IL)-4, IL-5, IL-9, IL-13] would subsequently be produced (Elias et al. 2003). Recently, formaldehyde has also been demonstrated to alter thiol biology, leading to the accelerated reduction of the endogenous bronchodilator S-nitrosoglutathione, thus providing another putative mechanistic link between formaldehyde exposure and airways disease (Thompson et al. 2008).

The results of this study, which pooled the results of seven published studies, suggest a positive relationship between formaldehyde exposure and childhood asthma. To place the observed results (OR of 1.17 per 10-µg/m3 increase) in context, when compared with individuals with no formaldehyde exposure, those with the highest levels of exposure reported in the seven studies (i.e., 80 µg/m3) would have 3.5-times higher odds of asthma. The results reported herein are consistent with much of the previously published literature regarding the association between formaldehyde exposure and childhood asthma. This should not be surprising in that many of these studies serve as the foundation of our meta-analysis. However, in addition to the seven studies included in the meta-analysis, two additional studies, each reporting a positive association, could not be included, yet they provide further support for the observed quantitative results (Pati and Parida 2005; Tavernier et al. 2006). Tavernier et al. (2006) reported elevated but not statistically significant ORs for specific levels of formaldehyde exposure; unfortunately, the authors did not provide the actual, quantitative values associated with those levels. Similarly, Pati and Parida (2005) simply reported that, "indoor exposure to formaldehyde… significantly increased the risk of having asthma." Additionally, Symington et al. (1991) compared the prevalence of respiratory symptoms exhibited by children living within 1 mile of a formaldehyde-emitting foundry with that of children living in other areas and reported no differences (Symington et al. 1991). Franklin et al. (2000) determined that individuals with a home formaldehyde concentration of at least 50 ppb had a significantly increased volume of exhaled nitric oxide, which serves as a marker of airway inflammation (Franklin et al. 2000). Venn et al. (2003) did not observe an association between persistent wheezing and formaldehyde exposure; however, among children with persistent wheezing, those reporting frequent nighttime symptoms had higher formaldehyde levels compared with those not experiencing nocturnal symptoms (Venn et al. 2003). Erdei et al. (2003) reported a significant increase in immune biomarkers in children exposed to high amounts of formaldehyde (Erdei et al. 2003). Doi et al. (2003) found only 2 of 122 asthmatic children have formaldehyde-specific IgE and concluded that formaldehyde is not a risk factor for childhood asthma (Doi et al. 2003).

By its nature, a systematic review incorporates many individual studies, each of which has its own limitations, and not surprisingly, our analysis revealed low to moderate between-study heterogeneity. Ultimately much of the heterogeneity appears to be attributed to a single study (Rumchev et al. 2002). The reason this study stands out can be partly ascribed to the precision of the OR for the association between formaldehyde and asthma; additionally, this study is unique in that the mean age of the participants was < 2 years. Infants and younger children may be even more vulnerable than older children to the effects of formaldehyde because of the small caliber of their airways. When the analysis was conducted without this study, the results of the fixed- and random-effects models were highly consistent, and there was a decrease in the measures of heterogeneity. Beyond the influence of the Rumchev et al. (2002) study, a number of study-specific limitations must also be mentioned. First, several studies used self-reported information on ever having been diagnosed with asthma (e.g., Krzyzanowski et al. 1990; Smedje and Norbäck 2001). However, research indicates that there is a high level of agreement between self-reported and physician-diagnosed asthma such that this issue is likely of minimal concern (Rönmark et al. 1999). Moreover, when stratified by asthma definition, the results were largely consistent. Another limitation faced by several studies is selection bias (Garrett et al. 1999; Rumchev et al. 2002; Tavernier et al. 2006). For example, Rumchev et al. (2002) hypothesized that because their study focused on indoor environmental risk factors for asthma, it was likely that the people who were most interested in this topic were more likely to participate in the study. The authors also suggested that selection bias may have arisen from low and potentially differential participation rates; however, they describe a number of strategies that were employed to minimize this problem. Although some studies provided adjusted estimates, others did not. Thus, our pooled results may be subject to residual confounding. The extent of this problem is a function of the individual study weights; the two studies that did not provide adjusted estimates generally had higher weights than those that did. Finally, the temporal relationship between etiologically relevant formaldehyde exposure and asthma cannot be established in most of the studies included in our analysis because of their cross-sectional designs. As a result, our pooled results are largely cross-sectional in nature, and the measured formaldehyde levels do not reflect personal exposures. This problem is compounded by the inclusion of those studies wherein "ever asthma" was used as an indication of a positive outcome, because such a definition will capture transient outcomes whose etiology may lie in acute exposures that occurred in the distant past and may not be captured by current exposure levels. The study by Smedje and Norbäck (2001) does not suffer from this potential limitation given its use of a cohort study design. The inability to quantify etiologically relevant formaldehyde levels is attributable to several factors. Formaldehyde levels were not measured at the same time of the year from one study to the next. This is important, because formaldehyde levels can vary with temperature and humidity. Whereas formaldehyde levels were measured at the subjects' home in some studies, others focused on the school setting. Taken together, the implication is that the observed formaldehyde levels and their association with asthma may not reflect the true the magnitude of formaldehyde exposure, specifically that preceding asthma onset.


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