Formaldehyde Exposure and Asthma in Children: A Systematic Review

Objective Despite multiple published studies regarding the association between formaldehyde exposure and childhood asthma, a consistent association has not been identified. Here we report the results of a systematic review of published literature in order to provide a more comprehensive picture of this relationship. Data sources After a comprehensive literature search, we identified seven peer-reviewed studies providing quantitative results regarding the association between formaldehyde exposure and asthma in children. Studies were heterogeneous with respect to the definition of asthma (e.g., self-report, physician diagnosis). Most of the studies were cross-sectional. Data extraction For each study, an odds ratio (OR) and 95% confidence interval (CI) for asthma were either abstracted from published results or calculated based on the data provided. Characteristics regarding the study design and population were also abstracted. Data synthesis We used fixed- and random-effects models to calculate pooled ORs and 95% CIs; measures of heterogeneity were also calculated. A fixed-effects model produced an OR of 1.03 (95% CI, 1.02–1.04), and random effects model produced an OR of 1.17 (95% CI, 1.01–1.36), both reflecting an increase of 10 μg/m3 of formaldehyde. Both the Q and I2 statistics indicated a moderate amount of heterogeneity. Conclusions Results indicate a significant positive association between formaldehyde exposure and childhood asthma. Given the largely cross-sectional nature of the studies underlying this meta-analysis, further well-designed prospective epidemiologic studies are needed.

Acute exposure to formaldehyde can cause eye, nose, throat, and skin irritation, whereas longterm exposure has been associated with certain cancers (e.g., sinonasal) as well as asthma (Daisey et al. 2003). Exposure to formaldehyde occurs in certain occupational settings (e.g., embalmers), but exposure via formaldehydeemitting products such as par ticle board, urea formaldehyde insulation, carpeting, and furniture is more common (Garrett et al. 1999). In the United States, the legal occupational limit for shortterm (i.e., < 15 min) formaldehyde exposure is 2 ppm, and the longterm limit (i.e., > 15 min) is 0.75 ppm [Occupational Safety and Health Administration (OSHA) 2005]. In contrast, the National Institute for Occupational Safety and Health suggests that exposure be limited to much lower levels: 0.016 ppm (long term) and 0.1 ppm (short term).
Much of the research regarding the health effects of formaldehyde has focused on cancer, whereas less attention has been paid to more common conditions such as asthma. In the United States, the prevalence of asthma is approximately 7% among adults and 9% among children (Akinbami et al. 2009;Moorman et al. 2007). Among adults, some studies have reported a positive asso ciation between formaldehyde and asthma (Wieslander et al. 1997), while others have not (Krzyzanowski et al. 1990). It has been suggested that certain groups, specifically chil dren, may be particularly sensitive to formal dehyde exposure; however, as with adults, the results have been inconsistent, with some studies reporting an association (Garrett et al. 1999) and others not (Symington et al. 1991). All of these studies have specific limi tations including small sample sizes (Delfino et al. 2003), the use of selfreported asthma (Smedje et al. 1997), and potential selection bias (Garrett et al. 1999). In addition, the extent of formaldehyde exposure varies widely across studies. For example, Mi et al. (2006) reported a range of 3-20 µg/m 3 , whereas the range reported by Rumchev et al. (2002) was ~ 0-224 µg/m 3 . However, the former study derived measurements from schools while the latter study obtained measurements from homes. Moreover, most studies are cross sectional and fail to provide information on exposure levels that reflect individual expo sure (in magnitude and/or duration).
Although there have been multiple reviews of the literature pertaining to form aldehyde and asthma in children, these have all been qualitative (Mendell 2007). The rela tionship between formaldehyde and respira tory symptoms has received attention recently because of concerns regarding air quality in mobile homes and travel trailers provided by the Federal Emergency Management Agency (FEMA) to displaced Gulf Coast residents in the aftermath of Hurricane Katrina. We conducted the current study, a systematic review of the literature regarding the potential association between formaldehyde exposure and asthma in children, to shed additional light on the issue.

Methods
This review was conducted using a modified version of the Metaanalysis of Observational Studies in Epidemiology (MOOSE) guide lines for the conduct of systematic reviews and metaanalysis of observational studies (Stroup et al. 2000). We identified studies through the PubMed/MEDLINE (National Library of Medicine 2009) and Google Scholar (2009) databases, employing a search strategy that combined text word (e.g., "form aldehyde and asthma and children") and medical subject headings to identify reports regarding formaldehyde exposure and asthma. The reference lists of the identified studies were also reviewed to identify other relevant studies. Studies were initially selected if they appeared to contain qualitative or quantitative estimates for the association between form aldehyde exposure and asthma in children. We were specifically interested in studies that compared children with and without asthma with respect to formaldehyde exposure. All of the studies initially selected were in English.
In total, we identified 18 articles that met the aforementioned criteria, and after a detailed review, determined that 10 arti cles contained information suitable for use in a systematic review. Three review articles were excluded (Burr 1999;Daisey et al. 2003;Mendell 2007). Three additional articles were excluded because they were not asthma specific, but rather focused on respi ratory symptoms (e.g., chest discomfort) or pulmonary function (Franklin et al. 2000;Symington et al. 1991;Wantke et al. 1996). Two studies were excluded because, although asthmaspecific, they did not contain a refer ence or control group (Delfino et al. 2003;Erdei et al. 2003). For the 10 articles included, volume 118 | number 3 | March 2010 • Environmental Health Perspectives we abstracted information regarding study design and setting, subject response/participa tion rates, definition of asthma (e.g., physician diagnosis), sample size, average (minimum and maximum) formaldehyde levels, average age of study subjects, and quantitative esti mates (or raw data) for the association between formaldehyde exposure and asthma as well as whether such estimates were adjusted and, if so, for what measures ( Table 1). Three of 10 studies did not contain actual formaldehyde measurements, and attempts to obtain this information from the study authors have been unsuccessful to date (Doi et al. 2003;Pati and Parida 2005;Tavernier et al. 2006).
Once the relevant results from each study were extracted, we determined that homog enizing the individual study results using a single unit of formaldehyde measurement would be necessary. Because most studies reported their results as odds ratios (ORs) per 10µg/m 3 unit increase in formaldehyde, this was chosen as the common metric. Thus, results for those studies using different units were transformed. For example, if a study reported an OR reflecting a 1µg/m 3 increase in formaldehyde, the natural logarithm of the OR was calculated and multiplied by 10; this value was then exponentiated to obtain an OR for a 10µg/m 3 unit increase in form aldehyde. This process was repeated for the 95% confidence interval (CI). Thus, for each study, an OR and 95% CI for the association between asthma and a 10µg/m 3 unit increase in formaldehyde exposure was obtained. One study (Zhao et al. 2008) provided two esti mates: one for indoor and another for out door exposure, both of which were used.
Pooled ORs and 95% CIs were obtained using inverse varianceweighted, fixedeffects, and randomeffects models. We tested hetero geneity using the Q test and quantified with the I 2 statistic. Whereas the Q test only determines whether statistically significant heterogeneity exists, the I 2 statistic calculates the proportion of the variability that can be attributed to het erogeneity across the studies. I 2 values of 25%, 50%, and 75% have been suggested as indica tors of low, moderate, and high heterogeneity, respectively. Fixedeffects models are consid ered appropriate for values of < 50%, whereas for values of ≥ 50%, randomeffects models are preferred. To evaluate whether the observed results were unduly influenced by any indi vidual study and to determine if there was any publication bias, an influence plot and a funnel plot, respectively, were used.

Results
Overall, 10 studies involving 6,387 partici pants including 635 with diagnosed or self reported asthma were selected for systematic review, of which seven studies were able to be used in the metaanalysis involving a total of 5,930 participants, 364 of whom had diag nosed asthma (Table 1). Most studies were crosssectional; half relied on selfreported information on asthma diagnoses, whereas the remainder used actual physician diagno ses. Studies of the former type generally que ried participants about whether they had ever been diagnosed with asthma, and thus those responding affirmatively are best charac terized as prevalent cases. With respect to those stud ies using physician diagnosis, based on the study designs as they were described, it was frequently clear that those with asthma would also be best characterized as prevalent cases. In only one study was it entirely clear that the cases were truly incident (i.e., newly diag nosed). Participation rates ranged from 46% to 99%; however, this information was not available for half of the studies.
The results for each individual study as well as the fixed and randomeffects pooled ORs and 95% CIs are shown in Figure 1. The forest plots for both fixed and randomeffects models can be seen in Figures 1 and 2, respec tively. The results of the fixedeffects model indicate a 3% increase (95% CI, 1.02-1.04, p < 0.0001) in asthma risk for each 10µg/m 3 unit increase in formaldehyde, whereas the randomeffects model indicates a 17% increase (95% CI, 1.01-1.22, p = 0.0158). The Q and I 2 statistics were 14.28 (p < 0.0001) and 51%, respectively, indicating the presence of moder ate betweenstudy heterogeneity.
The influence plot indicated that one study (Rumchev et al. 2002) may have had  an undue influence on the study results (data not shown). When this study was excluded, the resulting ORs from fixed and randomef fects models were 1.24 (95% CI, 1.09-1.42) and 1.24 (95% CI, 1.07-1.44), respectively ( Table 2). The Q and I 2 statistics were 6.76 and 11.2%, respectively. Table 2 presents the pooled results strat ified according to specific study character istics. Based on the fixedeffects model, the OR for selfreported asthma was 1.22 (95% CI, 1.02-1.46), whereas the OR for diag nosed asthma was 1.03 (95% CI, 1.02-1.04). For the randomeffects model, the ORs for selfreported and diagnosed asthma were 1.26 (95% CI, 0.97-1.64) and 1.12 (95% CI, 0.88-1.44), respectively. When strati fied according to study design, the ORs for crosssectional studies were 1.25 (95% CI, 1.08-1.44) for fixed effects and 1.26 (95% CI, 1.03-1.55) for random effects. There was only one cohort study and one case-control study; the results of these individual stud ies appear in Table 1. With respect to the exposure setting (home vs. school), assum ing fixed effects, the OR was 1.03 (95% CI, 1.02-1.04) for home exposure, whereas for school exposure the OR was 1.32 (95% CI, 1.05-1.66). For the randomeffects model, the OR for home exposure was 1.10 (95% CI, 0.95-1.27), and the OR for school expo sure was 1.33 (95% CI, 1.02-1.74). Only one study (Zhao et al. 2008) evaluated outdoor exposure, and its results appear in Table 1. Finally, the fixed and randomeffects results for the four studies (Mi et al. 2006;Smedje and Norbäck 2001;Smedje et al. 1997;Zhao et al. 2008) that provided participation rates (66%, 82%, 90%, and 99%) were stronger than the results for those for which participa tion rates were unknown.
The funnel plot did not show evidence of publication bias either with or without Rumchev et al. 2002 (data not shown).

Discussion
Asthma is a disorder characterized by epi sodic symptoms and a physiology associated with airway hyperresponsiveness, broncho constriction, and excessive mucus produc tion. 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 stud ies have suggested a link between inhalation exposure to formaldehyde and the develop ment 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 wellrecognized irritant affecting mul tiple tissues; it has been demonstrated to provoke transient decline in pulmonary func tion (Paustenbach et al. 1997). As a small molecule, formaldehyde may associate with larger protein molecules (e.g., albumin) to create newly antigenic moieties. Such expo sure 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 elabo ration of mediators traditionally associated with the asthmatic (early and latephase) response. Alternatively, formaldehyde inhala tion, through its nonspecific irritant effect, could provoke mucosal inflammation in air ways. If the resultant inflammatory response is T helper2 dominant, cytokine mediators typically associated with asthma [interleukin (IL)4, IL5, IL9, IL13] 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 Snitrosoglutathione, thus providing another putative mechanistic link between formalde hyde 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 10µg/m 3 increase) in context, when compared with indi viduals with no formaldehyde exposure, those with the highest levels of exposure reported in  the seven studies (i.e., 80 µg/m 3 ) would have 3.5times higher odds of asthma. The results reported herein are consistent with much of the previously published literature regarding the association between formaldehyde expo sure and childhood asthma. This should not be surprising in that many of these studies serve as the foundation of our metaanalysis. However, in addition to the seven studies included in the metaanalysis, 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 sta tistically 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 . . . signifi cantly increased the risk of having asthma." Additionally, Symington et al. (1991) com pared the prevalence of respiratory symptoms exhibited by children living within 1 mile of a formaldehydeemitting 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 associa tion between persistent wheezing and formalde hyde 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 formaldehydespecific IgE and concluded that formaldehyde is not a risk factor for childhood asthma (Doi et al. 2003). By its nature, a systematic review incor porates many individual studies, each of which has its own limitations, and not sur prisingly, our analysis revealed low to moder ate betweenstudy 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 randomeffects 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 studyspecific limi tations must also be mentioned. First, sev eral studies used selfreported 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 selfreported and physiciandiagnosed asthma such that this issue is likely of minimal con cern (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 stud ies 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 pro vide 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 stud ies included in our analysis because of their crosssectional designs. As a result, our pooled results are largely crosssectional 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 indica tion 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 suf fer from this potential limitation given its use of a cohort study design. The inability to quantify etiologically relevant formalde hyde 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 humid ity. Whereas formaldehyde levels were mea sured 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 magni tude of formaldehyde exposure, specifically that preceding asthma onset.

Conclusions
Subject to the limitations discussed above, the results of this systematic review suggest that there is a positive association between form aldehyde levels and childhood asthma. Taken in conjunction with a plausible biological mechanism, the results of this study provide important evidence regarding the potential causal link between formaldehyde and asthma in children. This is not to suggest that closure can be brought to this issue. Welldesigned prospective epidemiologic studies are needed to shed additional light on this issue.