686 R. Golden the goal to determine if formaldehyde exposures in their homes might have been responsible. Although the Rumchev et al. (2002) study concluded that children exposed to formaldehyde levels of >60 μg/m3 (49 ppb) were at increased risk of having asthma, it does not rule out the potential contributory role of other exposures, particularly those reported in a later follow-up study by the same authors. This later study (Rumchev et al., 2004) investigated associations between domestic exposure to volatile organic compounds (VOCs) and asthma. After controlling for confounding variables, the authors noted that “…children exposed to concentrations of total VOCs of >60 mg/m3 (median level of exposure) had a fourfold increased risk of having asthma while children exposed to single compounds such as benzene at levels of >20 mg/ m3 (median level of exposure) had an eightfold increased risk of asthma.” Since the studies by Rumchev et al. (2002, 2004) are among the only ones that explore the potential effects of multiple indoor air pollutants (i.e., formalde- hyde and numerous VOCs) on childhood asthma, it is not possible to conclude that formaldehyde acting alone, in the absence of other potential co-exposures, either causes or exacerbates asthma. 2.Other studies and evaluations In a study by Ezratty et al. (2007), 12 subjects with inter- mittent asthma and allergy to pollen were exposed, at rest, in a double-blind crossover study to either formalde- hyde (0.4 ppm) or purified air for 60 minutes. The order of exposure to formaldehyde and air-only was randomized, and exposures were separated by 2 weeks. There was also an allergen inhalation challenge after each exposure. Airway responsiveness to methacholine and lower air- way inflammation (i.e., as measured by inflammatory cells in sputum) were also assessed 8 hours after allergen challenge. Formaldehyde exposure did not affect aller- gen-induced increase in responsiveness to methacholine and there was no formaldehyde-associated effect on the airway inflammatory response. In this study, exposure to 0.4 ppm formaldehyde had no significant deleterious effect on airway allergen responsiveness of patients with intermittent asthma. A comprehensive report by the National Academy of Sciences Institute of Medicine (NAS, 2000) examined the evidence for associations between indoor biologic and chemical exposures and either the development or exacerbation of asthma. The report concluded that there is inadequate evidence to determine an association between formaldehyde exposure and asthma induction and only limited evidence of an association between formaldehyde and respiratory symptoms. More recently, a National Academy of Sciences report summarized the available controlled clinical studies evaluating the irritant effects of formaldehyde in asthmatic and non-asthmatic individuals, finding no differences in sensitivity between the two groups (NAS/NRC, 2007). The report concluded that “asthmatic individuals exposed to airborne formalde- hyde at exposure concentrations at or below 3 ppm do not appear to be at greater risk of suffering airway dysfunction than nonasthmatic individuals.” ATSDR (1999) concluded that investigations into the possibility of a relationship between formaldehyde and asthma have provided very limited evidence of an association. In addition, several clinical investigations of asthma cases suspected to be due to formaldehyde failed to confirm even a single case based on inhala- tion challenge tests (Frigas et al., 1984; Grammer et al., 1993; Pross et al., 1987; Krakowiak et al., 1998). There are also studies indicating that asthmatic individuals are not more sensitive to the irritant effects of formalde- hyde than healthy people (Sheppard et al., 1986; Sauder et al., 1987; Kulle et al., 1993; Green et al., 1987; Witek et al., 1987). A recent meta-analysis of seven studies that reported associations between formaldehyde exposure and asthma in children concluded that there was a significant posi- tive association (McGuin et al., 2010), with the majority of the weight for this association based on the studies by Garrett et al. (1999) and Rumchev et al. (2002). Although the studies in this meta-analysis were heterogeneous with respect to the definition of asthma (e.g., self-report vs. physician diagnosis), the conclusions are based on the assumption that formaldehyde was the sole cause of the reported results. Although acknowledging the largely cross-sectional nature of the studies underlying the meta- analysis, and the need for prospective studies, there was no discussion of (or citations to) the companion studies by Garrett et al. (1998) or Rumchev et al. (2004) on the same cohort of children in which asthma symptoms were also associated with other constituents (e.g., VOCs or fungal spores) of indoor air. Formaldehyde is primarily metabolized via an initial spontaneous reaction with glutathione (GSH) to form S-hydroxymethylglutathione, followed by a reaction catalyzed by formaldehyde dehydrogenase (ADH3), an enzyme in the family of alcohol dehydrogenases, which converts the intermediate to S-formylglutathione, which is further metabolized by S-formylglutathione hydro- lase to yield formate and reduced glutathione. Active research is presently underway to determine whether ADH3, also termed formaldehyde dehydrogenase (FDH) or S-nitrosoglutathione reductase (GNSO), which has been shown to play a key role in the enzymatic oxida- tion of formaldehyde and reduction of nitrosothiols that regulate bronchial tone, may also play a role in the risk of asthma (Staab et al., 2009; Thompson et al., 2009). However, it is presently unknown if there are polymor- phic forms of ADH3, which would suggest a hypotheti- cal possibility of differential sensitivity to formaldehyde effects on bronchial sensitivity. Considering the reported associations between form- aldehyde vapor exposure and childhood or adult asthma risk, there remain a number of unanswered questions ranging from whether formaldehyde is not a risk factor at all, the only risk factor, or may act in concert with other identified or as yet unidentified factors in the etiology of Critical Reviews in Toxicology