(e.g., Zhang et al, 2009; DeVoney et al., 2006a, 2006b) none are supported by any empirical data (Heck and Casanova, 2004; Golden et al., 2006; Pyatt et al., 2008; IARC, 2006). Recent toxicokinetic and toxicogenomic data demonstrating clear dose-dependent transitions for formaldehyde-induced toxicity further call into question whether either NPC or leukemia might be a consequence of exposure to formaldehyde. Although IARC, NTP, and US EPA have all concluded that exposure to formaldehyde is associated with increased risk of NPC and leukemia, as discussed in this review, the scientific evidence for these conclusions is equivocal at best. Particularly in conjunction with some of the most recent data that call into question whether formaldehyde exposure is capable of causing either NPC or leukemia, it raises the issue if these collective regula- tory or authoritative conclusions are driven solely by science or if policy considerations and a precautionary approach might play a contributory role. The abundant data suggesting that such approaches are not neces- sary for evaluation formaldehyde-induced toxicity and potential effects in humans are described and discussed. A related issue concerns the role that uncertainty might play in the regulatory decision-making process. Although uncertainty is clearly justified in reaching decisions con- cerning chemicals for which there are little data, this is hardly the situation with formaldehyde, a naturally occurring endogenous compound, which is one of the most widely studied chemicals in existence. In fact, for potential formaldehyde-induced adverse effects, as dis- cussed in this review, because there appears to be an unprecedented dichotomy between certainty and uncer- tainty, the resolution of this dilemma hinges on how the abundant data are interpreted. Ultimately, however, after contemplating the complex and interrelated issues addressed in this review, readers must judge for them- selves whether the totality of the data are supportive of demonstrating causal associations between formalde- hyde and either NPC or leukemia. II.Disposition of inhaled formaldehdye A.Formaldehyde as an endogenous compound Formaldehyde is naturally produced as a metabolic by- product by all living organisms and serves as a source of methyl units, which are transferred via tetrahydrofolate into the one-carbon pool for incorporation into various macromolecules (IARC, 2006; Dhareshwar and Stella, 2007). Due to its natural presence, there are predictable and fairly constant levels (i.e., 1–2 μM or ≈2.5 ppm) in the blood. Because of its high enzymatic activity, the ability of formaldehyde dehydrogenase (FDH; also designated aldehyde dehydrogenase, ADH3) to metabolize gaseous formaldehyde in the upper respiratory tract is so efficient that when humans, monkeys, or rats are exposed by inha- lation to formaldehyde, no change in normal endogenous blood levels can be detected at the end of exposure. Heck et al. (1985) determined the effect of inhalation exposure © 2011 Informa Healthcare USA, Inc. Indoor air exposure limit for formaldehyde 675 to formaldehyde on blood concentrations in rats and humans. Following exposure of F344 rats to 14.4 ppm for 2 hours, formaldehyde concentrations of 2.24 ± 0.07 and 2.25 ± 0.07 μg/g were measured in the blood in exposed rats and controls, respectively. Formaldehyde concentra- tions in human venous blood from four males and two females were determined by analyzing blood samples collected before and after exposure to 1.9 ppm form- aldehyde for 40 minutes. Average formaldehyde blood concentrations before and after exposure were 2.61 and 2.77 μg/g blood, respectively. In neither rats nor humans was there a statistically significant effect of formalde- hyde exposure on average concentrations in the blood. In a similar study, Casanova et al. (1988) exposed three rhesus monkeys to formaldehyde at 6 ppm, 6 hours/day, 5 days/week for 4 weeks. The formaldehyde concentra- tion in the blood immediately after the final exposure in the three exposed and three unexposed animals were 1.84 and 2.42 μg/g blood, respectively. The inability of inhaled formaldehyde to alter normal endogenous blood concentrations suggests that this metabolic feature most likely protects internal organs from effects of low levels of formaldehyde, such as the concentrations typically found in an indoor environment, and also suggests that no adverse internal effects from formaldehyde would be expected from such levels (ATSDR, 1999). Because of this extensive metabolic capability as well as the recent con- firmatory discovery that no inhaled formaldehyde gets past the nasal epithelium into the systemic circulation, formaldehyde should be more properly characterized as a chemical with adverse effects (i.e., sensory irritation) occurring only at the point of contact after a concentra- tion is achieved in excess of endogenous levels and that exceeds the body’s ability to maintain homeostasis. This “threshold” level is reached and primarily at the point of contact, i.e., eyes, nose, or throat. Additionally, in aqueous systems formaldehyde exists primarily (>99.9%) in its hydrated form of methanediol, with only a small amount (<0.1%) as free formaldehyde. Because free formaldehyde can diffuse from tissues in the upper respiratory tract into exhaled air, small, but mea- surable, amounts can be detected in the breath. These levels are the result of the naturally occurring formalde- hyde present in all tissues as a part of normal metabolic processes. Although there are analytical challenges in accurately determining formaldehyde concentrations in human breath (Moser et al., 2005; Kushch et al., 2008), the levels detected using a chemical-specific methodol- ogy fall into the low-ppb (parts-per-billion) range (i.e., <0.5–1.7 ppb) (Riess et al., 2010). These data clearly chal- lenge the current regulatory presumption that there is no safe level of exposure to formaldehyde as well as the risk assessment methodology based on the default no- threshold assumption. B.Potential for distant site toxicity An obvious requirement for any formaldehyde-induced inhalation effects other than those that result from