678 R. Golden DNA adducts in white blood cells or bone marrow, have substantial implications with respect to the likelihood of formaldehyde-induced leukemia as a consequence of either effects on circulating stem or hematopoietic pro- genitor cells or distant site toxicity. The above findings have now been extended to non-hu- man primates. A study by Moeller et al. (2010) determined the presence of endogenous and exogenous formaldehyde in DNA from bone marrow of cynomolgus macaques exposed to 1.9 and 6.1 ppm of 13CD2-formaldehyde for 6 hours a day for 2 consecutive days. In bone marrow, no exogenous adducts were detected, even though ~10-fold larger amounts of DNA were analyzed to intentionally bias the results toward detecting such adducts. However, endogenous N2-hydroxymethyl-dG adducts were present at 17.48 ± 2.61 and 12.43± 3.63 adducts/107 dG in bone marrow DNA from the 1.9 and 6.1ppm exposures, respec- tively. This study confirms the findings by Lu et al. (2010a) in a non-human primate and further demonstrates that inhaled formaldehyde is not delivered to tissue sites dis- tal to the nasal epithelium. Since additional tissues from numerous sites distant to the point of contact were col- lected at necropsy, these will be analyzed in a future paper to better characterize the distribution of exogenous and endogenous formaldehyde-DNA adducts in non-human primates following formaldehyde inhalation exposure. The substantial understanding of formaldehyde kinetics and toxicogenomics in the upper respiratory tract plays an important supporting role in subsequent discussions of sensory irritation as well as both nasopha- ryngeal cancer and leukemia. This body of data informs both local effects in nasal epithelial tissues as well as the likelihood of formaldehyde delivery to distant sites. III.Sensory irritation A.Fundamental aspects of odor detection and sensory irritation The most common effects from exposure to formalde- hyde vapor involve sensory irritation of the eyes, nose, and throat when sufficient concentrations are reached, with eye irritation generally accepted as the most sensi- tive endpoint. Although the ability of formaldehyde to cause or exacerbate asthma symptoms is also of con- cern, this is addressed separately as an important related issue of whether children might be more sensitive than adults to formaldehyde-related sensory irritation. With respect to formaldehyde-induced sensory irritation, this phenomenon involves a dose-response continuum in which low levels begin to trigger the sensory nerves, but the rate of removal (i.e., detoxification) of formaldehyde from tissues in the nose and upper airways is sufficient to limit accumulation and prevent tissue damage. As expo- sure concentrations increase, compensation and repair mechanisms will be progressively overwhelmed with an increasing likelihood of adverse effects. The continuum of effects due to increasing formaldehyde concentrations can be broken down into those associated first with odor detection, followed by sensory irritation and associated upper respiratory tract endpoints when progressing to higher concentrations and effects such as frank tissue damage and nasal tumors, which are discussed later in this review. Consequently, it is important to determine the concentration(s) of formaldehyde that can reliably be associated with causing the symptoms of sensory irritation as distinct from (i.e., unconfounded) odor detection. Although there is a large database in rodent studies characterizing the sensory irritation effects of formal- dehyde (e.g., Nielsen et al., 1999; Alarie and Anderson, 1979; Anderson et al., 1979; Kane and Alarie, 1977), these data are not reviewed or relied upon in this evaluation. Although such data provide valuable insights on formal- dehyde and potential interactive effects with other irri- tant chemicals, the documented respiratory differences between rats (obligatory nose breathers) and humans (oronasal breathing) render the findings from such stud- ies of limited relevance. Furthermore, the availability of numerous controlled human studies makes reliance on animal data unnecessary for evaluating this endpoint. Formaldehyde can be a strongly irritating gas at spe- cific concentrations and also has a distinct, pungent smell. However, odor perception and the threshold for sensory irritation are sometimes not clearly differenti- ated and generally exist on a concentration gradient, but may overlap, i.e., some individuals may detect the odor before perceiving eye irritation or vice versa. In the case of formaldehyde, however, the progression of responses is clear, with human studies showing that for most individuals, odor perception generally precedes sensory irritation. Importantly, sensory irritation and odor perception are different and distinct physiological phenomena. Odor is the sensation of smell carried by the olfactory nerve (first cranial nerve). Sensory irrita- tion involves stimulation of the trigeminal nerve (fifth cranial nerve), and near triggering concentrations is generally considered to be a physiological and not a toxic response in that no tissue damage or cellular injury is involved (Gaffney and Paustenbach, 2007; Paustenbach and Gaffney, 2006; Dalton, 2002, 2003). This is particu- larly the case for formaldehyde-induced sensory irrita- tion as discussed in this review and does not imply that formaldehyde-induced cytotoxicity does not occur at concentrations in excess of those necessary to trigger the symptoms of sensory irritation (i.e., ≥2 ppm). Sensory irritation encompasses a graded series of responses generally categorized as ranging from slight to moderate to severe. For formaldehyde, eye irritation is generally the most sensitive indicator of exposure and represents the threshold response for sensory irritation. At higher exposure levels, stimulation of the trigeminal nerves in the nasal passages and the upper respiratory tract rep- resents the next step of sensory irritation (i.e., nose and throat irritation) (Paustenbach et al., 1997). This would be followed by frank tissue damage (i.e., cytotoxicity) at sufficient concentrations. Critical Reviews in Toxicology