674 R. Golden of increased risk of cancer, particularly nasopharyngeal and leukemia, including the concept that there is no safe level of exposure for these endpoints. Seemingly lost in the debate is the fact that formaldehyde is one of the most studied chemicals in use today (NAS, 2007). The biochemistry and kinetics of formaldehyde are well understood and extensively characterized, due largely to the fact that it is an endogenous compound found in all living organisms and plays a well-established role in nor- mal metabolic processes. With respect to the relationship between formaldehyde exposure and sensory irritation, there is an abundance of high-quality empirical data derived from numerous controlled human exposure stud- ies from which to draw weight of evidence–based conclu- sions (e.g., NAS, 2007, 2008; US EPA, 2005; SCOEL, 2008; WHO, 2010). These data are relied upon in this review as the basis for deriving an acceptable residential indoor air exposure limit for formaldehyde (i.e., 24 hours/day, 7 days/week). Also considered are sensory irritation in children and other potentially sensitive individuals and asthmatics, since these issues have also received consid- erable attention. Inhaled formaldehyde at sufficient concentrations has been established as a carcinogen for nasal tumors in rodents, with numerous studies documenting this phe- nomenon. In addition, the biochemistry and kinetics, including adducts and non-linear tissue accumulation, are well examined. With respect to formaldehyde-in- duced nasal tumors in rodents and their likely relevance to humans, there are abundant mode-of-action (MOA) data now available, including chronic toxicogenomic data as specifically called for in the NAS (2007a) report Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment that now bring an unprecedented ability to assess this endpoint for purposes of risk assessment. These data will be discussed in the context of whether it is necessary, in a regulatory context, to continue to treat formaldehyde with various precautionary approaches, which embrace considerable uncertainty and require that substantial empirical data be ignored. Other non-cancer endpoints have also been reported to be associated with exposure to formaldehyde (e.g., reproductive/developmental, neurological, and immune effects). Although some of the studies reporting such effects relied on unconventional routes of administration such as intraperitoneal or intravascular injection, others do not. However, the recent demonstration that inhaled formaldehyde does not move past the nasal epithelium to reach distant sites (Lu et al., 2010a, 2010b; Moeller et al., 2010; Swenberg et al., 2010) raises questions about how distant site effects might occur. Consequently, these end- points are not addressed in this review. However, because of the intense interest surrounding leukemia (unequivo- cally also a distant site disease), both the abundant epide- miology data, which are the principal basis for the claimed association, as well as the data pertaining to biological plausibility are discussed in considerable detail. The purpose of this paper is to provide the logic and rationale for deriving a residential indoor air concen- tration for formaldehyde using the most defensible sci- entific data related to exposures and/or effects reliably associated with this chemical, including both cancer and non-cancer effects. Although the number derived is not meant to imply that the present occupational exposure values are not protective of worker health, it should be noted that such values have been developed for 40 hours/ week exposures, whereas a residential values must be for 24/7 exposures and be protective for a lifetime for all individuals, including infants, children, and the elderly. However, as discussed in this review, formaldehyde is an exception to Haber’s Law, which states that the inci- dence and/or severity of a toxic effect depends on the both the exposure and duration, i.e., exposure concen- tration (c) rate times the duration time (t) of exposure (c × t). Consequently, for formaldehyde-induced sensory irritation, once symptoms are produced at a certain concentration, they are not exacerbated with additional duration of exposure. This has substantial implications for establishing exposure limits for this endpoint. With respect to the main non-cancer effect considered, i.e., sensory irritation (with the eyes as the most sensitive tar- get organ), the discussion and analysis that follow can be considered a de facto weight-of-evidence review of this topic because the primary data relied upon—controlled human exposure studies—have been reviewed and ana- lyzed multiple times by numerous regulatory and other authoritative bodies from around the world, with the con- clusions reached reflecting a consensus (e.g., NAS, 2007, 2008; US EPA, 2005; Nielson and Wolkoff, 2010; Wolkoff and Nielson, 2010; SCOEL, 2008; BfR, 2006; WHO, 2010). For the two cancer endpoints of potential concern (i.e., nasopharyngeal cancer [NPC] and leukemia), more controversial conclusions have recently been reached regarding these issues. Based primarily on several large epidemiology studies conducted by the National Cancer Institute (NCI) (e.g., Hauptmann et al., 2003, 2004, 2009; Beane Freeman et al., 2009), the International Agency for Research on Cancer (IARC, 2009), the National Toxicology Program (NTP, 2010), and the US Environmental Protection Agency (US EPA, 2010a) have interpreted these data as demonstrating causal associa- tions between formaldehyde exposure and NPC as well as a number of lymphohematopoietic cancers (mainly leukemia). However, several critical reanalyses of the epidemiology data have raised concerns as to whether the reported associations are causally related to formal- dehyde exposure (Marsh et al., 2004, 2005, 2007, 2010). Although there is abundant mode of action (MOA) data for formaldehyde-induced nasal tumors in rodents (e.g., McGregor et al., 2006; Conolly et al., 2003, 2004; Andersen et al., 2008, 2010), the same cannot be said for lymphohematopoieitc cancers. Instead, for this grouping of cancers, despite a number of unproven hypotheses that attempt to explain how formaldehyde might lead to the development of lymphohematopoietic cancers Critical Reviews in Toxicology