Critical Reviews in Toxicology, 2011; 41(8): 672–721 © 2011 Informa Healthcare USA, Inc. ISSN 1040-8444 print/ISSN 1547-6898 online DOI: 10.3109/10408444.2011.573467 REVIEW ARTICLE Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards Robert Golden ToxLogic LLC, Potomac, Maryland, USA Abstract Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence–based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard. Keywords: Formaldehyde, indoor air, leukemia, mode of action, nasopharyngeal cancer, risk assessment, sensory irritation Contents Abstract I.Introduction ...................................................................................................................................................................... 673 II. Disposition of inhaled formaldehyde............................................................................................................................ 675 A. Formaldehyde as an endogenous compound .......................................................................................................... 675 B. Potential for distant site toxicity................................................................................................................................. 675 1. Formaldehyde kinetics............................................................................................................................................ 676 2. Stable isotope studies with inhaled 13CD2-formaldehyde .................................................................................... 677 III. Sensory irritation ........................................................................................................................................................... 678 A. Fundamental aspects of odor detection and sensory irritation .............................................................................. 678 B. Formaldehyde-induced tissue damage in the upper respiratory tract ................................................................... 679 C. Short- versus long-term exposure for formaldehyde-induced sensory irritation ................................................. 680 D. Exposure-response characterization of formaldehyde-induced sensory irritation.............................................. 680 1. Occupational and residential exposure studies .................................................................................................... 680 Address for Correspondence: Robert Golden, ToxLogic LLC, 9808 Clagett Farm Drive, Potomac, MD, 20854, USA. E-mail: rgolden124@aol. com (Received 25 August 2010; revised 14 March 2011; accepted 16 March 2011) 672