Isocyanates, a group of reactive chemicals [with the functional group N = C = O (NCO)] used extensively in the production of numerous polyurethane foams, coatings, and a wide array of consumer products, are a major cause of occupational asthma worldwide. The polyurethane industry has expanded dramatically, along with the number of workers and consumers at risk for exposure. Inhalation has long been considered the primary route of isocyanate exposure, induction of sensitization, and asthma; research, practice, and regulation have focused almost exclusively on understanding and preventing inhalation exposures. Airborne isocyanate exposures have been reduced through improved controls and use of less-volatile isocyanates. Yet isocyanate asthma continues to occur, not uncommonly in work settings where measured isocyanate respiratory exposures are very low or nondetectable, but where there is opportunity for skin exposure. Karol et al. (1981) Nicholson et al. 2005 Tarlo and Liss 2005 Methods Definition of terms Bello et al. 2004 Sheaarer and Fleisher 2003 Abbas et al. 2000 Literature search We have been active in the field of isocyanate research and have collected > 800 published and unpublished articles and documents from 1951 to the present; these articles and documents are related to isocyanates and span many disciplines. In addition, we performed computerized searches of the literature on Medline [1966 to the present (National Library of Medicine, Bethesda, MD)], National Institute for Occupational Safety and Health (NIOSH), Occupational Safety and Health Administration (OSHA) and U.S. Environmental Protection Agency (EPA) databases and Google (google.com) using the key words “isocyanate,” “diisocyanate,” “asthma,” “sensitization,” “exposure,” “dermal,” “skin,” “occupational,” “methylene diphenyl diisocyanate,” and other synonymous terms. Additional articles were identified from the reference lists of the selected relevant articles. We reviewed primarily English-language articles, as well as selected articles in German, Danish, and French. Human and animal articles that addressed isocyanate skin exposure, sensitization, and health effects were retained for further analysis. We also included clinical, epidemiologic, and biomarker studies and case reports that mentioned skin as a potential route of exposure or had low isocyanate air levels based on exposure data or work processes. Results and Discussion Health effects of isocyanate exposure Bernstein 1996 Wisnewski et al. 2006 Baur et al. 1994 Musk et al. 1988 Wisnewski et al. 2006 2 Wisnewski et al. 1999 2000 Kanerva et al. 2001 Wisnewski et al. 2006 Bernstein et al. 1993 Lenaerts-Langanke 1992 Liss et al. 1988 Nemery and Lenaerts 1993 Zammit-Tabona et al. 1983 Workplace and environmental isocyanate exposures Figure 1 Table 1 Bello et al. 2004 NIOSH 1996 Carroll et al. 1976 Dietemann-Molard et al. 1991 Peters and Murphy 1971 Alomar 1986 Morgan and Haworth 2003 Vilaplana et al. 1987 Legris et al. 1995 Gagne et al. 2003 Krone et al. 2003 Darcey et al. 2002 De Zotti et al. 2000 Orloff et al. 1998 Allport et al. 2003 Boutin et al. 2006 Krone and Klingner 2005 Bello et al. 2004 3 3 Bello et al. 2004 Measuring isocyanate skin exposure Quantification of isocyanate skin exposure is important for research, prevention, and control. Assessment of skin exposure, in general, is much less developed than that of inhalation exposure. Skin exposure sampling methods typically are nonstandardized, have undergone limited validation, and can be technically challenging. Isocyanate skin sampling is further complicated by several factors, including the reactivity of NCO groups toward skin proteins, water, or other compounds, and the complexity of most isocyanate exposures. Biomarkers such as urinary metabolites, if available, could potentially be used to assess internal dose, but would not distinguish between skin and respiratory exposure. Liu et al. 2000 Bello et al., in press Fent et al. 2006 Bello et al. 2005 Wester et al. 1999 Pronk et al. 2006 Workplace isocyanate skin exposure NIOSH 1999 NIOSH 1998 1999 Bello et al., in press Bello et al., in press Alliance for the Polyurethanes Industry 2005 Boutin et al. 2006 Littorin et al. 2002 Liu et al. 2000 NIOSH 1998 Fent et al. (2006) Pronk et al. (2006) Effectiveness of personal protective equipment Liu et al. 2000 Pronk et al. 2006 Collin-Hansen et al. 2006 Skin absorption of isocyanates 14 Leibold et al. 1999 Vock and Lutz 1997 Bello et al. 2006 Wisnewski et al. 2000 Creely et al. 2006 Kääriä et al. 2001 Maitre et al. 1996 Creely et al. 2006 Maitre et al. (1996) Moody and Maibach 2006 Smith Pease et al. 2002 Boman and Maibach 2000 Skin sensitization Kimber and Dearman 2002 Goossens et al. 2002 Herrick 2002 Alomar 1986 Frick et al. 2003 Goossens et al. 2002 Wilkinson et al. 1991 Frick et al. 2004 Goossens et al. 2002 Herrick et al. 2003 Strid et al. 2005 Cummings et al. 2006 Lack et al. 2003 Saloga and Knop 2000 Smith Pease et al. 2002 Tinkle et al. 2003 Isocyanate skin exposure, sensitization, and asthma Animal models Table 2 Vanoirbeek et al. 2006 Zhang et al. 2004 Ban et al. 2006 Rattray et al. 1994 Ban et al. (2006) Herrick et al. 2002 Karol et al. 1981 Rattray et al. 1994 Herrick et al. 2002 Vanoirbeek et al. 2004 Table 2 Herrick et al. 2002 Karol et al. 1981 Vanoirbeek et al. 2004 Human studies Mapp et al. 2005 Wisnewski et al. 2006 Liss et al. 1988 Welinder et al. 1988 Wisnewski et al. 2006 Donnelly et al. 2004 Legris et al. 1995 Sommer et al. 2000 Valks et al. 2003 Petsonk et al. (2000) Leanerts-Langanke (1992) Bernstein et al. (1993) Redlich et al. 2001 Woskie et al. 2004 Stowe et al. 2006 Liss et al. 2006 Welinder et al. 1988 Wisnewski et al. 2004 Ye et al. 2006 Baur 2003 Tarlo et al. 1997 Bernstein et al. 1993 Leanerts-Langanke 1992 Tarlo et al. 1997 Basketter et al. 2006 Boukhman and Maibach 2001 Regulatory standards for isocyanate skin exposure American Conference of Governmental Industrial Hygienists (ACGIH) 2006 NIOSH (2005) Bakke et al. 2006 Baur 2003 Research needs In this review we highlight several important areas for further research regarding isocyanate skin exposure, ideally using multidisciplinary approaches involving animal models and clinical and epidemiologic investigations. Such approaches should lead to a better understanding of the mechanistic pathways that result in isocyanate asthma and the role of skin exposure in this process. A key research need not unique to issues regarding skin exposure is the development of a good marker of isocyanate sensitization or “pre-clinical” asthma that correlates well with the subsequent development of asthma. Such a marker would greatly enhance isocyanate research, including elucidation of exposure–response relationships, and facilitate diagnosis and prevention. There is a need to better assess isocyanate skin exposures in the workplace and other environments and to incorporate these exposure data into epidemiologic and clinical studies. The typically more sporadic nature of such exposures further complicates real-world exposure assessment and requires algorithms that employ a combination of daily activities (diaries), questionnaires, and task-based exposure data. Development of route-specific bio-markers, such as those specific for skin or lung, would greatly facilitate isocyanate exposure assessment. Skin exposure methodologies and biomarkers of exposure can be further developed and validated using integrated animal models. Numerous host and environmental determinants of isocyanate skin exposure have barely been investigated. Isocyanate skin absorption likely depends on various factors including molecular size and coexposures (e.g., polyols, solvents, and other additives), which could enhance absorption. The role of host factors, such as history of eczema and hand washing, warrant further investigation, as does the effectiveness of gloves, protective clothing, and other preventive strategies. Bello et al., in press Conclusion Munn (1965) The more one knows about these fascinating compounds [isocyanates] the more fascinated one becomes. So diverse are their uses, it is obvious that they are here to stay, and that their use will increase. So numerous have been the accounts of their effects, it is obvious not merely they are hazardous but that the nature and extent of their hazard has not always been fully appreciated.