ObjectiveIsocyanates (di- and poly-), important chemicals used worldwide to produce polyurethane products, are a leading cause of occupational asthma. Respiratory exposures have been reduced through improved hygiene controls and the use of less-volatile isocyanates. Yet isocyanate asthma continues to occur, not uncommonly in settings with minimal inhalation exposure but opportunity for skin exposure. In this review we evaluate the potential role of skin exposure in the development of isocyanate asthma.Data sourcesWe reviewed the published animal and human literature on isocyanate skin-exposure methods, workplace skin exposure, skin absorption, and the role of skin exposure in isocyanate sensitization and asthma.Data extractionWe selected relevant articles from computerized searches on Medline, U.S. Environmental Protection Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, and Google databases using the keywords “isocyanate,” “asthma,” “skin,” “sensitization,” and other synonymous terms, and our own extensive collection of isocyanate publications.Data synthesisIsocyanate production and use continues to increase as the polyurethane industry expands. There is substantial opportunity for isocyanate skin exposure in many work settings, but such exposure is challenging to quantify and continues to be underappreciated. Isocyanate skin exposure can occur at work, even with the use of personal protective equipment, and may also occur with consumer use of certain isocyanate products. In animals, isocyanate skin exposure is an efficient route to induce sensitization, with subsequent inhalation challenge resulting in asthma-like responses. Several lines of evidence support a similar role for human isocyanate skin exposure, namely, that such exposure occurs and can contribute to the development of isocyanate asthma in certain settings, presumably by inducing systemic sensitization.ConclusionsIntegrated animal and human research is needed to better understand the role of skin exposure in human isocyanate asthma and to improve diagnosis and prevention. In spite of substantial research needs, sufficient evidence already exists to justify greater emphasis on the potential risks of isocyanate skin exposure and the importance of preventing such exposures at work and during consumer use of certain isocyanate products.

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The adduct data suggest that, among current workers, o-toluidine exposure substantially exceeds aniline exposure and that 4-ABP exposure, if it occurs at all, is not widespread. These data support the conclusion that occupational exposure to o-toluidine is the most likely causal agent of the bladder cancer excess observed among workers in the rubber chemicals department of the plant under study, although exposures to aniline and 4-ABP cannot be ruled out.

The total isocyanate group (microg NCO/m(3)) is recommended as the most feasible and practical metric (unit) by which to express polyisocyanate exposures for research, control, and regulatory purposes. The establishment of a comprehensive isocyanate OEL that simplifies the current agent-by-agent approach and expands coverage to polyisocyanates is also recommended.

Formation of mutagenic activity as a result of aqueous chlorination of a model humic acid substrate has been previously demonstrated. In the present study, solvent extracts of solutions of the chlorinated model substrate, which responded positively in the Ames test, were analyzed by gas chromatography/mass spectroscopy (GC/MS) in an attempt to identify the mutagenic components. Results of GC/MS analyses of methylene chloride, ether, and closed-loop-stripping extracts indicated that trihalomethanes and haloacetic acids, -acetonitriles, -propanones, -propenah, -propenenitriles, -propenes, -phenols, and -thiophenes were formed by the aqueous chlorination of humic acid at neutral pH. The concentrations of nine of the halogenated byproducts accounted for about onefourth of the total organic halogen (TOX) content of the aqueous chlorinated humic acid solution. The similarity of mutagenic compounds identified in this study with compounds previously identified in drinking water suggests that the reaction of chlorine with natural aquatic humic material is a likely source of mutagen formation in drinking water. Some data on the production of halogenated compounds from the chlorination of the model humic acid in the presence of bromide (Br-) are also included.

Objective Outline the knowledge gaps and research priorities identified by a broad-base of stakeholders involved in the planning and participation of an international conference and research agenda workshop on isocyanates and human health held in Potomac, Maryland in April 2013. Methods A multi-modal iterative approach was employed for data collection including pre-conference surveys, review of a 2001 consensus conference on isocyanates, oral and poster presentations, focused break-out sessions, panel discussions and post-conference research agenda workshop. Results Participants included representatives of consumer and worker health, health professionals, regulatory agencies, academic and industry scientists, labor, and trade associations. Conclusions Recommendations were summarized regarding knowledge gaps and research priorities in the following areas: worker and consumer exposures; toxicology, animal models, and biomarkers; human cancer risk; environmental exposure and monitoring; and respiratory epidemiology and disease, and occupational health surveillance.

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