Exposure to isocyanate, the essential cross-linker for making polyurethane, is a leading cause of occupational asthma world-wide. Three major types of isocyanate are used commercially, methylene-diphenyl diisocyanate (MDI) and toluene diisocyanate (TDI), or aliphatic, hexamethylene diisocyanate (HDI). Despite being the newest of the three, MDI has overtaken the isocyanate market in production and consumption, for many reasons, including its unique applications and properties. Importantly, at room temperature, MDI has a much lower vapor pressure than HDI or TDI, and exists as a solid, rather than a (volatile) liquid. Thus, MDI is presumed to be "safer", because the potential for respiratory tract exposure is thought to be restricted to times when the chemical is heated or aerosolized (sprayed), i.e. during application. MDI is widely used in making flexible and rigid foams, coatings, elastomers and numerous other polyurethane-based products. Exposure to MDI is the best-recognized risk factor for the development of MDI asthma and exposure reduction is the primary strategy of disease prevention. Contemporary methods of monitoring MDI exposure are severely limited, and new approaches are needed to help protect millions of people exposed at work. In this new phase II application for the project "Biomonitoring Methylene Diphenyl Diisocyanate (MDI) exposure and body burden", we aim to develop innovative biomonitoring approaches to exposure surveillance for MDI. The investigative team consists of scientists and physicians from Yale University School of Medicine and the small business, L2 Diagnostics, who are applying their expertise with immunoassays, to develop blood tests that measure (2) different MDI exposure biomarkers. One biomarker is MDI-specific antibodies (IgG), produced by the immune system in response to exposure. The second biomarker is the chemical (MDI) itself conjugated to albumin, the major "protein adduct" in vivo. To date, we have successfully completed the (4) Specific Aims of the projects 1st phase, and published supportive findings (Wisnewski et al Analytical Biochem 2010;PMID: 20123080), including the generation of key reagents, and their extensive characterization. Completion of these milestones demonstrates our readiness to embark on the specific aims of the project's 2nd phase (listed below), which should lead to new commercial assays for biomonitoring MDI exposure, which will help prevent ongoing exposures and new cases of MDI asthma.
(Aim 1) Define the analytical performance characteristics of two new laboratory assays to measure (biomarkers of) MDI exposure.
(Aim 2) Determine the clinical sensitivity of new MDI exposure (laboratory-based) assays, among MDI exposed workers and different populations of control unexposed individuals.
(Aim 3) Using the new MDI exposure assays, establish the kinetics of MDI immune sensitization, and indications for use in evaluating exposed workers.

Public Health Relevance

This application will develop two new immunoassays to bio-monitor MDI exposure in the workplace thus, ensuring adequate safety in polyurethane manufacture, and protecting the health of the US workforce.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
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Special Emphasis Panel (ZRG1-CVRS-H (11))
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Shaughnessy, Daniel
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L2 Diagnostics, LLC
New Haven
United States
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Gui, Wei; Wisnewski, Adam V; Neamtiu, Iulia et al. (2014) Inception cohort study of workers exposed to toluene diisocyanate at a polyurethane foam factory: initial one-year follow-up. Am J Ind Med 57:1207-15
Wisnewski, Adam V; Liu, Jian (2013) Molecular determinants of humoral immune specificity for the occupational allergen, methylene diphenyl diisocyanate. Mol Immunol 54:233-7
Wisnewski, Adam V; Liu, Jian; Redlich, Carrie A (2013) Connecting glutathione with immune responses to occupational methylene diphenyl diisocyanate exposure. Chem Biol Interact 205:38-45
Wisnewski, Adam V; Mhike, Morgen; Hettick, Justin M et al. (2013) Hexamethylene diisocyanate (HDI) vapor reactivity with glutathione and subsequent transfer to human albumin. Toxicol In Vitro 27:662-71
Hettick, Justin M; Siegel, Paul D; Green, Brett J et al. (2012) Vapor conjugation of toluene diisocyanate to specific lysines of human albumin. Anal Biochem 421:706-11
Wisnewski, Adam V; Stowe, Meredith H; Nerlinger, Abby et al. (2012) Biomonitoring Hexamethylene diisocyanate (HDI) exposure based on serum levels of HDI-specific IgG. Ann Occup Hyg 56:901-10