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Original Articles

Isocyanates and Human Health

Multistakeholder Information Needs and Research Priorities

Lockey, James E. MD, MS; Redlich, Carrie A. MD, MPH; Streicher, Robert PhD; Pfahles-Hutchens, Andrea MS; Hakkinen, Pertti (Bert) J. PhD; Ellison, Gary L. MPH; Harber, Philip MD, MPH; Utell, Mark MD; Holland, John MD, MPH, MS; Comai, Andrew MS; White, Marc PhD

Author Information
Journal of Occupational and Environmental Medicine: January 2015 - Volume 57 - Issue 1 - p 44-51
doi: 10.1097/JOM.0000000000000278
  • Free


On April 3 to 4, 2013, an international multidisciplinary conference entitled “Isocyanates and Health: Past, Present and Future” was held in Potomac, Maryland. After the conference, representatives of consumer and worker health research and regulatory agencies, academic and industry scientists, labor, and trade associations met to discuss opportunities to advance communication, collaboration, and research funding to better address information gaps and research priorities among stakeholders. The purposes of the conference and follow-up meeting were to (1) identify most current knowledge about isocyanates and discuss the important issues concerning potential exposures and worker and consumer health effects of isocyanates, including exposure monitoring, environmental controls, surveillance, and clinical management, and (2) identify and discuss research gaps to inform future research priorities and information dissemination. This summary reports on the knowledge gaps and research priorities identified across stakeholders, and discusses the potential for greater collaboration across government, academic, industry, and worker organizations to improve worker and consumer health.


Diisocyanates and polyisocyanates, commonly referred to as isocyanates, are a family of highly reactive chemicals and one of the most frequently reported causes of occupational asthma. The most common isocyanates include, but are not limited to, toluene diisocyanate, methylenebis (phenyl isocyanate), and hexamethylene diisocyanate, and related isomers, polymers, dimers, and trimers. Isocyanates react with the hydroxyl functional groups (ie, –OH) of di- and polyols to form urethane linkages in the production of polyurethane polymers, typically as two-part systems. One part contains the isocyanate, sometimes mixed with solvents, and the other polyol part contains additional chemicals unique to that polyurethane product or application, such as catalysts, blowing agents, solvents, surfactants, and fire retardants. Isocyanates are used in an extensive range of products with widespread industrial, commercial, and retail or consumer applications.1 Examples include flexible and rigid foams, sealants, elastomers, adhesives, and coatings, including paints and varnishes. Their use is extensive and includes utilization within automotive, construction, clothing and shoe, home furnishing, medical, and other industries.2 Spray-on polyurethane foams and coatings containing isocyanates are applied on-site in end-user settings such as insulation of residential or commercial buildings and as coatings to protect cement, wood, fiberglass, and metal.

Manufacture and application of isocyanate-containing products including polyurethane materials can result in inhalation and dermal exposures to isocyanate compounds. During production, processing, and curing, a variety of events and activities including accidental spills or leaks, application methods (spraying, painting, or rolling) for isocyanate-containing foams or coatings, cleaning and maintenance of equipment, and off-gassing from newly applied or produced materials, create situations where exposure to isocyanates may occur.3–6 Consumers may also apply products containing isocyanates, or may be incidentally exposed to commercial- or professional-grade products used by contractors or maintenance staff in their home or workplace.7,8 Isocyanate compounds can also be generated from thermal decomposition of polyurethane materials, from activities such as heating or grinding polyurethane materials, welding of metal with polyurethane coating, cutting polyurethane foams using hot-wire cutting methods, or drilling, soldering, sawing, or sanding of polyurethane materials.9

Isocyanates are potent sensitizers and remain one of the most commonly reported causes of occupational asthma worldwide.10–12 The reported prevalence of isocyanate asthma in exposed workers is highly variable, ranging from less than 1% to more than 30% in end-user settings such as spray applications or foam production.13–17

Other less commonly reported health effects include rhinitis, contact dermatitis, and hypersensitivity pneumonitis.18,19 Research, exposure monitoring, and preventive efforts to date have focused largely on inhalation exposure to diisocyanates, given that isocyanate asthma is the primary health concern. Nevertheless, it is likely that skin exposure is also a highly effective route of sensitization and increases the risk of isocyanate asthma.20,21 Diisocyanates at relatively high concentrations are also irritants, to the mucous membranes but should be distinguished from monoisocyanates, such as methyl isocyanate, which is not a cross-linking agent, but is an extremely volatile irritant compound used in the production of pesticides. The International Agency for Research on Cancer has classified 2,4-toluene diisocyanate, but none of the other diisocyanates, as a possible human carcinogen.22 Prueitt et al (2013) suggests that current data are inadequate to determine the carcinogenetic potential of isocyanates in humans.23

Of particular concern is the utilization of isocyanate-containing materials in end-user settings by small industry and contractors, or consumers under some circumstances. Specific concerns range from lack of knowledge of potential health hazards, inadequate exposure monitoring and appropriate monitoring methodology, inadequate engineering and industrial hygiene controls, variable use of personal protective gear including proper respiratory and skin protection, and lack of periodic medical monitoring of exposed workers.22,24–26

Given the widespread use of isocyanates and their known health effects, a comprehensive strategy would be useful to identify data gaps and critically appraise current and future research and data dissemination needs concerning isocyanates and health. In addition, a more coordinated approach should be established to fund collaborative research directed at better understanding isocyanate exposures and health risks related to the manufacture, processing, and use of polyurethane products.


The conference planning committee included representatives from the United States Centers for Disease Control and Prevention, specifically, the Agency for Toxic Substances and Disease Registry, and the National Institute for Occupational Safety and Health; the US National Institutes of Health, including the National Cancer Institute, National Institute of Environmental Health Sciences, and the National Library of Medicine; the US Environmental Protection Agency; Health Canada; academic scientists; labor; and industry.

The following professional organizations and agencies participated as sponsors for the conference: the American Academy of Clinical Toxicologists, the American Conference of Governmental Industrial Hygienists, the American College of Occupational and Environmental Medicine, American Industrial Hygiene Association, American Thoracic Society, Canadian Thoracic Society, the Canadian Institute for the Relief of Pain and Disability, European Society for Environmental and Occupational Medicine, the Occupational Medicine Specialists of Canada, the Occupational and Environmental Medical Association of Canada, Society for Risk Analysis, and the Society of Toxicology. Organization sponsors participated in the call for papers and posters.

The scientific committee represented a broad range of stakeholders who play different roles related to isocyanates and health including academic, government, industry, professional organizations, and consumer and worker health representatives (see for the list of scientific committee members).

The conference was organized on the following themes:

  • Worker and consumer exposure issues
  • Toxicology, animal models, and biomarkers
  • Human cancer risk
  • Environmental exposure and monitoring
  • Respiratory epidemiology and disease
  • Occupational health surveillance and management
  • Health communication and research to practice

Identification of Research Priorities

The planning and scientific committee for the conference and workshop used an iterative systematic approach for identification of research priorities.

Round 1: A preliminary list of knowledge gaps and research priorities were identified by the section chairs after reviewing (1) the 2001 international consensus report on isocyanates,27 and (2) a summary of knowledge gaps and research priorities arising from a multistakeholder meeting held in Montreal in September 2010 with US and Canadian regulators, academic and clinical stakeholders, and industry representatives. This preliminary list was then provided to section subcommittee members for their input.

Round 2: This preliminary list was translated into a series of targeted surveys relevant to the membership of each professional and agency sponsors. For instance, organizations whose focus was on toxicology were asked to review, update, revise, and comment on knowledge gaps and research priorities relevant to isocyanates and toxicology. Concurrently, delegates who had registered for the conference by October 2012 were asked to provide input on those areas of their content expertise across all conference themes.

Round 3: Abstract presenters and invited speakers were asked to note, if applicable, knowledge gaps and research priorities within their abstracts and posters.

Throughout the conference, delegates were provided with opportunities to review the preliminary knowledge gaps and research priorities. This included a report of the findings arising from concurrent sessions during the conference. On the final day, a plenary panel session was conducted to discuss the revised knowledge gaps and research priorities and opportunities to advance isocyanate research followed by an open audience discussion.

Round 4: After the conference the revised summary of knowledge gaps and research priorities was circulated to the full scientific committee for their review and input. Section chairs were responsible for taking this feedback under advisement and to update and revise the list of knowledge gaps and research priorities.

Round 5: The updated draft of the summary of knowledge gaps and research priorities was then circulated to all delegates for their final review and input. Section chairs were responsible for taking this feedback under advisement and to update and revise the list of knowledge gaps and research priorities. The knowledge gaps and research priorities within this publication reflect this iterative process.


The “worker and consumer exposures” section addressed the use of isocyanates in many diverse industries, and the use of polyurethane products in both occupational and consumer settings. A broad range of topics were discussed, including the use and effectiveness of worker protective equipment and controls, difficulties in sampling and measuring isocyanate exposures, evaluating consumer products for potential isocyanate and other chemical exposures, and the effectiveness of disseminating information about isocyanate hazards and protective measures to workers and consumers.

Several areas of knowledge gaps and research priorities were identified for worker and consumer exposures, including exposure assessment, dermal and inhalation exposures, exposure controls, testing of complex mixtures in polyurethane products, exposure characterization across an array of applications to identify appropriate controls, and hazard and risk communication. The priority theme across these areas was identifying and reducing exposures. A hierarchy of controls for workers and consumers for specific industries, settings, and applications should be further developed and evaluated. These practices include source reduction and elimination, ventilation and other engineering controls, education, signs, labels and warnings, and personal protective equipment. Potential consumer exposures should also be considered in developing these practices. Evaluating effectiveness of labeling and development of alternative forms of hazard communication are important to improve knowledge and compliance. Product testing is important in identifying and understanding potential consumer exposures to isocyanates and other chemicals related to polyurethane products. It is necessary to consider the diverse uses, application methods, formulations, environmental conditions, and curing rates of these products to adequately characterize and therefore reduce potential consumer exposures.

Table 1 describes knowledge gaps and research priorities related to worker and consumer exposures, many of which cut across other conference themes. Recognition and prevention or reduction of exposure is foremost in preventing adverse health outcomes among workers and consumers.

Worker and Consumer Exposures: Knowledge Gaps and Research Priorities


This multithemed section presented and discussed toxicity testing of isocyanates, animal models of allergic and asthmatic responses, and biomarkers of human exposure. Presenters outlined the immune and nonimmune hypotheses driving past and current research efforts at understanding isocyanate toxicity and asthma pathogenesis, and highlighted seminal studies from the literature. The strengths, limitations, and data gaps of current animal models, toxicity tests and biomarkers for use toward exposure, and risk assessment as well as disease prevention were summarized.

Important contemporary issues were discussed in the context of historical studies that inform current occupational exposure limits. The contributions of animal models to understanding isocyanate sensitization and asthma and the importance of the route of exposure were discussed. Animal models have replicated many of the features of human isocyanate asthma, including sensitization and Th2-like airway inflammation. These models have also demonstrated that isocyanate dermal exposure is highly effective at inducing systemic sensitization, which can contribute to the subsequent development of asthma after inhalational exposure. Limitations of current animal models were also described, due in part to inherent species differences in airway structure and anatomy and the challenges in delivering isocyanate to the airways.

Contemporary approaches to detect potential exposure biomarkers were discussed. Isocyanate metabolites and isocyanate–protein conjugates have been measured in human biological samples using liquid chromatography and mass spectrometry.28,29 Immunologic responses such as isocyanate-specific IgG and IgE have also been used as biomarkers of exposure and effect, respectively, in workers.30 Nevertheless, biomarker approaches have been difficult to validate, in part related to challenges in measuring workplace exposures. Uncertainty regarding the reactivity and metabolism of isocyanates in humans also continues to limit the development of exposure biomarkers.

Several knowledge gaps and research priorities were noted, which cut across other conference themes (Table 2), and may be addressed through future in vitro and in vivo studies using cell lines, animal models, and/or clinical samples. Priority questions include the following: (1) Can animal models or other approaches (in vitro, in silico) be used to compare the effects of different types, doses, and routes of isocyanate exposure to better predict human responses to isocyanates? (2) Can such models be used to develop better biomarkers of exposure and early isocyanate asthma? (3) What self-molecules are the major reaction targets for isocyanates after skin and airborne exposures in vivo? (4) How are isocyanates metabolized and which isocyanate metabolites and biomolecules are the best biomarkers of isocyanate exposure? (5) What are the most accurate and sensitive methods for quantification of proposed biomarkers in human serum or urine samples?

Toxicology, Animal Models, and Biomarkers: Knowledge Gaps and Research Priorities


The “human cancer risk” section provided a discussion of the current state-of-the-science regarding isocyanates and cancer, and included a review of the relevant published literature. There are few data available regarding the human carcinogenicity of most isocyanates. The International Agency for Research on Cancer has classified toluene diisocyanate as possibly carcinogenic to humans on the basis of evidence of tumors observed after gavage administration in experimental animal studies. Nevertheless, no strong or consistent patterns have been observed in limited epidemiology studies, and a recent review suggested that toluene diisocyanate is not likely to be carcinogenic.23 Because isocyanates cause allergic and other immune-mediated respiratory disorders, there could be a role of the immune system and inflammation pathways in cancer risk.

Major areas covered during the human cancer risk section included populations at risk and data that could be used to assess carcinogenicity, dose-response and duration of exposure, and mechanisms associated with cancer development. The limited epidemiology studies to date have been inadequate to determine the risk of cancer among individuals exposed to isocyanates in the workplace. A number of methodological issues exist within these studies, including limited exposure data, lack of dose-response, young cohorts with small numbers, short follow-up time, and limited information on smoking status. In addition, workers are exposed to complex mixtures of chemicals, including blowing agents, fire retardants, and organic solvents, which could act as confounders.

Many of the knowledge gaps and research priorities identified in the human cancer risk section overlap with those identified in other conference themes. For example, valid measurements of isocyanate exposure are essential to epidemiology research and critical in determining the potential cancer risk, if any, from isocyanate exposure. Also essential is access to populations of isocyanate-exposed workers, an important research priority that cuts across several research themes. The combination of animal models with human studies has the potential to accelerate the science concerning isocyanates and cancer risk. The latency period from the onset of exposure to the appearance of cancer could be years, and the development pathway could be an opportunity to understand the potential sequence of events that could lead to increased cancer risk among exposed workers. Research to understand the relation of isocyanate exposure to markers of early biological effect, such as inflammatory markers, potential DNA damage, or oxidative stress, should be explored longitudinally. Table 3 identifies the major areas of knowledge gaps and research priorities for human cancer risk.

Human Cancer Risk: Knowledge Gaps and Research Priorities


The “environmental exposure and monitoring” section addressed the detection and measurement of isocyanate compounds for the purposes of exposure assessment. This included methodology to address both inhalation exposure and dermal exposure. Isocyanate species of interest for exposure monitoring include not only those present in commercial isocyanate products, but also those species generated during the use of these products and during thermal degradation of polyurethane materials. The goals of this section were to understand how to improve isocyanate measurement methodologies (ie, to make them easier, more reliable, and more encompassing).

The current state-of-the-art in air and dermal sampling and analytical methodology is summarized below. Accurate assessment of isocyanate exposures is particularly challenging and has hampered clinical and epidemiology research. Better methods to detect isocyanate exposures are critical to understanding isocyanate health effects and to preventing exposure and disease.

Air Sampling

Air sampling and analytical methods for isocyanates require reaction with derivatizing reagents during sampling to stabilize reacting isocyanates, and to increase the detectability and quantifiability of isocyanates. Most methods sample air using either a fiber filter impregnated with a derivatizing reagent or an impinger containing a derivatizing reagent dissolved in an organic solvent, or both. Isocyanate species in particles or droplets are more challenging to collect than vapors. Furthermore, if the curing rate of the isocyanate system is rapid, a reagent-coated filter is not efficient in derivatizing isocyanate particles or droplets, resulting in underestimation of the isocyanate concentration. Impingers provide much better measurements in rapidly curing systems, but are often difficult to use for personal sampling. A solvent-free denuder/filter sampling system is being evaluated as an alternative for isocyanate aerosols.

Dermal Sampling

There are currently no standardized or validated methods for sampling of isocyanate exposure on skin. Several methods, such as skin wipes, tape stripping, and interception barriers, have been used in research settings. Current analytical methods for dermal sampling are generally modifications of methods for measuring isocyanates in air.


Analysis of occupational air samples for isocyanates is usually accomplished using liquid chromatography. Many analytical methods attempt to measure isocyanate-containing oligomers in addition to the diisocyanate monomers, even though pure analytical standards for these species are not generally available. The diisocyanate monomer may be only a minor component in the system, making it essential to target higher-molecular-weight species for exposure assessment. In rapidly curing systems, newly formed isocyanate intermediates may be important contributors to exposure. Nevertheless, current chromatographic methods are not designed to measure such species. A newly developed method that converts all aromatic isocyanate species in a sample to a single analyte for simplified quantification of the total isocyanate group is under evaluation by the National Institute for Occupational Safety and Health and partners in academia and industry.

Direct Reading

Direct-reading monitors using paper-tape technology are useful in the detection of isocyanate vapors. Nevertheless, they may not give accurate readings at low or high humidity, generally are not suitable for the measurement of isocyanate aerosols, and lack the sensitivity of chromatographic methods.

The knowledge gaps and research priorities for the environmental exposure and monitoring section fall into seven major areas: (1) air sampling methods, (2) dermal sampling methods, (3) analytical methods, (4) direct-reading monitors, (5) coexposures, (6) thermal degradation products, and (7) emissions from polyurethane products. Air sampling methods need to become easier to use, minimizing the need for impingers, enabling full-shift sampling, and capable of distinguishing vapor from particle exposure. Research on dermal sampling methodologies should include improved interception techniques rather than removal techniques that greatly underestimate exposure for rapidly curing isocyanates. Removal techniques should target relevant bound species rather than free isocyanates. Route-specific biomarkers of exposure (eg, specific protein adducts) should be sought to distinguish dermal from inhalation exposure. Total isocyanate analytical methods should be evaluated and improved, and liquid chromatography–tandem mass spectrometry should be much more widely used in isocyanate analysis for enhanced speciation and quantification. Depending on the type, direct-reading monitors need to become more sensitive, more robust, and more portable. Isocyanates and other compounds generated from thermal degradation of polyurethane represent an unrecognized and often unanticipated hazard. Recognition and characterization of such environments is a key priority. Methods to assess emissions from polyurethane products need to be improved and used to provide guidance on building reoccupancy times after installation of polyurethane product in building, such as spray foam insulation. Several of the environmental exposure and monitoring knowledge gaps and research priorities overlap with those expressed in the other themes. The most significant knowledge gaps and research priorities for the environmental exposure and monitoring section are listed in Table 4.

Environmental Exposure and Monitoring: Knowledge Gaps and Research Priorities


The closely related “respiratory epidemiology and disease” and “occupational health surveillance” sections addressed the human health effects of isocyanates including the clinical spectrum of isocyanate-induced disease, host and exposure risk factors, diagnosis and outcomes, medical surveillance of isocyanate-exposed workers, and prevention. A review of the clinical, epidemiologic, and surveillance literature identified a number of key knowledge gaps and research needs. Isocyanates are potent sensitizers, but there is no good test or marker for sensitization, as there is for typical high-molecular-weight allergens. Although asthma is the most commonly recognized health effect of exposure, isocyanates also cause rhinitis and conjunctivitis, hypersensitivity pneumonitis, contact dermatitis, and chronic airflow obstruction, with variable and overlapping clinical syndromes. Isocyanate asthma can be difficult to recognize and diagnose, and nonasthma health effects are rarely evaluated. The persistence of asthma after removal from exposure and the resultant poor socioeconomic outcomes for impaired workers have been well documented. Importantly, despite the expanding use of isocyanate-containing products in numerous industries and end-user settings, epidemiology and surveillance studies of isocyanate-exposed workers under current work conditions have been very limited. Furthermore, most isocyanate epidemiology studies, especially studies in end-user settings, have been cross-sectional, which are particularly prone to the healthy worker effect. Thus, critical unknowns such as the incidence and prevalence of isocyanate asthma under current work conditions, and which exposure and host factors modify the risk of developing isocyanate asthma remain poorly defined and are essential research priorities. Lack of such key information also hinders preventive efforts.

The occupational health surveillance section addressed available methods for screening groups of workers to detect those with possible occupational asthma, and diagnostic approaches to confirm (or rule out) occupational asthma. Current approaches are constrained by a number of factors including challenges in accurately assessing multiple isocyanate exposures, lack of surveillance of most exposed workers, lack of a readily available and accurate test for sensitization or isocyanate-induced asthma, limited availability and other concerns with specific inhalation challenge testing, adverse socioeconomic consequences of removing workers with isocyanate asthma from their current job, and lack of mandatory reporting of cases. There is also limited data on the efficacy of exposure reduction methods (eg, ventilation, respirators, and skin protection) in the workplace. More practical short-term goals include optimizing initial screening questionnaires and lung function testing, improving consistency of detailed clinical and exposure assessment of suspect cases, and developing standardized approaches for evaluating the efficacy of screening programs.

The respiratory epidemiology and disease and occupational health surveillance knowledge gaps and research priorities, outlined in Table 5, overlap substantially with other theme areas. An essential priority is access to cohorts of isocyanate-exposed workers in different work settings, including longitudinal follow-up of workers (preferably inception cohorts given the healthy worker effect), and also coordinated workplace exposure assessment. Such access to workers and their workplaces and exposure information is critical to addressing the key essential knowledge gaps and research priorities, including defining the risks of isocyanate asthma and other health effects in different work settings, identifying exposure and host risk factors, and developing improved approaches for surveillance and prevention. Access to isocyanate-exposed workers is also essential to address key knowledge gaps and research priorities identified by the other groups, including evaluation of novel exposure methods, validation of biomarkers of exposure and disease, relationship of animal and in vitro study results to human health effects, and development of effective approaches to translate research to practice, such as interventions to reduce worker exposures.

Respiratory Epidemiology and Disease and Occupational Health Surveillance: Knowledge Gaps and Research Priorities


Isocyanates are extensively used in numerous different commercial and consumer applications and contribute significantly to our quality of life and drive toward energy efficiency. The knowledge gaps and research priorities identified reflect the experiences, expertise, and multidisciplinary perspectives of the Isocyanate and Health Conference stakeholders and delegates. Many of the knowledge gaps and research priorities, although prioritized under a specific conference theme, were integral components to other areas, such as the need for epidemiology and surveillance studies of isocyanate-exposed workers, and improved methods to assess worker exposures. There was also recognition of the need to develop more effective processes to improve communication of potential health hazards and best prevention and control practices across different audiences, including workers and consumers, patients and health care providers, and researchers. Reducing the gaps between knowledge from basic science and clinical research and what is done in practice (eg, training, policy, and regulation) should be a dynamic informative process that improves understanding and compliance.

Important knowledge gaps and research priorities to better understand and prevent potential adverse health consequences from exposure to isocyanates were identified. It is recommended that a working group consisting of basic and clinical investigators from academic institutions, government, and industry, as well as employer, employee and consumer representatives be established to address the knowledge gaps and research priorities identified. A primary objective of the working group should be to create and facilitate funding pathways and to support collaborative interdisciplinary research to advance the science and knowledge of isocyanates, health, and prevention. A secondary objective should be to coordinate collaborative approaches to communicate and implement best prevention and control practices, engaging a spectrum of stakeholders, including governments, trade associations, employers, manufacturers, labor and consumer organizations, professional societies, academic and industry scientists, and specialists in knowledge communication.

It is hoped that this Isocyanate and Health Conference and the current summary document will lead to greater collaboration across government, academic, industry, and worker organizations to advance research and knowledge regarding isocyanate exposures and health effects, and lead to improved preventive measures.


Isocyanates and Health Conference, April 3 to 4, 2013, conference presentations, abstracts, and posters:




Thank you to the following scientific committee members and researchers: Karl Auerbach, John Balmes, David I. Bernstein, Dhimiter Bello, Charles Bevington, Janet M. Carter, Claude Emond, George Charles Fonger, Terry Gordon, Carol L. Hetfield, Timothy Hilbert, Vikas Kapil, Catherine Lemière, Gary M. Liss, Aubrey K. Miller, Andrew Maier, Martin Nicholas, Leena A. Nylander-French, Kenneth D. Rosenman, Katherine Sleasman, Gunnar Skarping, Eileen Storey, Susan M. Tarlo, and Adam V. Wisnewski. Special thanks to Tonya Hyde, the conference secretariat, and Connie Thrasher, administrative assistant to Dr James Lockey.


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