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NIOSH Respiratory Diseases Research Program

Evidence Package for the National Academies' Review 2006-2007

NIOSH Programs > Respiratory Diseases > Evidence Package > 4. Airways Diseases > 4.1 Work-Related Asthma

4.1b) Prevent and Reduce Isocyanate-Induced Asthma

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Issue 

The group of chemically reactive diisocyanate compounds, which includes MDI, TDI, and hexamethylene diisocyanate, are widely used in the production of urethane foams, fibers, coatings, paints, elastomers, and adhesives. In 2003, U.S. consumption was 1.9 billion pounds of MDI, and 1.1 billion pounds of TDI, with historical growth in consumption of seven percent per year for MDI, and 2.7 percent per year for TDI.109

In the transportation industries alone, over 253,000 U.S. workers are employed in facilities that use isocyanates.109 These compounds are used extensively in small businesses such as autobody repair, wood working, and spray-on truck-bed liner application shops. In addition, diisocyanates can be regenerated when heat is applied to polyurethane products (e.g. cutting pipes which contain the materials).

Diisocyanates are potent sensitizers, and have long been recognized as a cause of occupational asthma, rhinitis, and dermatitis. Continued exposure to diisocyanate compounds after development of occupational asthma is associated with developing more severe disease and experiencing poorer outcome. Numerous studies have documented that on average 5 to15 percent of those who work with diisocyanates develop occupational asthma, although both lower and higher proportions have been affected, depending on exposures.110,111 Only a minority of individuals affected by diisocyanate-related asthma will recover fully, and most will have asthma symptoms indefinitely, even after the condition is recognized and all diisocyanate exposures terminated. The overall socioeconomic costs of occupational asthma are high. Affected individuals suffer both chronic illness and reduced economic and employment potential.

Occupational asthma has become the most frequently diagnosed occupational respiratory disorder in the U.S. and many other industrialized countries.112 RDRP and other public surveillance systems have documented that the group of diisocyanate compounds has emerged as the first or second most commonly identified cause of occupational asthma in the U.S.,113 Canada,114 France,115 and the U.K.112 In Ontario, 58 percent of compensated claims for occupational asthma have been attributed to diisocyanates. Early recognition of occupational asthma and timely termination of exposure is associated with a greater chance of complete recovery. However, recognition has been problematic for two reasons. First, reliable markers of sensitization and pre-clinical disease are not well established. Second, documentation of chemical sensitization as the cause of occupational asthma by specific inhalation challenge is problematic, because specific inhalation challenge is not generally available and, even when it is available, it is an imperfect test. Although the current OSHA PEL for most diisocyanates is 20 ppb, once a worker has been sensitized to diisocyanates, severe asthmatic reactions are triggered at much lower concentrations. Further, no occupational exposure limits exist for many of the diisocyanate compounds, and diisocyanate sampling and analysis is problematic.

Documentation and monitoring of diisocyanate exposures is therefore complicated. Occupational exposure surveillance is also complicated by ample opportunities for non-occupational exposures. Consequently, exposure monitoring methods have not been satisfactory for many of the diisocyanate exposures, and primary prevention approaches have not been uniformly successful.

The mechanism of sensitization and the pathogenesis of asthma from diisocyanates remain unknown. Traditional immunologic mechanisms have not been able to account for the recognized patterns of disease and pathogenesis. Although genetic studies have tentatively identified several protective loci, traditional markers of atopy have not been useful as risk markers, and there is currently no accepted approach to identifying susceptibility factors or disease precursors. In addition, more exposure control methods need to be developed for the workplace.

Approach

Early RDRP publications brought attention to the problem of isocyanate asthma and recommended measures for disease prevention and mitigation. The NIOSH Criteria Document for TDI was published in 1973, and revised in 1978 to include all monomeric diisocyanates. In these documents, NIOSH recommended an exposure limit of five ppb, and a short-term exposure limit of 20 ppb, as well as periodic medical monitoring for potentially exposed workers. Several other key RDRP documents addressing diisocyanate exposures and health effects were published prior to 1996.

Over the past decade, RDRP intramural and extramural investigations in workplaces, and laboratory in vitro and animal studies, have explored pathogenesis, immunology, and clinical features for diisocyanate-related illness in workers and workplaces. One series of projects identified risk factors and early clinical indicators that could be useful in both primary and secondary prevention. Another used an in vivo mouse model of diisocyanate sensitization and a TNF receptor gene knockout strain to demonstrate the multiple and central roles of the mediator TNF-a in TDI-induced asthma. The findings are important in contrasting the mechanisms of diisocyanate asthma to that found in asthma caused by high molecular weight sensitizers.

Another RDRP study investigated workers in a wood products manufacturing plant that was using diisocyanates. The study found that workers who reported skin exposure to diisocyanate had a significantly increased risk of developing asthma-like symptoms, after accounting for the risk of inhalational exposures. This was the first human study to confirm several animal investigations indicating the potential for respiratory sensitization by skin exposure. In addition, the study found that workers who reported that they occasionally removed their respiratory protection were more likely to develop asthma symptoms.

These RDRP investigations have challenged some previous assumptions and hypotheses, as well as provided important insights into the biological mechanisms and pathogenesis of diisocyanate asthma.

The economics of medical monitoring for workers with potential exposure to these compounds has been modeled by RDRP scientists and, importantly, monitoring was found to be cost-effective.

Over the past decade, RDRP scientists also developed and standardized 17 exposure-monitoring methods that are now available through the “NIOSH Manual of Analytical Methods” (NMAM).

Through collaborations with industry partners involved in the production of TDI, RDRP is currently engaged in a demonstration-phase project involving application of current best practices to environmental and medical monitoring, and incorporating a structured evaluation of the effectiveness of these approaches. In light of the industry’s public commitment to product stewardship (labeled “Responsible Care”), it is expected that a demonstrably feasible, practical, and effective approach to hazard mitigation, combined with exposure and health monitoring, will become a standard of practice in the handling of isocyanates and result in measurable reductions in the prevalence and severity of exposure-related illness.

RDRP indirectly supports 33 states, one city, and one territory to conduct surveillance for WRA, as part of an asthma surveillance program funded directly primarily by the National Center for Environmental Health (NCEH). In addition, we have collaborated with the SENSOR program on the distribution, determinants, and trends in diisocyanate asthma in California, Michigan, Massachusetts, and New Jersey.

In 2003, asthma surveillance staff in both Michigan and Washington identified cases of asthma associated with application of spray-on truck-bed liners that resulted from exposure to diisocyanates. Subsequently, RDRP scientists conducted a field investigation of overspray in truck-bed lining shops through the HHE program and developed recommendations for control of overspray and other worker exposures.  Since then, RDRP has investigated and reported on strategies to control diisocyanate exposure associated with spray-on coatings used in heavy steel fabrication facilities.

Between 1989 and 2002, RDRP HHEs and field studies examined exposure controls at 46 worksites where diisocyanates represented a primary concern. Reports were sent to each site on specific approaches to exposure control and disease prevention for their operations.

Outputs and Transfer

To facilitate the identification and implementation of best practices in medical monitoring and disease prevention for diisocyanates, a Memorandum of Understanding (MOU) was signed by NIOSH and the American Chemistry Council Diisocyanates Panel in 2003. The collaboration has provided a forum for effective communications between RDRP and the industry, and has facilitated the adoption of work practices by collaborating companies based upon the latest RDRP research findings.

Since 1996, scientific products by RDRP-supported investigators have included 24 peer-reviewed articles on the toxicology and laboratory mechanisms of diisocyanate-induced disease, 16 articles covering clinical aspects including risk factors and methods for monitoring health of workers and detecting early exposure-related abnormalities, 16 articles on methods for monitoring of environmental exposures, and six articles on approaches to prevention and control (A4-10). Examples are:

NIOSH Alert: “Preventing Asthma and Death from Diisocyanate Exposure” (A4-11). This NIOSH Alert provides important guidance to employers and employees about the hazards, health outcomes, and prevention strategies for diisocyanates. This Alert was released in 1996 and over 15,000 copies were distributed.

NIOSH Alert: “Preventing Asthma and Death from MDI Exposure During Spray-on Truck-bed Liner and Related Applications” (A4-12). This Alert provides guidance to employers, often times small businesses, and employees about the hazards of spray-on application of MDI. This Alert was released in August 2006.

Citing RDRP work, including the 1996 NIOSH Alert (see above), the Washington State Department of Labor and Industries issued a Hazard Alert entitled “Spray-on Urethane Truck-bed Linings and Isocyanate Exposures” in March 2003 (A4-13). Likewise, the Michigan Occupational and Safety Health Administration (MIOSHA), which is supported by RDRP as part of the SENSOR Asthma Program, issued a Hazard Alert entitled “Spray-on Truck-bed Liner Operation Proves Fatal” in October 2003 (A4-14). The two state Alerts were followed by publications in the peer-reviewed literature in 2003 and 2005 (A4-15, A4-16).

The in vivo transgenic mouse work on sensitization was published in 2002 (5,  A4-17). The study of skin exposure to isocyanates in a manufacturing facility was published in 2000 (6, A4-18). After its publication, this article was discussed in the newsletter, “Occupational and Environmental Medicine Report.”

In 1998, RDRP sponsored a major international conference, “Occupational Asthma: In and Out of the Workplace,” in cooperation with the American Academy of Allergy, Asthma, and Immunology; the American Thoracic Society; the National Institute of Allergy and Infectious Disease; NIEHS; the National Heart, Lung, and Blood Institute; and EPA. Forty five subject matter experts presented papers. The conference was a forum for the discussion of new research and the exchange of ideas regarding the causes, mechanisms, and prevention of occupational asthma due to diisocyanate exposure (A4-19).

In 2002, RDRP sponsored the International Conference on Occupational and Environmental Exposures of Skin to Chemicals: Science and Policy, addressing skin exposures to chemicals and specifically the issue of diisocyanate sensitization and skin exposure. The conference was designed for occupational and environmental physicians, dermatologists, industrial hygienists, laboratory researchers and policy-makers who were interested in learning more about the relevant science, knowledge gaps and policy opportunities in this area. 74 papers and abstracts were presented at the conference, and a summary manuscript was prepared (A4-20 Part 1, Part 2).The proceedings are available on the NIOSH Web site: “Proceedings of the International Conference on Occupational and Environmental Exposures of Skin to Chemicals: Science and Policy” (http://www.cdc.gov/niosh/topics/skin/conference).

In 2004, RDRP published “Issues Related to Occupational Exposure to Isocyanates, 1989 to 2002” (A4-21). This publication summarized the lessons learned from the 46 field investigations of isocyanate operations in 2004.

Four published reports contributed 17 methods documented in the “NMAM” (see chapter 12) (7-10, A4-22, A4-23, A4-24, A4-25). These methods assure accurate and precise measurements of diisocyanates in the workplace. RDRP scientists are continually working to improve these methods, and publish research reports as well as revisions. The methods are widely implemented by industry, government agencies, and non-governmental and professional organizations.

RDRP publications have reported new approaches to monitoring workers and investigating diisocyanate asthma (11, A4-26), and have also documented the lack of availability and utility of some approaches (12, 13, A4-27, A4-28), and economic practicality (A4-29).

In 2006, RDRP established a NIOSH Web site that provides a single source of published references to the primary prevention of occupational asthma due to diisocyanates as well as other agents (A4-30).  (http://www.cdc.gov/niosh/topics/asthma/OccAsthmaPrevention.html). In the first six months, this site was accessed a total of 3,571 times.

Intermediate Outcomes

The British Occupational Health Research Foundation116 and an international consensus group have applied RDRP findings on diiocyanates.117

All U.S. manufacturers of TDI have committed to implement a protocol for worker health and environmental monitoring using the methods developed in collaboration with RDRP scientists. The collaboration involves an evaluation of the protocol, including its provisions for reporting findings, and its implementation. We expect the evaluation to show the protocol to be a feasible and effective approach to exposure monitoring. If so, it may become a standard of practice in the handling of isocyanates and result in measurable reductions in the prevalence and severity of exposure-related illness.

The Virginia Occupational Safety and Health Program in conjunction with the Region Three OSHA office began a local emphasis program to focus on businesses and workers who apply spray-on truck-bed liners. In addition, California OSHA conducted hearings in 2005 on standards for sensitizing substances, during which isocyanates in spray-on truck-bed liners were discussed.

Based on our efforts to date, especially the MOU with the American Chemistry Council Diisocyanates Panel, we believe that all U.S. manufacturers of diisocyanates and many end users are aware of the health effects of exposure to these agents and measures to mitigate them.

What’s Ahead

We will continue surveillance, laboratory, and field investigation activities for occupational asthma. Data collection from the joint government, industry, labor collaborative activity in the TDI plants will provide a leading indicator of potential health outcomes. The medical monitoring results should provide support for recommendations for disease prevention activities in these or similar plants. Transfer of recommended health and environmental monitoring approaches to other workplaces, particularly downstream users of diisocyanate products, will then be pursued.

109.  NIOSH [2006]. Preventing Asthma and Death from MDI Exposure During Spray-on Truck-bed Liner and Related Applications. Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2006-149.

110. Redlich CA, Karol MH [2002]. Diisocyanate asthma: clinical aspects and immunopathogenesis. International Immunopharmacology 2 (2-3):213-224.

111. RC Woellner, Hall S, Greaves I, Schoenwetter WF [1997]. Epidemic of asthma in a wood products plant using methylene diphenyl diisocyanate. American Journal of Industrial Medicine 31 (1):56-63. 

112. Hendrick DJ [2001]. The worldwide problem of occupational asthma. Clinical & Exp Allergy 31:1-4.

113. NIOSH [1999]. Work-Related Lung Disease Surveillance Report 1994. Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2000-105. 

114. Lagier F, Cartier A, Malo JL [1990]. Medico-legal statistics on occupational asthma in Quebec between 1986 and 1988. Revue des Maladies Respiratoires 7 (4):337-341.

115. Kopferschmitt-Kubler MC, Ameille J, Popin E, Calastreng-Crinquand A, Vervloet D, Bayeux-Dunglas MC, Pauli G, Observatoire National de Asthmes Professionnels Group [2002]. Occupational asthma in France: a 1-yr report of the observatoire National de Asthmes Professionnels project. European Respiratory Journal 19 (1):84-89.

117. International Consensus Report on Isocyanates – Risk assessment and management [2001]. 11.20-22 Hotel Norge Hoesbjoer, Norway.