REVIEW URRENT C OPINION

Nonoccupational and occupational exposure to isocyanates Louis Verschoor and Atie H. Verschoor

Purpose of review This review aims to update the knowledge on the burden of disease due to exposure to isocyanates. Health effects of isocyanates and their major products, polyurethanes, are mainly determined by sensitization to isocyanates. Recent studies on the genetic factors to explain individual susceptibility to sensitization are reviewed. Recent findings Production of isocyanates has rapidly increased in the past and is predicted to increase at an annual rate of around 5%. Consumer products and the construction area are the main drivers of growth. This leads to increased nonoccupational exposure. The use of sprayed polyurethane foams for insulation in existing homes is one such example of nonoccupational exposure. The percentage of people exposed who show health effects is not known. Occupational exposure increases are mainly caused by the increase in the workforce. The percentage of workers exhibiting health effects remained fairly stable at 5–15% in the last decade. To explain why not all people exposed to isocyanates develop adverse health effects, recent findings on sensitization to isocyanate are reviewed. The skin is the most important route for sensitization. Summary Increased production of isocyanates and rising use of these substances in consumer products is leading to an increased burden of disease, with an increase in nonoccupational exposure as well. Sensitization to isocyanates is the main route for adverse health effects. The skin is the major route for sensitization. Recently, several genetic factors have been identified that play a role in the individual susceptibility for sensitization. Keywords isocyanate, nonoccupational exposure, occupational asthma, polyurethane, sensitization, SPF

INTRODUCTION Adverse health effects due to exposure to isocyanates have been known for a long time [1]. Studies on the incidence and causative factors of occupational asthma identify isocyanates at the top of the list [2,3]. In the last 50 years, the production of isocyanates and their use as a component in the production of polyurethanes have rapidly increased. The main isocyanates produced are toluene diisocyanate or methylbenzene diisocyanate (TDI) and methylene diphenyl diisocyanate or diphenylmethane diisocyanate (MDI). To produce polyurethanes, TDI or MDI is mixed with polyols, either hydroxyl-terminated polyethers (in about 90% of total polyurethane manufacture) or hydroxyl-terminated polyesters. The number of reactive hydroxyl groups per polyol molecule is an important factor for the mechanical properties of the polymer. In the production process of polyurethanes, other chemicals are added to control

the polyurethane-forming reactions and to create exactly the right properties in the end product, such as catalysts (amines), pigments, flame retardants and blowing agents to create polyurethane foams. In the case of sprayed polyurethane foam (SPF), blowing gas is added, mostly hydrofluorocarbons (HFCs). All these additives as such also have adverse health effects [4]. Annual isocyanate production worldwide has doubled in the last 10 years to 9106 tonnes and will increase to 12106 tonnes in 2020 [5,6]. Annual Expertise Centre Environmental Medicine (ECEMed), Rijnstate Teaching Hospital Arnhem, Velp, the Netherlands Correspondence to Dr Louis Verschoor, MD, PhD, Expertise Centre Environmental Medicine (ECEMed), Rijnstate Teaching Hospital Arnhem, Internal Postbox 2925, PO Box 8, 6880 AA Velp, The Netherlands. Tel: +31 8800 55970; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:199–204 DOI:10.1097/MCP.0000000000000029

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KEY POINTS  Widespread use of isocyanates in consumer products leads to increased nonoccupational exposure.  Sensitization to isocyanates is the main reason for the increased burden of disease caused by these substances.  Investigating the susceptibility to sensitization is greatly increasing our understanding of the process, but has at present no therapeutic consequences.  The most effective treatment for people sensitized to isocyanates is to exclude exposure.

production of polyurethanes reached nearly 12106 tonnes in 2012 [7]. The prediction is that in the next 10 years production will increase at a mean annual rate of 5% [6]. Roughly a quarter of polyurethanes are produced as rigid foams used for construction and insulation. Forty percent of polyurethanes are used as flexible and molded foams in mattresses, cushions, furniture, car seats and car components. The remaining polyurethane production is for textiles, shoes, coatings and adhesives. Given this increase in production, occupational exposure to isocyanates in the USA alone has increased from 280 000 workers in 2005 to nearly a million workers worldwide in 2020 [5,8]. In the next decade, the majority of increased production capacity will take place in Asia [4]. Precautions that have been taken to minimize the exposure to isocyanates have decreased the percentage of workers with health complaints from 10–30% in the last century to 5–15%, and have remained fairly stable the last 10 years [9]. However, as the total workforce substantially increases, this will lead to a greater burden of disease. As these compounds are increasingly used in consumer products, the rise leads to increased nonoccupational exposure as well. Increased nonoccupational exposure also has consequences for the development of sensitization to isocyanates, because sensitized people are at increased risk given the increased use of these compounds in consumer goods. Special attention has been paid in the recent years to the adverse health effects caused by SPFs in both occupational and nonoccupational settings. It is important to realize that the use of SPF in housing insulation leads to a 7  24 h exposure for households.

HEALTH EFFECTS OF ISOCYANATES The direct toxic and irritant effects of isocyanates are well known: irritation of nose, throat and upper 200

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airways along with eye and skin irritation [10,11]. Complaints of the digestive tract also frequently occur [11]. Recently emphasis was laid on the association with occupational rhinitis and asthma [12 ]. A single acute exposure to high concentrations of isocyanates can cause reactive airways dysfunction syndrome (RADS) and intestinal obstruction [13,14 ]. The airway hyperreactivity may persist for years [15]. Acute exposure to high concentrations of isocyanates and continuous exposure to low levels of isocyanates may lead to sensitization, which means that even at extremely low levels of isocyanate, adverse health effects occur affecting primarily the upper airways, intestinal tract and skin [8]. The only effective treatment is total avoidance of exposure. The US National Institute for Occupational Safety and Health exposure limit for isocyanates is 0.05 mg/m3 or 0.005 ppm, the Occupational Safety and Health permissible exposure limit (PEL) is 0.2 mg/m3 as a 10-min ceiling limit (0.002 ppm). Limits in Europe range from 0.02 to 0.054 mg/m3 depending on the type of isocyanate [16]. This level is intended to prevent acute and chronic sensitization of workers, but does not prevent the health effects in workers already sensitized. Sensitization can occur after one large exposure as well as in the course of continuous low level exposure. Once sensitization has occurred, there is no lower limit under which complaints do not take place [9,16]. Sensitized persons can exhibit severe life-threatening effects up to death when exposed to isocyanates [17]. The intriguing question remains why only a small proportion of individuals occupationally exposed to isocyanates develop complaints and sensitization. No data are available on the proportion of consumers who develop adverse health effects and sensitization. &

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SENSITIZATION Sensitization is the process that occurs when exposure to a substance leads to an exaggerated response of the body at new exposure to that substance even at extremely low concentrations. In sensitization, the most pronounced reactions are exhibited in the airway system and the skin. Thus, the original idea was that sensitization was caused by inhalation of the substance into the airway system. This assumption led to measures to decrease the concentration of isocyanates in the air of the workplace as much as possible. Despite decreased concentrations in the working environment, the incidence of occupational asthma did not decline, even if concentrations of isocyanate were nearly unmeasurable [18]. Previous animal experiments gave evidence for the skin as a route not only for Volume 20  Number 2  March 2014

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Exposure to isocyanates Verschoor and Verschoor

skin sensitization but also for sensitization of the lung [19–21]. Later on, the mechanism was described in humans too [22–24,25 ]. As early as 1995, the warning ‘skin contact may result in allergic skin reaction or respiratory sensitization’ has been included in the material safety data sheets (MSDS) of isocyanates. The fact that the routes of sensitization are, in sequence of importance, skin and airways, means that emphasis should be placed on total skin and airway protection to prevent (non)occupational exposure to and adverse clinical manifestations of isocyanates. &&

SUSCEPTIBILITY TO SENSITIZATION Much work has been done on trying to find the predictors of sensitization. A weak correlation exists with the severity of the exposure [9]. First, attention was paid to allergic susceptibility. Although not conclusive, most studies did not find a correlation of sensitization with allergic phenomena in the medical history of individuals [26]. Evidence has been presented that immunologic and nonimmunologic factors are involved [27,28,29 ]. The mechanism by which nonimmunologic factors lead to respiratory changes in isocyanate-exposed people is challenging and still not understood [27]. The fact that 50–80% of cases with isocyanate-induced asthma do not exhibit specific IgE and IgG underlines the importance of nonimmunologic factors [16,28,29 ,30]. Thus, measurement of specific immunoglobulins cannot be used as a diagnostic tool in sensitization to isocyanates [27]. The same holds true for skin testing; half the patients with contact dermatitis to isocyanates have a negative skin test [31]. Challenge with isocyanates may lead to a severe asthma attack [32] and a single skin test with isocyanates can induce sensitization [33]. Recently, Shin et al. [34 ] reviewed the role of immune responses in isocyanate-induced occupational asthma. In occupational asthma, the pathogenesis is complex and involves, among others, irritative changes in airway epithelium leading to cytokine release, oxidative stress generation and autoantibody formation. Adaptive immune responses could also play a role. In a mouse model of isocyanate-induced asthma, an essential role for neutrophil and eosinophil granulocytes was found in airway hyperreactivity and inflammation response [35 ]. The effect of AMP-activated protein kinase (AMPK) was investigated in a mouse model. Activation of AMPK leads to an attenuation of airway inflammation and hyperresponsiveness [36 ]. Thus, recent studies on genetic susceptibility focused on the candidate genes involved in these processes. In an earlier study, Bernstein et al. [37] &

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identified susceptibility and resistance loci in the HLA region and in immune response genes (IL-4R alpha, IL-13 and CD14). In 2013 they published a candidate-gene association study [39 ] in a white population to replicate the findings of Kim et al. [38] in their genome-wide association study in Korean individuals. In both populations, an association was found between two CTNNA gene single nucleotide polymorphisms (SNPs) and isocyanate-induced asthma. Odds ratios (ORs) ranged from mean values of 6.82 to 9.05 in the white population and 1.41 to 5.84 in the Korean population. As these genes are responsible for decreased expression of alpha-T-catenin, the authors suggest that cellular adherence in the airways can be a mechanism involved in the development of isocyanate-induced asthma. On the basis of the same principle, Bose et al. [40 ] studied the survivors of the methyl isocyanate disaster in Bhopal. They concluded that the SNP C-159T in the CD14 gene might be a risk factor for developing chronic lung disease in these survivors. Yucesoy et al. [41 ] investigated the variations in the antioxidant defense genes, glutathione S-transferases, manganese superoxide dismutase and microsomal epoxide hydrolase, in a case–control study. Glutathione S-transferases, especially GSTP1, is abundant in respiratory epithelium and plays a major role in the redox balance and inflammatory responses. The study population consisted of a white population (French-Canadians). Three groups of patients were investigated: workers with respiratory symptoms with a positive (DAþ) or negative (DA) specific challenge test, and asymptomatic exposed workers. Isocyanate exposure was highest in the DAþ group. Atopy was evenly distributed among the groups. The percentage of smokers increased from DAþ to DA to asymptomatic exposed workers. The mean age of the asymptomatic exposed worker group was 10 years younger. Comparing DAþ and DA patients, OR values for decreased risk to become DAþ ranged from 0.19 to 0.47; OR values for increased risk exhibited a variation of 2.70 to 8.55. OR data comparing DAþ and asymptomatic exposed worker patients ranged from 0.06 to 0.32 and 6.22 to 10.36, respectively. These new studies certainly increase our understanding of the complex process of sensitization; however, it is unclear which role this knowledge may play in diagnosing and treating patients with isocyanate-induced sensitization. &

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NONOCCUPATIONAL EXPOSURE The increased use of isocyanate-containing products has raised the awareness of health problems related to nonoccupational exposure [11]. Jan et al. [42]

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described accidental exposure to xylene and isocyanate in schoolchildren. A total of 203 students developed symptoms of dyspnea, dizziness, nausea and sore throat. A total of 11% of the students had a history of asthma, which was strongly correlated with dyspnea after the incident. A total of 61% of the students with no history of asthma also developed dyspnea, nearly one-third of them requiring inhaled bronchodilator therapy. Further studies revealed a concentration of MDI 8000-fold above the safety level defined for a working environment. The US Centers for Disease Control and Prevention (CDC) reported community exposure to isocyanates which happened to be related to a nearby polyurethane foam manufacturing plant [43]. Tsuang and Huang [44 ] described an adult man and woman who developed cough, dyspnea, dizziness, nausea, headache and watery eyes after SPF had been applied to their attic. They had to move out of the house. Both patients had a positive metacholine test and had to be treated with bronchodilators and inhaled steroids to suppress their symptoms even after exposure was halted. Dietemann-Molard [32] reported respiratory symptoms, facial swelling and a skin rash in a sensitized individual after using a commercial SPF to insulate a window in his home. He later developed symptoms again while painting cars with isocyanate-containing paints. Redlich and Wilson [45 ] presented a paper at the International Conference ‘Isocyanates and Health: Past, Present and Future’ held in Potomac, MD, in April, 2013, reporting four families with severe complaints after their homes were insulated with SPF. They had to move out of their homes. Measurements carried out 2–20 months after the insulation procedure still showed elevated levels of a variety of components of the SPF. Three of the four families could not return to their homes. We described eleven persons from seven families with complaints directly related to the insulation of their homes with SPF [46 ]. Most had cough, sore throat, irritated eyes, dyspnea, nausea, headache, and some of them had intestinal symptoms. Moving out of the house decreased the complaints. Accidental exposure (picking up things from home) rapidly aggravated the symptoms. Crespo and Galan [47] analyzed the samples taken during the application of SPF and found values up to 0.077 (outdoor) and 0.400 mg/m3 (indoor). These values are 8–20 times above the threshold limit for occupational exposure. This increased risk of nonoccupational exposure with the development of adverse health effects and sensitization to isocyanates led the Environmental Protection Agency to consider a ban on SPFs in consumer products (16 April 2011). &

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OCCUPATIONAL EXPOSURE Three types of airways reaction to isocyanates have been described: acute irritation leading to RADS, asthma and hypersensitivity pneumonitis [9,13,18,48,49]. Recently, Nemery presented a paper at the Congress of the European Society of Pulmonology (Barcelona, September 2013) describing a patient with severe pulmonary fibrosis due to SPF exposure for 3 weeks, who had to be treated with lung transplantation. Safety measures were at first concentrated on decreasing the amount of toxic substance in the air with the presumption that sensitization occurs through exposure of the lung. However, even with unmeasurable concentrations in the air, sensitization still occurred [18]. Bronchial hyperreactivity (BHR) when measured is frequently present [13,15]. The main abnormalities found in workers with asthmatic complaints are decreased values for forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) [9,50]. These abnormalities can be found within a week of exposure [15]. Long-term exposure leads to further reductions in FVC and FEV1 [15]. Another follow-up study was published by Talini et al. [51 ], who described 46 patients followed for 11 years. Although they reported improvement in symptoms, pulmonary function (FEV1) and BHR, the percentage of patients needing therapy increased from 40 to 70% during follow-up. Removal from exposure was the single most effective treatment. Ott et al. [50] reported a follow-up of workers in an isocyanate production plant. Workers with isocyanate-induced asthma showed a decline of FEV1 during the first 2 years that remained stable thereafter. The overall incidence of isocyanate-induced asthma declined from 1.8% before 1980 to 0.7% thereafter. Long-term follow-up studies of individuals exposed to isocyanates are scarce. However, several studies have been published on the adverse effects in the victims from the 1984 Bhopal accident. Chronic lung disease persisted and an increase in cancer was observed [52,53]. &&

CHRONIC OBSTRUCTIVE PULMONARY DISEASE Albeit less often [16], chronic obstructive pulmonary disease (COPD) has also been described in people exposed to isocyanates. Pronk et al. [54] reported on the respiratory symptoms in 581 workers in the spray-painting industry with a mean exposure duration to isocyanates of 15 years. In 34% of the spray painters asthma-like symptoms were found, compared to 26% of the painters showing COPDlike symptoms. In the control group (office workers with no exposure), these percentages were 14 and Volume 20  Number 2  March 2014

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8%, respectively. Also, Bose and colleagues [40 ,55] differentiated between asthma and COPD in an isocyanate-exposed population of Central India. However, they did not report on the percentage of people in the study group suffering from asthma and COPD. Mikoczy et al. [56], in a study on 4175 isocyanate-exposed workers over a 40 year period, mentioned no increased mortality from COPD.

CONCLUSION Widespread use of isocyanates and polyurethanes leads to a significant burden of occupational lung disease. Further protective measures should decrease the occupational lung and skin disease. The use of isocyanates and polyurethanes in ever-more consumer products and SPFs in housing insulation are leading to an increase in the nonoccupational exposure. These developments cause not only an increased burden of disease in the population, but also a rise in people sensitized to isocyanates. The latter has severe consequences in a society with ubiquitous presence of these substances. Acknowledgements None. Conflicts of interest There are no conflicts of interest.

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Obstructive, occupational and environmental diseases 37. Bernstein DI, Wang N, Campo P, et al. Diisocyanate asthma and geneenvironment interactions with IL4RA, CD-14, and IL-13 genes. Ann Allergy Asthma Immunol 2006; 97:800–806. 38. Kim SH, Cho BY, Park CS, et al. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy 2009; 39:203– 212. 39. Bernstein DI, Kashon M, Lummus ZL, et al. CTNNA3 (alpha-catenin) gene & variants are associated with diisocyanate asthma: a replication study in a Caucasian worker population. Toxicol Sci 2013; 131:242–246. This report confirms the role of CTNNA gene variants in the susceptibility to isocyanate-induced asthma. 40. Bose P, Bathri R, De S, Maudar KK. CD14 C-159T polymorphism and & its association with chronic lung disease: a pilot study on isocyanate exposed population of central India. Indian J Hum Genet 2013; 19:188–195. This is another example of a study of the association between gene variants and clinical symptoms induced by isocyanate. 41. Yucesoy B, Johnson VJ, Lummus ZL, et al. Genetic variants in antioxidant & genes are associated with diisocyanate-induced asthma. Toxicol Sci 2012; 129:166–173. Also, this study reports on the association between gene variants and isocyanateinduced asthma. 42. Jan RL, Chen SH, Chang HY, et al. Asthma-like syndrome in school children after accidental exposure to xylene and methylene diphenyl diisocyanate. J Microbiol Immunol Infect 2008; 41:337–341. 43. CDC. Community exposure to toluene diisocyanate from a polyurethane foam manufacturing plant – North Carolina, 1997. MMWR Morb Mortal Wkly Rep 1998; 47:455–457. 44. Tsuang W, Huang TYC. Asthma induced by exposure to spray polyurethane & foam insulation in a residential home. J Occup Environ Med 2012; 54:272– 273. Two patients are reported who developed isocyanate-induced asthma after their home was insulated with SPF. 45. Redlich CA, Wilson L. A case series of families with symptoms associated & with home polyurethane spray foam insulation [abstract]. International Conference Isocyanates and Health 2013. Potomac, MD, USA. Four families are reported who developed clinical symptoms after their homes were insulated with SPF.

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Nonoccupational and occupational exposure to isocyanates.

This review aims to update the knowledge on the burden of disease due to exposure to isocyanates. Health effects of isocyanates and their major produc...
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