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
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases
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
www.co-pulmonarymedicine.com
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. &
&
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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] &
&
&
&
&
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. &
&
&
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]
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
201
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases
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). &
&
&
202
www.co-pulmonarymedicine.com
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Exposure to isocyanates Verschoor and Verschoor &
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.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Porter CV, Higgins RL, Scheel LD. A retrospective study of clinical, physiologic, and immunologic changes in workers exposed to toluene diisocyanate. Am Ind Hyg Assoc J 1975; 36:159–168. 2. Wheeler S, Rosenstock L, Barnhart S. A case series of 71 patients referred to a hospital-based occupational and environmental medicine clinic for occupational asthma. West J Med 1998; 168:98–104. 3. Diar Bakerly N, Moore VC, Vellore AD, et al. Fifteen-year trends in occupational asthma: data from the Shield surveillance scheme. Occup Med 2008; 58:169–174. 4. Consumer Product Safety Commission USA. Status report. Staff review of five amine catalysts in sprayed polyurethane foam. 19 September 2012. 5. Marketandmarket. Methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI) and polyurethane market (2011–2016). www.marketsandmarkets.com. 6. Ceresana. Market study: polyurethanes and isocyanates (MDI & TDI) (4C-4905). 2013. www.ceresana.com. 7. The essential chemical industry on line. York, UK: CIEC Promoting Science at the University of York; 2013. 8. NIOSH. Preventing asthma and death from isocyanate exposure. Public Health Service. CDC/NIOSH Alert; 1996; pp. 96–111. 9. Redlich CA, Karol MH. Diisocyanate asthma: clinical aspects and immunopathogenesis. Int Immunopharmacol 2002; 2:213–224. 10. Pronk A. Isocyanate exposure and respiratory health effects in the spray painting industry. Dissertation. The Netherlands: IRAS, University Utrecht; 2007. 11. Environmental Protection Agency (EPA, USA). Design for the Environment. An EPA partnership program: Health concerns associated with SPF. 2011. http://epa.gov/dfe/spf/health concerns.html.
12. Ameille J, Hamelin K, Andujar P, et al. Occupational asthma and occupational rhinitis: the united airways disease model revisited. Occup Environ Med 2013; 70:471–475. In this study, a correlation is found between asthma and rhinitis in occupational disease. 13. Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest 1985; 88:376–384. 14. Shadnia S, Ahmadimanesh M, Ghazi-Khansari M, Zamani N. Intestinal ob& struction in acute inhalational toluene 2,4-diisocyanate gas toxicity. Int J Occup Environ Med 2013; 4:164–166. This is a case report presenting intestinal obstruction as an extraordinary manifestation of acute isocyanate toxicity. 15. Dahlqvist M, Tornling G, Plato N, Ulfvarson U. Effects within the week on forced vital capacity are correlated with long term changes in pulmonary function: reanalysis of studies on car painters exposed to isocyanate. Occup Environ Med 1995; 52:192–195. 16. Fisseler-Eckhoff A, Bartsch H, Zinsky R, Schirren J. Environmental isocyanateinduced asthma: morphologic and pathogenetic aspects of an increasing occupational disease. Int J Environ Res Public Health 2011; 8:3672–3687. 17. Lee SM, Koh D. Lessons from an isocyanate tragedy. Singapore Med J 2008; 49:372–374. 18. Jang A, Choi I, Koh Y, et al. Increase in airway hyperresponsiveness among workers exposed to methylene diphenyl diisocyanate compared to workers exposed to toluene diisocyanate at a petrochemical plant in Korea. Am J Ind Med 2000; 37:663–667. 19. Karol MH, Hauth BA, Riley EJ, et al. Dermal contact with toluene diisocyanate (TDI) produces respiratory tract hypersensitivity in guinea pigs. Toxicol Appl Pharmacol 1980; 53:260–270. 20. Rattray NJ, Botham PA, Hext PM, et al. Induction of respiratory hypersensitivity to diphenylmethane-4-4-diisocyanate (MDI) in guinea pigs. Influence of route of exposure. Toxicology 1994; 88:15–30. 21. Spergel JM, Mizoguchi E, Brewer JP, et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to metacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998; 101:1614–1622. 22. Petsonk EL, Wang ML, Lewis DM, et al. Asthma-like symptoms in wood product plant workers exposed to methylene diphenyl diisocyanate. Chest 2000; 118:1183–1193. 23. Krone CA, Klingner TD. Isocyanates, polyurethane and childhood asthma. Pediatr Allergy Immunol 2005; 16:368–379. 24. Bello D, Herrick CA, Smith TJ, et al. Skin exposure to isocyanates: reasons for concern. Environ Health Perspect 2007; 115:328–335. 25. Arrandale V, Meijster T, Pronk A, et al. Skin symptoms in bakery and auto body && shop workers: associations with exposure and respiratory symptoms. Int Arch Occup Environ Health 2013; 86:167–175. The study describes the relationship between exposure and skin symptoms, with special focus on the relation between skin and respiratory symptoms. 26. Malten KE. Recently reported causes of contact dermatitis due to synthetic resins and hardeners. Contact Dermatitis 1979; 5:11–23. 27. Maestrelli P, Boschetto P, Fabbri LM, et al. Mechanisms of occupational asthma. J Allergy Clin Immunol 2009; 123:531–542. 28. Wisnewski AV, Jones M. Pro/con debate: is occupational asthma induced by isocyanates an immunoglobulin E-mediated disease? Clin Exp Allergy 2010; 40:152–162. 29. Budnik LT, Preisser AM, Permentier H, Baur X. Is specific IgE antibody analysis & feasible for the diagnosis of methylene diphenyl diisocyanate-induced occupational asthma? Int Arch Occup Environ Health 2013; 86:417–430. This study describes the use of specific isocyanate–albumin conjugates for antibody assays used in the diagnosis of isocyanate-induced airway disease. Even using this method, false-negative results were obtained. 30. WHO Concise International Chemical Assessment Document 27. Diphenylmethane diisocyanate (MDI). Geneva; 2000. 31. Goossens A, Detienne T, Bruze M. Occupational allergic contact dermatitis caused by isocyanates. Contact Dermatitis 2002; 47:304–308. 32. Dietemann-Molard A, Kopferschmitt-Kubler MC, Meyer PD, et al. Allergic asthma due to domestic use of insulating polyurethane foam. Lancet 1991; 338:953. 33. Tervainen K, Jolanski R, Estlander T, et al. Immunologic contact urticaria due to airborne methyl hexahydrophthalic and methyltetrahydrophthalic anhydride. Contact Dermatitis 1995; 32:204–209. 34. Shin YS, Kim MAK, Park H-S. Cells and mediators in diisocyanate-induced & occupational asthma. Curr Opin Allergy Clin Immunol 2013; 13:125–131. This study confirms the role of immune responses in isocyanate-induced asthma. 35. De Vooght V, Smulders S, Haenen S, et al. Neutrophil and eosinophil & granulocytes as key players in a mouse model of chemical-induced asthma. Toxicol Sci 2013; 131:406–418. The report highlights the contribution of granulocytes to isocyanate-induced asthma by using depleting leukocyte strategies. 36. Park SJ, Lee KS, Kim SR, et al. AMPK activation reduces vascular permeability & and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma. Inflamm Res 2012; 61:1069–1083. An AMPK activator decreased the inflammatory and hyperreactive response of the lung induced by isocyanate. &
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
203
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
204
www.co-pulmonarymedicine.com
46. Verschoor L, Verschoor AH. Home insulation with PUR should be banned [In Dutch]. Medisch Contact 2013; 68:540–542. Seven families are reported who developed clinical symptoms after their homes were insulated with SPF. 47. Crespo J, Galan J. Exposure to MDI during the process of insulating buildings with sprayed polyurethane foam. Ann Occup Hyg 1999; 43:415–419. 48. Baur X, Dewair M, Rommelt H. Acute airway obstruction followed by hypersensitivity pneumonitis in an isocyanate (MDI) worker. J Occup Med 1984; 26:285–287. 49. Vanderplas O, Malo JL, Dugas M, et al. Hypersensitivity pneumonitis like reaction among workers exposed to diphenylmethane diisocyanate (MDI). Am Rev Res Dis 1993; 47:338–346. 50. Ott MG, Klees JE, Poche SL. Respiratory health surveillance in a toluene diisocyanate production unit, 1967–97: clinical observations and lung function analyses. Occup Environ Med 2000; 57:43–52. 51. Talini D, Novelli F, Bacci E, et al. Mild improvement in symptoms and && pulmonary function in a long-term follow-up of patients with toluene diisocyanate-induced asthma. Int Arch Allergy Immunol 2013; 161:189–194. This study reports follow-up for a mean of 11 years in 46 patients with isocyanateinduced asthma. Although the symptoms and lung function improved, medication use increased. 52. Dhara VR, Gassert TH. The Bhopal syndrome: persistent questions about acute toxicity and management of gas victims. Int J Occup Environ Health 2002; 8:380–386. 53. Senthilkumar CS, Malla TM, Sah NK, Ganesh N. Cancer morbidity among methyl isocyanate exposed long-term survivors and their offspring: a hospitalbased five year descriptive study (2006–2011) and future directions to predict cancer risk in the affected population. Asian Pac J Cancer Prev 2011; 12:3443–3452. 54. Pronk A, Preller L, Raulf-Heimsoth M, et al. Respiratory symptoms, sensitization, and exposure–response relationships in spray painters exposed to isocyanates. Am J Respir Crit Care Med 2007; 176:1090–1097. 55. Bose P, Bathri R. Association of microsatellite instability and chronic obstructive pulmonary disorder in isocyanate-exposed population of Bhopal. Indian J Hum Genet 2012; 18:172–176. 56. Mikoczy Z, Welinder H, Tinnerberg H, et al. Cancer incidence and mortality of isocyanate exposed workers from the Swedish polyurethane foam industry: updated findings 1959–98. Occup Environ Med 2004; 61:432–437. &
Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases
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
www.co-pulmonarymedicine.com
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. &
&
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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] &
&
&
&
&
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. &
&
&
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]
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
201
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstructive, occupational and environmental diseases
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). &
&
&
202
www.co-pulmonarymedicine.com
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Exposure to isocyanates Verschoor and Verschoor &
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.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Porter CV, Higgins RL, Scheel LD. A retrospective study of clinical, physiologic, and immunologic changes in workers exposed to toluene diisocyanate. Am Ind Hyg Assoc J 1975; 36:159–168. 2. Wheeler S, Rosenstock L, Barnhart S. A case series of 71 patients referred to a hospital-based occupational and environmental medicine clinic for occupational asthma. West J Med 1998; 168:98–104. 3. Diar Bakerly N, Moore VC, Vellore AD, et al. Fifteen-year trends in occupational asthma: data from the Shield surveillance scheme. Occup Med 2008; 58:169–174. 4. Consumer Product Safety Commission USA. Status report. Staff review of five amine catalysts in sprayed polyurethane foam. 19 September 2012. 5. Marketandmarket. Methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI) and polyurethane market (2011–2016). www.marketsandmarkets.com. 6. Ceresana. Market study: polyurethanes and isocyanates (MDI & TDI) (4C-4905). 2013. www.ceresana.com. 7. The essential chemical industry on line. York, UK: CIEC Promoting Science at the University of York; 2013. 8. NIOSH. Preventing asthma and death from isocyanate exposure. Public Health Service. CDC/NIOSH Alert; 1996; pp. 96–111. 9. Redlich CA, Karol MH. Diisocyanate asthma: clinical aspects and immunopathogenesis. Int Immunopharmacol 2002; 2:213–224. 10. Pronk A. Isocyanate exposure and respiratory health effects in the spray painting industry. Dissertation. The Netherlands: IRAS, University Utrecht; 2007. 11. Environmental Protection Agency (EPA, USA). Design for the Environment. An EPA partnership program: Health concerns associated with SPF. 2011. http://epa.gov/dfe/spf/health concerns.html.
12. Ameille J, Hamelin K, Andujar P, et al. Occupational asthma and occupational rhinitis: the united airways disease model revisited. Occup Environ Med 2013; 70:471–475. In this study, a correlation is found between asthma and rhinitis in occupational disease. 13. Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest 1985; 88:376–384. 14. Shadnia S, Ahmadimanesh M, Ghazi-Khansari M, Zamani N. Intestinal ob& struction in acute inhalational toluene 2,4-diisocyanate gas toxicity. Int J Occup Environ Med 2013; 4:164–166. This is a case report presenting intestinal obstruction as an extraordinary manifestation of acute isocyanate toxicity. 15. Dahlqvist M, Tornling G, Plato N, Ulfvarson U. Effects within the week on forced vital capacity are correlated with long term changes in pulmonary function: reanalysis of studies on car painters exposed to isocyanate. Occup Environ Med 1995; 52:192–195. 16. Fisseler-Eckhoff A, Bartsch H, Zinsky R, Schirren J. Environmental isocyanateinduced asthma: morphologic and pathogenetic aspects of an increasing occupational disease. Int J Environ Res Public Health 2011; 8:3672–3687. 17. Lee SM, Koh D. Lessons from an isocyanate tragedy. Singapore Med J 2008; 49:372–374. 18. Jang A, Choi I, Koh Y, et al. Increase in airway hyperresponsiveness among workers exposed to methylene diphenyl diisocyanate compared to workers exposed to toluene diisocyanate at a petrochemical plant in Korea. Am J Ind Med 2000; 37:663–667. 19. Karol MH, Hauth BA, Riley EJ, et al. Dermal contact with toluene diisocyanate (TDI) produces respiratory tract hypersensitivity in guinea pigs. Toxicol Appl Pharmacol 1980; 53:260–270. 20. Rattray NJ, Botham PA, Hext PM, et al. Induction of respiratory hypersensitivity to diphenylmethane-4-4-diisocyanate (MDI) in guinea pigs. Influence of route of exposure. Toxicology 1994; 88:15–30. 21. Spergel JM, Mizoguchi E, Brewer JP, et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to metacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998; 101:1614–1622. 22. Petsonk EL, Wang ML, Lewis DM, et al. Asthma-like symptoms in wood product plant workers exposed to methylene diphenyl diisocyanate. Chest 2000; 118:1183–1193. 23. Krone CA, Klingner TD. Isocyanates, polyurethane and childhood asthma. Pediatr Allergy Immunol 2005; 16:368–379. 24. Bello D, Herrick CA, Smith TJ, et al. Skin exposure to isocyanates: reasons for concern. Environ Health Perspect 2007; 115:328–335. 25. Arrandale V, Meijster T, Pronk A, et al. Skin symptoms in bakery and auto body && shop workers: associations with exposure and respiratory symptoms. Int Arch Occup Environ Health 2013; 86:167–175. The study describes the relationship between exposure and skin symptoms, with special focus on the relation between skin and respiratory symptoms. 26. Malten KE. Recently reported causes of contact dermatitis due to synthetic resins and hardeners. Contact Dermatitis 1979; 5:11–23. 27. Maestrelli P, Boschetto P, Fabbri LM, et al. Mechanisms of occupational asthma. J Allergy Clin Immunol 2009; 123:531–542. 28. Wisnewski AV, Jones M. Pro/con debate: is occupational asthma induced by isocyanates an immunoglobulin E-mediated disease? Clin Exp Allergy 2010; 40:152–162. 29. Budnik LT, Preisser AM, Permentier H, Baur X. Is specific IgE antibody analysis & feasible for the diagnosis of methylene diphenyl diisocyanate-induced occupational asthma? Int Arch Occup Environ Health 2013; 86:417–430. This study describes the use of specific isocyanate–albumin conjugates for antibody assays used in the diagnosis of isocyanate-induced airway disease. Even using this method, false-negative results were obtained. 30. WHO Concise International Chemical Assessment Document 27. Diphenylmethane diisocyanate (MDI). Geneva; 2000. 31. Goossens A, Detienne T, Bruze M. Occupational allergic contact dermatitis caused by isocyanates. Contact Dermatitis 2002; 47:304–308. 32. Dietemann-Molard A, Kopferschmitt-Kubler MC, Meyer PD, et al. Allergic asthma due to domestic use of insulating polyurethane foam. Lancet 1991; 338:953. 33. Tervainen K, Jolanski R, Estlander T, et al. Immunologic contact urticaria due to airborne methyl hexahydrophthalic and methyltetrahydrophthalic anhydride. Contact Dermatitis 1995; 32:204–209. 34. Shin YS, Kim MAK, Park H-S. Cells and mediators in diisocyanate-induced & occupational asthma. Curr Opin Allergy Clin Immunol 2013; 13:125–131. This study confirms the role of immune responses in isocyanate-induced asthma. 35. De Vooght V, Smulders S, Haenen S, et al. Neutrophil and eosinophil & granulocytes as key players in a mouse model of chemical-induced asthma. Toxicol Sci 2013; 131:406–418. The report highlights the contribution of granulocytes to isocyanate-induced asthma by using depleting leukocyte strategies. 36. Park SJ, Lee KS, Kim SR, et al. AMPK activation reduces vascular permeability & and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma. Inflamm Res 2012; 61:1069–1083. An AMPK activator decreased the inflammatory and hyperreactive response of the lung induced by isocyanate. &
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
203
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
204
www.co-pulmonarymedicine.com
46. Verschoor L, Verschoor AH. Home insulation with PUR should be banned [In Dutch]. Medisch Contact 2013; 68:540–542. Seven families are reported who developed clinical symptoms after their homes were insulated with SPF. 47. Crespo J, Galan J. Exposure to MDI during the process of insulating buildings with sprayed polyurethane foam. Ann Occup Hyg 1999; 43:415–419. 48. Baur X, Dewair M, Rommelt H. Acute airway obstruction followed by hypersensitivity pneumonitis in an isocyanate (MDI) worker. J Occup Med 1984; 26:285–287. 49. Vanderplas O, Malo JL, Dugas M, et al. Hypersensitivity pneumonitis like reaction among workers exposed to diphenylmethane diisocyanate (MDI). Am Rev Res Dis 1993; 47:338–346. 50. Ott MG, Klees JE, Poche SL. Respiratory health surveillance in a toluene diisocyanate production unit, 1967–97: clinical observations and lung function analyses. Occup Environ Med 2000; 57:43–52. 51. Talini D, Novelli F, Bacci E, et al. Mild improvement in symptoms and && pulmonary function in a long-term follow-up of patients with toluene diisocyanate-induced asthma. Int Arch Allergy Immunol 2013; 161:189–194. This study reports follow-up for a mean of 11 years in 46 patients with isocyanateinduced asthma. Although the symptoms and lung function improved, medication use increased. 52. Dhara VR, Gassert TH. The Bhopal syndrome: persistent questions about acute toxicity and management of gas victims. Int J Occup Environ Health 2002; 8:380–386. 53. Senthilkumar CS, Malla TM, Sah NK, Ganesh N. Cancer morbidity among methyl isocyanate exposed long-term survivors and their offspring: a hospitalbased five year descriptive study (2006–2011) and future directions to predict cancer risk in the affected population. Asian Pac J Cancer Prev 2011; 12:3443–3452. 54. Pronk A, Preller L, Raulf-Heimsoth M, et al. Respiratory symptoms, sensitization, and exposure–response relationships in spray painters exposed to isocyanates. Am J Respir Crit Care Med 2007; 176:1090–1097. 55. Bose P, Bathri R. Association of microsatellite instability and chronic obstructive pulmonary disorder in isocyanate-exposed population of Bhopal. Indian J Hum Genet 2012; 18:172–176. 56. Mikoczy Z, Welinder H, Tinnerberg H, et al. Cancer incidence and mortality of isocyanate exposed workers from the Swedish polyurethane foam industry: updated findings 1959–98. Occup Environ Med 2004; 61:432–437. &
Volume 20 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
