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Review of the occupational exposure to isocyanates: Mechanisms of action

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Environmental Health and Preventive Medicine Aims and scope

Abstract

Polyurethanes are useful polymers in a large variety of technical and consumer products that are generally made from diisocyanates and polyols or similar compounds. Toluene diisocyanate (TDI), 4,4′-methylenediphenyl diisocyanate (MDI) and 1,6′-hexamethylene diisocyanate (HDI) are useful for polyurethane products. Isocyanates are reactive chemicals that can be handled without problems in manufacturing or technical environments. In general, consumers may only have contact with these chemicals on rare occasions. The objective of this study was to review the mechanisms of action of inhalation of isocyanates. This paper describes, in summary, the potential occupational exposure to isocyanates, the chemistry and reactivity of isocyanates, the results from genotoxicity studies, investigative toxicity studies, metabolism and results from epidemiology studies on isocyanate-exposed workers. The overall conclusion is that because humans are not exposed to high levels of respiratory isocyanate particles, concerns over the possible development of lung tumors should not be relevant. There are many mechanisms of action induced by isocyanates, but those entities are unclear. This is because these mechanisms act simultaneously and are complex.

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References

  1. Aul DJ, Bhaumik A, Kennedy AL, Brown WE, Lesage J, Malo JL. Specific IgG response to monomeric and polymeric diphenylmethane diisocyanate conjugates in subjects with respiratory reactions to isocyanates. J. Allergy Clin. Immunol. 1999; 103: 749–755.

    Article  PubMed  CAS  Google Scholar 

  2. Raulf-Heimsoth M, Baur X. Pathomechanisms and pathophysiology of isocyanate-induced diseases-summary of present knowledge. Am. J. Ind. Med. 1998; 34: 137–143.

    Article  PubMed  CAS  Google Scholar 

  3. Kennedy AL, Stock MF, Alarie Y, Brown WE. Uptake and distribution of14C during and following inhalation exposure to radio-active toluene diisocyanate. Toxicol. Appl. Pharmacol. 1989; 100: 286–292.

    Article  Google Scholar 

  4. Kennedy AL, Wilson TR, Stock MF, Alarie Y, Brown WE. Distribution and reactivity of inhaled14C labeled toluene diisocyanate (TDI) in rats. Arch. Toxicol. 1994; 68: 434–443.

    Article  PubMed  CAS  Google Scholar 

  5. Johnson M. The anti-inflammatory profile of fluticasone propionate. Allergy 1995; 50: s11–14

    Article  PubMed  CAS  Google Scholar 

  6. Karol MH, Jin R, Lantz RC. Immunohistochemical detection of toluene diisocyanate (TDI) adducts in pulmonary tissue of guinea pigs following inhalation exposure. Inhal. Toxicol. 1997; 9: 63–83.

    Article  CAS  Google Scholar 

  7. Jin R, Day BW, Karol MH. Toluene diisocyanate protein adducts in the bronchoalveolar lavage of guinea pigs exposed to vapors of the chemical. Chem. Res. Toxicol. 1993; 6: 906–912.

    Article  PubMed  CAS  Google Scholar 

  8. Sepai O, Schutze D, Heinrich U, Henschler D, Sabbioni G. Hemoglobin adducts and urine metabolites of 4,4′-methylendianiline after 4,4′-methylendiphenyl diisocyanate exposure of rats. Chem. Biol. Interact 1995; 97: 185–198.

    Article  PubMed  CAS  Google Scholar 

  9. Day BW, Jin R, Karol M.In vivo andin vitro reaction of toluene diisocyanate isomers with guinea pig hemoglobin. Chem. Res. Toxicol. 1996; 9: 568–573.

    Article  PubMed  CAS  Google Scholar 

  10. Day BW, Jin R. Formation, solvolysis, and transcarbamylation reactions of bis (S-glutathionyl) adducts of 2,4- and 2,6-diisocyanate toluene. Chem. Res. Toxicol. 1997; 10: 424–431.

    Article  PubMed  CAS  Google Scholar 

  11. Sabbioni G, Hartley R, Henschler D, Hollrigl-Rosta A, Schneider S. Isocyanate-specific hemoglobin adduct in rats exposed to 4,4′-methylenediphenyl diisocyanate. Chem. Res. Toxicol. 2000; 13: 82–89.

    Article  PubMed  CAS  Google Scholar 

  12. Bailey E, Brooks AG, Bird I, Farmer PB, Street B. Monitoring exposure to 4,4′-methylendianiline by the gas chromatographymass spectrometry determination of adducts to hemoglobin. Anal. Biochem. 1990; 190: 175–181.

    Article  PubMed  CAS  Google Scholar 

  13. Sepai O, Henshler D, Sabbioni G. Albumin adducts, hemoblobin adducts and urinary metabolites in workers exposed to 4,4′-methylendiphenyl diisocyanate. Carcinogenesis 1995; 16: 2583–2587.

    Article  PubMed  CAS  Google Scholar 

  14. Redlich CA, Karol MH, Graham C, Homer RJ, Holm CT, Wirth JA, Cullen MR. Airway isocyanate-adducts in asthma induced by exposure to hexamethylene diisocyanate. Scand. J. Work Environ. Health 1997; 23: 227–231.

    PubMed  CAS  Google Scholar 

  15. Lind P, Dalene M, Lindstrom V, Grubb A, Skarping G. Albumin adducts in plasma from workers exposed to toluene diisocyanate. Analyst 1997; 122: 151–154.

    Article  PubMed  CAS  Google Scholar 

  16. Czuppon AB, Marczynski B, Baur X. Detection of protein changes in serum of workers following inhalation exposure to toluene diisocyanate vapors. Toxicol. Ind. Health 1992; 8: 407–413.

    PubMed  CAS  Google Scholar 

  17. Saetta M, Maestrelli P, Di Stefano A, De Marzo N, Milani GF, Pivirotto F, Mapp CE, Fabbri LM. Effect of cessation of exposure to toluene diisocyanate (TDI) on bronchial mucosa of subjects with TDI-induced asthma. Am. Rev. Respir. Dis. 1992; 145: 169–174.

    PubMed  CAS  Google Scholar 

  18. Saetta MA, Di Stefano, Maestrelli PN, De Marzo, Milani GF, Pivirotto F, Mapp CE, Fabbri LM. Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate. Am. Rev. Respir. Dis. 1992; 145: 160–168.

    PubMed  CAS  Google Scholar 

  19. Vock EH, Hoymann HG, Heinrich U, Lutz WK. P-Postlabeling of a DNA adduct derived from 4,4′-methylendianiline in the olfactory epithelium of rats exposed by inhalation to 4,4′-methylendiphenyl diisocyanate. Carcinogenesis 1996; 17: 1069–1073.

    Article  PubMed  CAS  Google Scholar 

  20. Marczynski B, Czuppon AB, Marek W, Baur X. Indication of DNA strand breaks in human white blood cells after in vitro exposure to toluene diisocyanate (TDI). Toxicol. Ind. Health 1992; 8:157–169.

    PubMed  CAS  Google Scholar 

  21. Marczynski B, Czuppon AB, Hoffarth HP, Marek W, Baur X. DNA damage in human white blood cells after inhalative exposure to methylendiphenyl diisocyanate (MDI)-Case report. Toxicol. Lett. 1992; 60: 131–138.

    Article  PubMed  CAS  Google Scholar 

  22. Marczynski B, Czuppon AB, Schreiber GH, Marek W, Baur X. DNA double-strand breaks and apoptosis after in vitro exposure to toluene diisocyanate. Toxicol. In. Vitro 1993; 7: 531–535.

    Article  CAS  Google Scholar 

  23. Vock EH, Vamvakas S, Gahlmann R, Lutz WK. Investigation of the induction of DNA double strand breaks by methylenediphenyl-4,4′-diisocyanate in cultured human lung epithelial cells. Toxicol. Sci. 1998; 46: 83–89.

    Article  PubMed  CAS  Google Scholar 

  24. Czuppon AB, Marczynski B, Scheer E, Hartmann R, Baur X. Increased incidence of anti-dsDNA autoantibody concentration in sera of workers occupationally exposed to diisocyanates. Toxicol. Lett. 1993; 66: 29–34.

    Article  PubMed  CAS  Google Scholar 

  25. Gamer AO, Hellwig J, Doe JE, Tyl RW. Prenatal toxicity of inhaled polymeric methylenediphenyl diisocyanate (MDI) aerosols in pregnant Wister rats. Toxicol. Sci. 2000; 54: 431–440.

    Article  PubMed  CAS  Google Scholar 

  26. Ito N, Hiasa Y, Konishi Y, Marugami M. The deveropment of carcinoma in liver of rats treated with m-toluylenediamine and the synergistic and antagonistic effects with other chemicals. Cancer. Res. 1969; 29: 1137–1145.

    PubMed  CAS  Google Scholar 

  27. Schoental R. Carcinogenic and chronic effects of 4,4′-diamino-diphenylmethane, an epoxyresin hardener. Nature 1968; 219: 1162–1163.

    Article  PubMed  CAS  Google Scholar 

  28. Doe JE, Hoffmann HD. Toluene diisocyanate: an assessment of carcinogenic risk following oral and inhalation exposure. Toxicol. Ind. Health 1995; 11: 13–32.

    PubMed  CAS  Google Scholar 

  29. Maki-Paakkanen J, Norppa H. Chromosome aberrations and sister-chromatid exchanges induced by technical grade toluene diisocyanate and methylenediphenyl diisocyanate in cultured human lymphocytes. Toxicol. Lett. 1987; 36: 37–43.

    Article  PubMed  CAS  Google Scholar 

  30. Gulati DK, Witt K, Anderson E, Zeiger E, Shelby MD. Chromosome aberration and sister chromatid exchange tests in Chinese hamster ovary cells in vitro III: Results with 27 chemicals. Environ. Mol. Mutagen. 1989; 13: 133–193.

    Article  PubMed  CAS  Google Scholar 

  31. The International Agency for Research on Cancer (IARC). Toluene diisocyanate. IARC Monogr. Eval. Carcinog. Risks Hum. 1999; 71 Pt 2: 865–879.

    Google Scholar 

  32. The International Agency for Research on Cancer (IARC). 4,4′-Methylenediphenyl diisocyanate and polymeric 4,4′-methylenediphenyl diisocyanate. IARC Monogr. Eval. Carcinog. Risks Hum. 1999; 71 Pt 3: 1049–1058.

    Google Scholar 

  33. Anderson D, Styles JA. The bacterial mutation test. Six tests for carcinogenicity. Br. J. Cancer. 1978; 37: 924–930.

    PubMed  CAS  Google Scholar 

  34. Andersen M, Binderup ML, Kiel P, Larsen H, Maxild J. Mutagenic action of isocyanates used in the production of polyurethanes. Scand. J. Work Environ. Health 1980; 6: 221–226.

    PubMed  CAS  Google Scholar 

  35. Foureman P, Mason JM, Valencia R, Zimmering S. Chemical mutagenesis testing inDrosophila. X. Results of 70 coded chemicals tested for National Toxicology Program. Environ. Mol. Mutagen. 1994; 23: 208–227.

    Article  PubMed  CAS  Google Scholar 

  36. Shimizu H, Suzuki Y, Takemura N, Goto S, Matsushima H. The results of microbial mutation test for forty-three industrial chemicals. Jpn. J. Ind. Health 1985; 27: 400–419.

    CAS  Google Scholar 

  37. Herbold B, Haas P, Seel K, Walber U. Studies on the effect of the solvents dimethylsulfoxide and ethyleneglycoldimethylether on the mutagenicity of four types of diisocyanates in Salmonella/microsome test. Mutat. Res. 1998; 412: 167–175.

    PubMed  CAS  Google Scholar 

  38. Seel K, Walber U, Herbold B. Chemical behavior of seven aromatic diisocyanates (toluenediisocyanates and diphenylmethanediisocyanates) under in vitro conditions in relationship to their results in the Salmonella/microsome test. Mutat. Res. 1999; 438: 109–123.

    PubMed  CAS  Google Scholar 

  39. Baur X, Marek W, Ammon J, Czuppon AB, Marczynski B, Raulf-Heimsoth M, Roemmelt H, Fruhmann G. Respiratory and other hazards of isocyanate. Int. Arch. Occup. Environ. Health 1994; 66: 141–152.

    Article  PubMed  CAS  Google Scholar 

  40. Hagmar L, Welinder H, Mikoczy Z. Cancer incidence and mortality in the Swedish polyurethane foam manufacturing industry. Br. J. Ind. Med. 1993; 50: 537–543.

    PubMed  CAS  Google Scholar 

  41. Hagmar L, Stromberg U, Welinder H, Mikoczy Z. Incidence of cancer and exposure to toluene diisocyanate and methylene diphenyldiisocyanate: A cohort based case referent study in the polyurethane foam manufacturing industry. Br. J. Ind. Med. 1993; 50: 1003–1007.

    PubMed  CAS  Google Scholar 

  42. Sorohan T, Pope D. Mortality and cancer mortality of production workers in the United Kingdom flexible polyurethane foam industry. Br. J. Ind. Med. 1993; 50: 528–536.

    Google Scholar 

  43. Frew AJ. The immunology of respiratory allergies. Toxicol. Lett. 1996; 86: 65–72.

    Article  PubMed  CAS  Google Scholar 

  44. Blaikie L, Morrow T, Wilson AP, Hext P, Hartop PJ, Rattray NJ, Woodcock D, Botham PA. A two-centre study for the evaluation and validation of an animal model for the assessment of the potential of small molecular weight chemicals to cause respiratory allergy. Toxicology 1995; 96: 37–50.

    Article  PubMed  CAS  Google Scholar 

  45. Ban M, Hettich D, Goutet M, Bonnet P. TDI inhalation in guineapigs involves migration of dendritic cells. Toxicol. Lett. 1997; 93: 185–194.

    Article  PubMed  CAS  Google Scholar 

  46. Hesbert A, Ban M, Bonnet P, Bottin MC, Lemonnier M, De Ceaurriz J. Interdependence of polymophonuclear neutrophils and macrophages stained for N-acetyl-β-glucosaminidase in lavage effluents from toluene diisocyanate exposed rat lungs. Toxicol. Lett. 1991; 56: 53–59.

    Article  PubMed  CAS  Google Scholar 

  47. Labow RS, Meek E, Santerre JP. Differential synthesis of cholesterol esterase by monocyte-derived macrophages cultured on poly (ether or ester)-based poly (urethane)s. J. Biomed. Mater. Res. 1998; 39: 469–477.

    Article  PubMed  CAS  Google Scholar 

  48. Young RP, Barker RD, Pile KD, Cockson OCM, Newman Taylor JA. The association of HLA-DR3 with specific IgE to inhaled acid anhydrides. Am. J. Respir. Crit. Care. Med. 1995; 151: 219–221.

    PubMed  CAS  Google Scholar 

  49. Sandford A, Weir T, Pare P. The genetics of asthma. Am. J. Respir. Crit. Care. Med. 1996; 153: 1749–1765.

    PubMed  CAS  Google Scholar 

  50. Bernstein JA, Munson J, Lummus ZL, Balakrishnan K, Leikauf G. T-cell receptor Vβ gene segment expression in diisocyanate-induced occupational asthma. J. Allergy. Clin. Immunol. 1997; 99: 245–250.

    Article  PubMed  CAS  Google Scholar 

  51. Bignon JS, Aron Y, Lu LY, Kopferschmit MC, Garnier R, Mapp CE, Fabbri LM, Pauli G, Lockhart A, Charron D, Swierezewski E. HLA class II alleles in isocyanate-induced asthma. Am. J. Respir. Crit. Care. Med. 1994; 149: 71–75.

    PubMed  CAS  Google Scholar 

  52. Balboni A, Baricordi OR, Fabbri LM, Gandini E, Ciaccia A, Mapp CE. Association between toluene diisocyanate-induced asthma and DQB1 markers: a possible role for aspartic acid at position 57. Eur. Respir. J. 1996; 9: 207–210.

    Article  PubMed  CAS  Google Scholar 

  53. Mapp CE, Balboni A, Baricordi R, Fabbri LM. Human leukocyte antigen associations in occupational asthma induced by isocyanates. Am. J. Respir. Crit. Care. Med. 1997; 156: s139–143.

    Google Scholar 

  54. Bernstein JA. Overview of diisocyanate occupational asthma. Toxicology 1996; 111: 181–189.

    Article  PubMed  CAS  Google Scholar 

  55. Rihs HP, Barbalho Krolls T, Huber H, Baur X. No evidence for the influence of HLA class II alleles in isocyanate-induced asthma. Am. J. Ind. Med. 1997; 32: 1–6.

    Article  Google Scholar 

  56. Robinson DS, Hamid Q, Bentley AM, Ying S, Kay AB, Durham SR. Activation of CD4+ T cells, increased Th2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J. Allergy Clin. Immunol. 1993; 92: 313–324.

    Article  PubMed  CAS  Google Scholar 

  57. Romagnani S. Biology of human Th1 and Th2 cells. J. Clin. Immunol. 1995; 15: 121–129.

    Article  PubMed  CAS  Google Scholar 

  58. Dearman RJ, Basketter DA, Kimber I. Variable effects chemical allergens on serum IgE concentration in mice. Preliminary evaluation of a novel approach to the identification of respiratory sensitizers. J. Appl. Toxicol. 1992; 12: 317–323.

    Article  PubMed  CAS  Google Scholar 

  59. Dearman RJ, Spence LM, Kimber I. Characterization of murine immune responses to allergic diisocyanate. Toxicol. Appl. Pharmacol. 1992; 112: 190–197.

    Article  PubMed  CAS  Google Scholar 

  60. Dearman RJ, Basketter DA, Kimber I. Characterization of chemical allergens as a function of divergent cytokine secretion profiles induced in mice. Toxicol. Appl. Pharmacol. 1996; 138: 308–316.

    Article  PubMed  CAS  Google Scholar 

  61. Dearman RJ, Moussavi A, Kemeny DM, Kimber I. Contribution of CD4+ and CD8+T lymphocyte subsets to the cytokine secretion patterns induced in mice during sensitization to contact and respiratory chemical allergens. Immunol. 1996; 89: 502–510.

    Article  CAS  Google Scholar 

  62. Finoto S, Fabbri LM, Rado V, Mapp CE, Maestrelli P. Increase in numbers of CD8 positive lymphocytes and eosinophils in peripheral blood of subjects with late asthmatic reactions induced by toluene diisocyanate. Br. J. Ind. Med. 1991; 48: 116–121.

    Google Scholar 

  63. Walker C, Bode E, Boer L, Hansel T, Blaser K, Virchow J Jr. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am. Rev. Respir. Dis. 1992; 148: 109–115.

    Google Scholar 

  64. Maestrelli P, Occari P, Turato G, Papiris SA, Di Stefano A, Mapp CE, Milani GF, Fabbri LM, Saetta M. Expression of interleukin (IL)-4 and IL-5 proteins in asthma induced by toluene diisocyanate (TDI). Clin. Exp. Allergy 1997; 27: 1292–1298.

    Article  PubMed  CAS  Google Scholar 

  65. Maestrelli P, Saetta M, Mapp CE, Fabbri LM. Mechanisms of occupational asthma. Clin. Exp. Allergy 1997; 27: 47–54.

    Article  PubMed  CAS  Google Scholar 

  66. Fabbri LM, Maestrelli P, Saetta M, Mapp CE. Mechanisms of occupational asthma. Clin. Exp. Allergy 1994; 24: 628–635.

    Article  PubMed  CAS  Google Scholar 

  67. Maestrelli P, Del prete GF, De Carli M, D'Elios MM, Saetta M, Di Stefano A, Mapp CE, Romagnani S, Fabbri LM. CD-8 T-cells clones producing interleukin-5 and interferon-gamma in bronchial mucosa of patients with asthma induced by toluene-diisocyanate. Scand. J. Work Environ. Health 1994; 20: 376–381.

    PubMed  CAS  Google Scholar 

  68. Satoh T, Kramarik JA, Tollerud DJ, Karol MH. A murine model for assessing the respiratory hypersensitivity potential of chemical allergens. Toxicol. Lett. 1995; 78: 57–66.

    Article  PubMed  CAS  Google Scholar 

  69. Orloff KG, Batts Osborne D, Kilgus T, Metcalf S, Cooper M. Antibodies to toluene diisocyanate in an environmentally exposed population. Environ. Health Perspect. 1998; 106: 665–666.

    Article  PubMed  CAS  Google Scholar 

  70. Nagai S. Pathogenesis of hypersensitivity pneumonitis. Igaku No Ayumi 1992; 162: 736–739. [in Japanese].

    Google Scholar 

  71. Yoshizawa Y, Ohtsuka M, Noguchi K, Uchida Y, Suko M, Hasegawa S. Hypersensitivity pneumonitis induced by toluene diisocyanate: sequelate of continuous exposure. Ann. Intern. Med. 1989; 110: 31–34.

    PubMed  CAS  Google Scholar 

  72. Baur X, Chen Z, Flagge A, Posch A, Raulf-Heimsoth M. EAST and CAP specificy for the evaluation of IgE and IgG antibodies to diisocyanate-HAS conjugates. Int. Arch. Allergy Immunol. 1996; 110: 332–338.

    Article  PubMed  CAS  Google Scholar 

  73. Baur X. Hypersensitivity pneumonitis (extrinsic allergic alveolitis) induced by isocyanates. J. Allergy Clin. Immunol. 1995; 95: 1004–1010.

    Article  PubMed  CAS  Google Scholar 

  74. Nakashima K, Takeshita T, Morimoto K. Occupational hypersensitivity pneumonitis due to isocyanates: Mechanisms of action and case reports in Japan. Industrial. Health 2001; 39: 269–279.

    Article  PubMed  CAS  Google Scholar 

  75. Thompson T, Belsito DV. Allergic contact dermatitis from a diisocyanate in wool processing. Contact Dermatitis. 1997; 37: 239.

    Article  PubMed  CAS  Google Scholar 

  76. Desrosiers M, Nguyen B, Ghezzo H, Leblanc C, Malo JL. Nasal response in subjects undergoing challenges by inhaling occupational agents causing asthma through the nose and mouth. Allergy 1998; 53: 840–848.

    Article  PubMed  CAS  Google Scholar 

  77. Nosko M, Altunkova I, Baltadjieva D, Liapin M, Bocheva S, Tanev M. Immune mechanisms of the occupational sensitization with methylen-dyphenyl diisocyanate (MDI). Cent. Eur. J. Public. Health 1998: 199–201.

  78. Nishimura T, Tani T. On the skin manifestation caused by toluene-diisocyanate (TDI). Hifu To Hinyou 1964; 26: 56–63 [in Japanese].

    Google Scholar 

  79. Miki T, Shima S, Tachikawa S, Yoshida T, Ito T, Kudo T. Health hazards in workers of small scale polyurethane production factory. Sangyo Igaku. 1986; 28: 128–129 [in Japanese].

    PubMed  CAS  Google Scholar 

  80. Liu Y, Sparer J, Woskie SR, Cullen MR, Chung JS, Holm CT, Redlich CA. Quantitative assessment of isocyanate skin exposure in auto body shops: A pilot study. Am. J. Ind. Med. 2000; 37: 264–274.

    Article  Google Scholar 

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Nakashima, K., Takeshita, T. & Morimoto, K. Review of the occupational exposure to isocyanates: Mechanisms of action. Environ Health Prev Med 7, 1–6 (2002). https://doi.org/10.1007/BF02898058

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