Carcinogenic risk of toluene diisocyanate and 4,4'-methylenediphenyl diisocyanate: epidemiological and experimental evidence

Crit Rev Toxicol. 2001 Nov;31(6):737-72. doi: 10.1080/20014091111974.


Diisocyanates are highly reactive compounds widely used, for example, in the production of polyurethane foams, elastomers, paints, and adhesives. The high chemical reactivity of these compounds is also reflected in their toxicity: diisocyanates are one of the most important causes of occupational asthma but also other adverse effects, such as irritation and toxic reactions, have been described in exposed subjects. One of the open questions is whether occupational isocyanate exposure is a carcinogenic hazard. The few epidemiological studies available have been based on young cohorts and short follow-up and are not conclusive. Toluene diisocyanate (TDI) has been classified as carcinogenic in animals on the basis of gavage administration studies, but no conclusions are available on inhalation exposure. For 4,4'-methylene diphenyldiisocyanate (MDI) there is suggestive evidence for carcinogenicity in rats. The possible carcinogenic mechanism of TDI and MDI is not clear. Both chemicals have been positive in a number of short-term tests inducing gene mutations and chromosomal damage. The reactive form could be either the diisocyanate itself or may derive from the metabolic activation of the aromatic diamine derivatives formed by hydrolysis. TDI and MDI react with DNA in vivo and in vitro. However, the structure of the adducts has not been identified. Especially from the in vivo experiment it is not known if the adducts are a product from the reaction with the isocyanate or the corresponding amine. In conclusion, both TDI and MDI are highly reactive chemicals that bind to DNA and are probably genotoxic. The alleged animal carcinogenicity of TDI and MDI would suggest that occupational exposure to these compounds is a carcinogenic risk. The few epidemiological studies available have not, however, been able to clarify if TDI and MDI are occupational carcinogens.

Publication types

  • Review

MeSH terms

  • Animals
  • Blood Proteins / drug effects
  • Carcinogenicity Tests
  • Carcinogens / metabolism
  • Carcinogens / toxicity*
  • Chemical Industry
  • DNA Adducts / drug effects
  • Female
  • Humans
  • Isocyanates / pharmacokinetics
  • Isocyanates / toxicity*
  • Male
  • Mutagenicity Tests
  • Neoplasms / chemically induced*
  • Neoplasms / metabolism
  • Occupational Exposure
  • Protein Binding
  • Salmonella typhimurium / drug effects
  • Salmonella typhimurium / genetics
  • Toluene 2,4-Diisocyanate / pharmacokinetics
  • Toluene 2,4-Diisocyanate / toxicity*


  • Blood Proteins
  • Carcinogens
  • DNA Adducts
  • Isocyanates
  • Toluene 2,4-Diisocyanate
  • 4,4'-diphenylmethane diisocyanate