Carcinogenic Risk of Toluene Diisocyanate and 4,4′-Methylenediphenyl Diisocyanate: Epidemiological and Experimental Evidence

Abstract

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.

Effect ofMoringa oleiferaLam. Seed Extract on Toluene Diisocyanate-Induced Immune-Mediated Inflammatory Responses in Rats

“…Although the pathogenesis of diisocyanate-induced asthma is still largely unknown (Baur et al, 1994;Bolognesi et al, 2001), increasing evidence from human and laboratory animal models has indicated that the OA induced by TDI shares several features with allergic asthma (Wisnewski and Redlich, 2001). Indeed intranasal instillation of TDI resulted in systemic T H 2-dominated immune responses characterized by lower T H 1 cytokines (IFNγ ) associated with a rise in T H 2 cytokines (IL-4, IL-5, IL-6, and TNFα).…”

Development of a biodegradable tissue adhesive based on functionalized 1,2‐ethylene glycol bis(dilactic acid). II.

“…19 Although this behavior would be beneficial for an adhesive the degradation or hydrolysis of adhesive systems based on aromatic diisocyanates results in formation of aromatic diamines that are known to be carcinogenic. 20 However, we have reported in a previous study that sufficient solidification speed can be achieved even with aliphatic diisocyanates when aqueous solution of chitosan chloride is used instead of pure water. 21 Chitosan chloride contains AOH and ANH 2 groups that enable reaction with isocyanate groups under formation of stable urethane or urea bonds and acceleration of solidification.…”

The role of isocyanates in fire toxicity

“…Isocyanates are not considered human carcinogens, although TDI is classified as an animal carcinogen and MDI as a suggested animal carcinogen (Rom & Markowitz 2007). Additionally, epidemiologic studies on mainly TDI and MDI foam production workers have not shown a higher prevalence for any cancer (Bolognesi et al 2001).…”

“…2) and 3) further decomposition of the materials to primary amines, secondary amines, vinyl esters and carbon dioxide. Adapted from Jiao et al (2013) (Jiao et al 2013) No (Nehez et al 1989) No (Nehez et al 1989 Severe (Vernot et al 1977) Severe (Vernot et al 1977) Toluene-2,4-diisocyanate (2,4-TDI) (Bolognesi et al 2001) No (Zocca et al 1990) Yes (Buschmann 1990) Insufficient evidence (Hughes et al 2014) Lungs (Hughes et al 2014) Irreversible decline in pulmonary function (Centers for Disease Cotrol and Prevention 2015e)…”