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Very little is known about the dermal uptake of isocyanates, and dermal exposure to isocyanates has been discussed as a factor involved in the induction of respiratory diseases. To investigate the dermal uptake of diphenylmethane-4,4'-diisocyanate (4,4'-MDI). Four volunteers were dermally exposed to 10, 25, 49 and 50 mg 4,4'-MDI, respectively, for eight hours. The exposed areas were tape stripped. Urine and blood were biologically monitored for 48 hours. Tape strips, plasma, and urine were analysed by liquid chromatography-mass spectrometry. In total, 35-70% of the applied dose of 4,4'-MDI was absorbed by the skin. Very low fractions of applied dose were found in the tape strips. The 4,4'-MDA concentration in plasma and urine was low, but peaked in urine at 10-14 hours and plasma at 8-32 hours after exposure. 4,4'-MDI is readily absorbed by human skin. Only small fractions of 4,4'-MDI remain as such in the superficial skin layers. The amounts found in blood and urine were only small fractions of the total applied doses which indicates that very small amounts of 4,4'-MDI penetrate the skin and reach the blood stream. The dermal uptake and distribution of 4,4'-MDI is much slower compared to that associated with airway uptake. Our data strongly indicate that formation of 4,4'-MDA from 4,4'-MDI upon reacting with water in the skin can only occur to a very limited extent.

Background: The animal assay Guinea Pig Maximization Test (GPMT) uses Freund’s complete adjuvant (FCA) to enhance the dermal sensitization in the animals. In a previous study, the degree of sensitization when investigating diphenylmethane-4,4′-diisocyanate (4,4′-MDI) varied. 4,4′-MDI is known to be a reactive diisocyanate and concern was risen that its instability and reaction with FCA might affect the outcome. Objectives: To investigate the stability of 4,4′-MDI and its possible reaction with components in FCA. Methods: The same preparations as used in the GPMT were prepared, i.e. 1.0% w/v 4,4ʹ-MDI in FCA/paraffin oil (40/60 v/v) and stored under different conditions for 48 hours. The content of 4,4′-MDI in both FCA/paraffin oil mixtures as well as in samples of pure substance were monitored by chemical analysis using gel permeation chromatography (GPC). Results: The 4,4′-MDI content in pure substance can decrease substantially within a few months. A rapid decrease in 4,4′-MDI concentration was also seen in 4,4′-MDI/FCA preparations stored in refrigerator and room temperature. Conclusion: The outcome of 4,4ʹ-MDI sensitization in GPMT might be affected by the instability of the pure substance as well as its reaction with FCA. Major effects can be expected if these two factors are interacting. Hence, fresh 4,4ʹ-MDI should be used and preparations of induction substances should be prepared in close connection to the intradermal injection.

We have previously shown that the concentration of diphenylmethane-4,4'-diisocyanate (4,4'-MDI) in commercial test preparations was so low that patch testing with the same was not reliable. The stability of 4,4'-MDI in petrolatum (pet.) was compared with pet. preparations of polymeric diphenylmethane diisocyanate (PMDI), which consists of a complex mixture of monomeric isomers and oligomers of MDI. Preparations of 4,4'-MDI and PMDI were stored under 3 different conditions, i.e. at room temperature, refrigerated and frozen. They were analysed continuously during 1 year with regard to the content of 4,4'-MDI, 3-ring oligomers and 4-ring oligomers using liquid chromatography-mass spectrometry. PMDI preparations kept frozen were stable for a year. All other preparations failed to fulfil the requirements of stability, i.e. +/- 20% of the initial concentration. Storage in a freezer prolonged the lifetime for 4,4'-MDI. The decrease in concentration for preparations kept at room temperature and refrigerated was less rapid in PMDI preparations than in 4,4'-MDI preparations. PMDI preparations are better suited for patch testing patients exposed to MDI because they are more stable and homogeneous than 4,4'-MDI preparations. They better reflect possible allergens that workers are exposed to because products used in industry contain both monomers and oligomers.

Allergic asthma is a complex chronic inflammatory disease of the airways and its etiology is multifactorial. It involves the recruitment and activation of many inflammatory and structural cells, all of which release inflammatory mediators that result in typical pathological changes of asthma. The features of asthma addressed in this Brown Norway (BN) rat animal model include an analysis of cellular infiltrations in the lung, inflammatory factors in bronchoalveolar lavage (BAL), total immunoglobulin E (IgE) production in serum, and changes in delayed-onset respiratory reactions upon four inhalation challenges (every 2 wk) with polymeric diphenylmethane diisocyanate (MDI) aerosol in two groups of topically sensitized rats. The dependence on the induction-related variables was analyzed by using almost identical surface area doses but different total doses per animal. This regimen caused acute exacerbations of delayed-onset respiratory reactions, for which intensity increased with each challenge. After the fourth challenge BAL neutrophils, lymphocytes, eosinophils, cell counts, protein, and lactate dehydrogenase (LDH) as well as lung weights were significantly increased in sensitized rats relative to naive but challenged controls. Histopathology revealed activated bronchial lymphatic tissue, increased recruitment of inflammatory cells, the beginning of peribronchial/peribronchiolar fibrosis, thickening of alveolar septae, and vascular hypertrophy. Total IgE in serum was significantly increased in sensitized rats. Thus, high-dose topical induction to, and repeated inhalation challenges with, MDI was associated with a marked neutrophilic and a less consistent eosinophilic inflammatory response. With regard to the relative sensitivity of endpoints, those that integrate independently a series of complex physiological events appeared to be most practical to probe positive responses in this animal model. These include postchallenge changes in Penh to identify respiratory responses delayed in onset as well as inflammatory changes in BAL. In summary, this extension of a previous study that used 16 mg MDI/m(3) instead of 39 mg MDI/m(3) that was used in the current study for challenge exposures demonstrates that protocol variables are most critical for the outcome of test. Moreover, the sensitivity of this bioassay to define the typical asthma phenotype can be markedly improved by measurements of respiratory responses delayed in onset rather than immediate in onset. Accordingly, to increase the efficacy of this asthma model moderately irritant concentrations of the hapten have to be used for challenge and at least three to four adequately spaced challenge exposures are required to elicit a typical asthma phenotype.