Haneen Hamada – Experimental and Clinical Studies on Contact Allergy to Diphenylmethane-4,4’-diisocyanate and Related Substances
concurrent reactions are due to co-exposure or possible cross-reactivity. Patch test preparations of 4,4’-MDI have been shown to contain only fractions of what is stated. Concentrations of 4,4’-MDI in test preparations decrease rapidly.
The aims of this thesis were:( i) to study the dermal uptake and metabolism of isocyanates by dermal provocation of volunteers with different doses of 4,4’-MDI;( ii) to investigate the sensitizing capacities and cross-reactivity patterns of some common isocyanates and the corresponding amines in order to provide a better understanding of isocyanate contact allergy; and( iii) to investigate the cause behind the rapid decrease in 4,4’-MDI in patch-test preparations.
The main findings were as follows:( i) The distribution after dermal uptake of diphenylmethane-4,4’-diisocyanate( 4,4’- MDI) appears to be a slower process than what is seen for airway uptake. Instead, our results indicated that the distribution of 4,4’-MDI in the skin and the subsequent elimination is a slow process, and the proportion absorbed into the skin was approximately half of the amount applied. The main amount absorbed reacts with cell components or forms polyurea and is probably released as diphenylmethane-4,4’-diamine( 4,4’- MDA) by spontaneous or enzymatic hydrolysis over weeks or months, distributed systemically, and finally eliminated. A proportion of reacted 4,4’-MDI is probably eliminated from the skin upon cellular renewal. Patch testing with freshly made preparations of 2 % 4,4’-MDI might lead to active sensitization. Thus, a concentration of 0.5 % in pet., which has been recommended by the European Society for Contact Dermatitis( ESCD) based on our results, should be used( Papers I and II).( ii) 4,4’-MDI, 4,4’-MDA, dicyclohexylmethane-4,4’-diisocyanate( 4,4’-DMDI), dicyclohexylmethane-4,4’-diamine( 4,4’-DMDA), and p-phenylene diamine( PPD) are strong sensitizers among our group of sensitizers. 4,4’-MDI sensitized animals cross-react to 4,4’-MDA and to 4,4’-DMDI and animals sensitized to 4,4’-MDA cross-reacted to 4,4’-DMDA. PPD-sensitized animals showed cross-reactivity to 4,4’-MDA and there was an indication of cross-reactivity to 4,4’-DMDA. 4,4’-MDI-sensitized animals did not show cross-reactivity to PPD, so PPD cannot be used as a marker of 4,4’-MDI allergy.( iii) 4,4’-MDI reacts with water, protein, or other components found in Freund’ s complete adjuvant used in the Guinea Pig
Maximization Test( GPMT). Aged, pure 4,4’-MDI is instable, even when stored in the freezer. The outcome of 4,4’-MDI sensitization in the GPMT might be affected by the instability of the pure substance and also its reaction with Freund’ s complete adjuvant. Induction substances should be prepared in close connection with the intradermal injection( Papers III, IV, and V).( iv) Evaporation and reaction with water can be excluded as significant factors for the instability of the 4,4’-MDI patch test preparations. Most data indicate that trimerization and perhaps also dimerization is the main factor influencing this instability. The 4,4’-MDI trimer might be a weak allergen due to the higher molecular weight making it more difficult to penetrate through the skin. Since many patients have been patch tested with aged 4,4’-MDI patch test preparations( where the patients do not react), we can conclude that if the trimer is present, it does not cross-react with 4,4’-MDI( Paper VI).
List of publications
I. Hamada H, Isaksson M, Bruze M, Engfeldt M, Liljelind I, Axelsson S, et al. Dermal uptake study with 4,4 ′-diphenylmethane diisocyanate led to active sensitization. Contact Dermatitis 2013: 66: 101 – 105
II. Hamada H, Liljelind I, Bruze M, Engfeldt M, Isaksson M, Jönsson B, et al. Assessment of dermal uptake of diphenylmethane-4,4 ′-diisocyanate using tape stripping and biological monitoring. Eur J Dermatol( in print).
III. Hamada H, Bruze M, Zimerson E, Isaksson M, Engfeldt M. Sensitization and cross-reactivity patterns of contact allergy to diisocyanates and corresponding amines. Investigation of diphenylmethane-4,4 ′-diisocyanate, diphenylmethane-4,4 ′-diamine, dicyclohexylmethane-4,4 ′-diisocyanate, and dicylohexylmethane4,4 ′-diamine. Contact Dermatitis. 2017 May 29. doi: 10.1111 / cod. 12809. [ Epub ahead of print ] PMID: 28555927.
IV. Hamada H, Bruze M, Zimerson E, Isaksson M, Engfeldt M. Sensitizing capacities and cross-reactivity patterns of some diisocyanates and amines using the guinea pig maximization test. Can p-phenylenediamine be used as a marker for diisocyanate contact allergy? Submitted.
V. Hamada H, Bruze M, Zimerson E, Isaksson M, Engfeldt M. Factors affecting the concentration of diphenylmethane-4,4 ′- diisocyanate in Freund’ s complete adjuvant. Can they affect the outcome of the guinea pig maximization test? J Clin Exp Dermatol Res 2017; 8: 402.
VI. Hamada H, Engfeldt M, Bruze M, Isaksson M, Zimerson E. The mystical instability of diphenylmethane-4,4 ′-diisocyanate( 4,4 ′- MDI) in petrolatum patch test preparations used for diagnoses of contact allergy. In manuscript.
22 Dissertation
Forum for Nord Derm Ven 2018, Vol. 23, No. 1