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