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Chemical and Clinical Studies of Isocyanate Contact Allergy with focus on diphenylmethane diisocyanate

Engfeldt, Malin LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series 2007:30.
Abstract
Isocyanates are highly reactive compounds used in the production of polyurethane. Exposure to isocyanates is mainly associated with respiratory disorders, but may also result in allergic contact dermatitis. Reports describing contact allergy to isocyanates are few in number and it has been considered a rare phenomenon. In the present study it is shown that the low frequency of reported cases could partly be explained by weaknesses in the method used to detect contact allergy arising from isocyanates, i.e. patch testing with the commercially available isocyanate series. These series generally comprise petrolatum preparations of the four diisocyanates diphenylmethane-4,4'-diisocyanate (4,4'-MDI), 2,4-toluene diisocyanate (2,4-TDI),... (More)
Isocyanates are highly reactive compounds used in the production of polyurethane. Exposure to isocyanates is mainly associated with respiratory disorders, but may also result in allergic contact dermatitis. Reports describing contact allergy to isocyanates are few in number and it has been considered a rare phenomenon. In the present study it is shown that the low frequency of reported cases could partly be explained by weaknesses in the method used to detect contact allergy arising from isocyanates, i.e. patch testing with the commercially available isocyanate series. These series generally comprise petrolatum preparations of the four diisocyanates diphenylmethane-4,4'-diisocyanate (4,4'-MDI), 2,4-toluene diisocyanate (2,4-TDI), 1,6-hexamethylene diisocyanate (1,6-HDI) and isophorone diisocyanate (IPDI), as well as two corresponding amines, 4,4'-diaminodiphenylmethane (4,4'-MDA) and isophorone diamine (IPDA).



The following results are reported in the thesis. (i) Chemical analyses of isocyanate series obtained from four American and nine European patch testing departments showed that patch test preparations of 2,4-TDI, 1,6-HDI and IPDI contained the declared concentrations, but the concentration of 4,4'-MDI was generally so low that patch testing with it could not be considered reliable. (ii) A stability study showed that preparations of technical grade MDI, i.e. polymeric MDI (PMDI), were more stable and more homogeneous than preparations of pure 4,4'-MDI during the course of a year. (iii) A patch test study revealed that PMDIs rendered as many positive reactions as 4,4'-MDI, (iv) that positive reactions to 4,4'-MDI and PMDI appear late, i.e. after day 3 and sometimes also after day 7, and (v) that the amine 4,4'-MDA is a good marker for 4,4'-MDI contact allergy.



In order to optimize patch testing with isocyanates it is thus recommended that patients be tested with their own work products containing technical grade isocyanates since they better reflect the possible allergens that patients are in fact exposed to. It is not yet known if the isomers presently used in commercial preparations are the most potent allergens in technical grade products or if there are other monomers and/or oligomers that cause skin problems. When contact allergy to MDI is suspected patients can also be tested with 4,4'-MDA since it is a marker for 4,4'-MDI contact allergy. Isocyanate patch tests should be read on day 3 or 4 as well as on day 7. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

I detta arbete studerades olika aspekter av lapptestdiagnostiken vid misstänkt kontaktallergi mot en grupp ämnen som kallas isocyanater. Dessa ämnen innehåller reaktiva isocyanatgrupper med den kemiska strukturen -N=C=O. Isocyanater används framförallt vid tillverkningen av polyuretan (PUR) som bildas när iso-cyanater reagerar med flerfunktionella alkoholer till en polymer. PUR-produkter är några av de vanligaste plastmaterialen i vår omgivning och förekommer som t ex lack, färg, lim och som skumgummi i möbler och madrasser. Vid framställningen av PUR-produkter finns det stor risk för isocyanatexponering. Den mest välkända risken med isocyanater är effekten på luftvägarna där man löper risk att... (More)
Popular Abstract in Swedish

I detta arbete studerades olika aspekter av lapptestdiagnostiken vid misstänkt kontaktallergi mot en grupp ämnen som kallas isocyanater. Dessa ämnen innehåller reaktiva isocyanatgrupper med den kemiska strukturen -N=C=O. Isocyanater används framförallt vid tillverkningen av polyuretan (PUR) som bildas när iso-cyanater reagerar med flerfunktionella alkoholer till en polymer. PUR-produkter är några av de vanligaste plastmaterialen i vår omgivning och förekommer som t ex lack, färg, lim och som skumgummi i möbler och madrasser. Vid framställningen av PUR-produkter finns det stor risk för isocyanatexponering. Den mest välkända risken med isocyanater är effekten på luftvägarna där man löper risk att utveckla t ex bronkit och astma. Mindre välkänt är att isocyanatexponering även kan ge upphov till kontakt-allergi. Antalet rapporterade fall av kontaktallergi mot isocyanater är dock lågt och gruppens hudpåverkande effekt har i allmänhet ansetts låg. I avhandlingen påvisas brister i den metod som för närvarande används för att detektera kontaktallergier mot isocyanater, dvs lapptestning med kommersiella isocyanatserier. Dessa brister skulle till viss del kunna förklara den låga frekvensen av kontaktallergier mot vissa isocyanater. I kommersiella isocyanatserier ingår vaselinberedningar av fyra isocyanater difenylmetan-4,4'-diisocyanat (4,4'-MDI), 2,4-toluendiisocyanat (2,4-TDI), 1,6-hexametylendiisocyanat (1,6-HDI) samt isoforondiisocyanat (IPDI) och i två fall även deras motsvarande aminföreningen, 4,4'-diaminodifenylmetan (4,4'-MDA) och isoforondiamin (IPDA).



Följande resultat rapporteras i avhandlingen: (i) Kemiska analyser av isocyanatserier som användes vid 4 amerikanska och 9 europeiska hudkliniker visade att testberedningar innehållande 2,4-TDI, 1,6-HDI samt IPDI i de flesta fall hade en koncentration motsvarande den deklarerade medan beredningar innehållande 4,4'-MDI i samtliga fall hade en koncentration som var långt under den deklarerade och att man vid användning av dessa löper en mycket stor risk att misslyckas med att påvisa kontaktallergi mot MDI. (ii) En stabilitetsstudie visade att beredningar av en teknisk variant av MDI (PMDI) var mer stabila och mer homogena än beredningar av ren 4,4'-MDI. En lappteststudie visade att (iii) beredningar av PMDI fångade lika många positiva reaktioner som beredningar av ren 4,4'-MDI; att (iv) positiva reaktioner för 4,4'-MDI och PMDI uppkommer sent, dvs efter dag 3 och ibland även efter dag 7 samt att (v) aminen 4,4'-MDA är en bra markör för kontaktallergi mot 4,4'-MDI.



Med utgångspunkt från de fynd som presenterar i avhandlingen rekommenderas att patienter testas med sina egna arbetsprodukter eftersom de mer komplexa tekniska isocyanatvarianterna bättre representerar de möjliga allergen som patienter exponeras för i arbetslivet. Är misstanke om kontaktallergi mot 4,4'-MDI föreligger kan patienterna även testas med 4,4'-MDA eftersom det är en markör för kontaktallergi mot 4,4'-MDI. Lapptester innehållande isocyanater bör läsas på både dag 3 eller 4 samt på dag 7 eftersom de kan uppkomma sent. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Docent Boman, Anders, Institutionen för Medicin, Karolinska Instititutet, Stockholm
organization
publishing date
type
Thesis
publication status
published
subject
keywords
venereologi, Dermatologi, venereology, Dermatology, occupational, allergic contact dermatitis, polyurethane
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2007:30
pages
140 pages
publisher
Department of Occupational and Environmental Dermatolog, Deparment of Dermatology, Malmö University Hospital
defense location
Lilla Aulan, Entrance 59, Medicinskt Forskningscentrum, Malmö University Hospital
defense date
2007-03-09 09:15:00
ISSN
1652-8220
ISBN
978-91-85559-07-7
language
English
LU publication?
yes
additional info
M Frick, E Zimerson, D Karlsson, Å Marand, G Skarping, M Isaksson and M Bruze. 2004. Poor Correlation between Stated and Found Concentrations of Diphenylmethane-4,4'-Diisocyanate (4,4'-MDI) in Petrolatum Patch Test Preparations Contact Dermatitis, vol 51 pp 73-79.
. 2005. Chemical Analysis of 2,4-Toluene Diisocyanate, 1,6-Hexamethylene Diisocyanate and Isophorone Diisocyanate Dermatitis, vol 16 pp 1-6.
M Frick-Engfeldt, E Zimerson, D Karlsson, G Skarping, M Isaksson and M Bruze. 2005. Chemical Analysis of 2,4-Toluene Diisocyanate, 1,6-Hexamethylene Diisocyanate and Isophorone Diisocyanate Dermatitis, vol 16 pp 1-6.
M Frick-Engfeldt, E Zimerson, D Karlsson, G Skarping, M Isaksson and M Bruze. 2007. Is It Possible to Improve the Patch Test Diagnostics for Isocyanates?: A Stability Study of Petrolatum Preparations of Diphenylmethane-4,4'- Diisocyanate (4,4'-MDI) and Polymeric Diphenylmethane Diisocyanate (PMDI) Contact Dermatitis, vol 56 pp 27-34.
M Frick-Engfeldt, M Isaksson, E Zimerson and M Bruze. . How to Optimize Patch Testing with Diphenylmethane Diisocyanate (MDI) (submitted)
M Frick, M Isaksson, B Björkner, M Hindsén, A Pontén and M Bruze. 2003. Occupational Allergic Contact Dermatitis in a Company Manufacturing Boards Coated with Isocyanate Lacquer Contact Dermatitis, vol 48 pp 255-260.
id
61b936c3-0c50-4a04-aeb8-5b6f2a8b2f0c (old id 548182)
date added to LUP
2016-04-01 15:19:59
date last changed
2019-05-21 22:05:24
@phdthesis{61b936c3-0c50-4a04-aeb8-5b6f2a8b2f0c,
  abstract     = {{Isocyanates are highly reactive compounds used in the production of polyurethane. Exposure to isocyanates is mainly associated with respiratory disorders, but may also result in allergic contact dermatitis. Reports describing contact allergy to isocyanates are few in number and it has been considered a rare phenomenon. In the present study it is shown that the low frequency of reported cases could partly be explained by weaknesses in the method used to detect contact allergy arising from isocyanates, i.e. patch testing with the commercially available isocyanate series. These series generally comprise petrolatum preparations of the four diisocyanates diphenylmethane-4,4'-diisocyanate (4,4'-MDI), 2,4-toluene diisocyanate (2,4-TDI), 1,6-hexamethylene diisocyanate (1,6-HDI) and isophorone diisocyanate (IPDI), as well as two corresponding amines, 4,4'-diaminodiphenylmethane (4,4'-MDA) and isophorone diamine (IPDA).<br/><br>
<br/><br>
The following results are reported in the thesis. (i) Chemical analyses of isocyanate series obtained from four American and nine European patch testing departments showed that patch test preparations of 2,4-TDI, 1,6-HDI and IPDI contained the declared concentrations, but the concentration of 4,4'-MDI was generally so low that patch testing with it could not be considered reliable. (ii) A stability study showed that preparations of technical grade MDI, i.e. polymeric MDI (PMDI), were more stable and more homogeneous than preparations of pure 4,4'-MDI during the course of a year. (iii) A patch test study revealed that PMDIs rendered as many positive reactions as 4,4'-MDI, (iv) that positive reactions to 4,4'-MDI and PMDI appear late, i.e. after day 3 and sometimes also after day 7, and (v) that the amine 4,4'-MDA is a good marker for 4,4'-MDI contact allergy.<br/><br>
<br/><br>
In order to optimize patch testing with isocyanates it is thus recommended that patients be tested with their own work products containing technical grade isocyanates since they better reflect the possible allergens that patients are in fact exposed to. It is not yet known if the isomers presently used in commercial preparations are the most potent allergens in technical grade products or if there are other monomers and/or oligomers that cause skin problems. When contact allergy to MDI is suspected patients can also be tested with 4,4'-MDA since it is a marker for 4,4'-MDI contact allergy. Isocyanate patch tests should be read on day 3 or 4 as well as on day 7.}},
  author       = {{Engfeldt, Malin}},
  isbn         = {{978-91-85559-07-7}},
  issn         = {{1652-8220}},
  keywords     = {{venereologi; Dermatologi; venereology; Dermatology; occupational; allergic contact dermatitis; polyurethane}},
  language     = {{eng}},
  publisher    = {{Department of Occupational and Environmental Dermatolog, Deparment of Dermatology, Malmö University Hospital}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Chemical and Clinical Studies of Isocyanate Contact Allergy with focus on diphenylmethane diisocyanate}},
  volume       = {{2007:30}},
  year         = {{2007}},
}