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Experimental and Clinical Studies on Contact Allergy to Diphenylmethane-4,4′-diisocyanate and Related Substances

Hamada, Haneen LU (2017)
Abstract
The exposure to isocyanates is more of an occupational problem than a consumer problem. The main route of exposure is assumed to be through inhalation. Isocyanates that have high vapor pressure, such as TDI, can be airborne at room temperature. Other isocyanates such as MDI are volatile only when heated. Industrial processes that can cause exposure to isocyanates are, for example, spraying or heating. Inhalation of isocyanates can cause disorders of the respiratory tract. Isocyanates are well known to cause direct toxic and irritant effects, such as irritation of the nose, throat, and upper airways and also eye and skin irritation. In animal and human studies, it has been found that isocyanates cause skin sensitization and sensitization of... (More)
The exposure to isocyanates is more of an occupational problem than a consumer problem. The main route of exposure is assumed to be through inhalation. Isocyanates that have high vapor pressure, such as TDI, can be airborne at room temperature. Other isocyanates such as MDI are volatile only when heated. Industrial processes that can cause exposure to isocyanates are, for example, spraying or heating. Inhalation of isocyanates can cause disorders of the respiratory tract. Isocyanates are well known to cause direct toxic and irritant effects, such as irritation of the nose, throat, and upper airways and also eye and skin irritation. In animal and human studies, it has been found that isocyanates cause skin sensitization and sensitization of the lung. The sensitization mechanism and metabolism of isocyanates is not fully understood. Concurrent reactions are often seen between different isocyanates and their different corresponding amines. It is not always evident whether the 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 aim of the first two papers included in this thesis was to study the dermal uptake and metabolism of isocyanates by dermal provocation of volunteers with different doses of 4,4′-MDI. This was done by the tape-stripping technique and studies on plasma and urine over time. The aim of papers three, four, and five was 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. In order to do so, the guinea pig maximization test (GPMT) was used. The aim of paper six was 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 GPMT. Aged, pure 4,4′-MDI is instable, even when stored in the freezer. The outcome of 4,4ʹ-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).
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author
supervisor
opponent
  • docent Hagvall, Lina, Göteborg
organization
publishing date
type
Thesis
publication status
published
keywords
4,4′-MDI, freund's complete adjuvant, Guinea pig maximization test, 4,4'-MDA, 4,4'-DMDA, 4,4'-DMDI, PPD, p-phenylenediamine, 2,4-TDI, Toluene diisocyanate, trimer, FCA, Cross-reactivity, dermal uptake, contact allergy, contact dermatitis
pages
82 pages
publisher
Lund University, Faculty of Medicine
defense location
Aulan, Kvinnokliniken, SUS, Malmö.
defense date
2017-09-01 09:15
ISBN
978-91-7619-492-8
language
English
LU publication?
yes
id
465f2608-b6ba-472b-bdee-c51900264631
date added to LUP
2017-08-04 18:31:21
date last changed
2017-08-18 10:44:49
@phdthesis{465f2608-b6ba-472b-bdee-c51900264631,
  abstract     = {The exposure to isocyanates is more of an occupational problem than a consumer problem. The main route of exposure is assumed to be through inhalation. Isocyanates that have high vapor pressure, such as TDI, can be airborne at room temperature. Other isocyanates such as MDI are volatile only when heated. Industrial processes that can cause exposure to isocyanates are, for example, spraying or heating. Inhalation of isocyanates can cause disorders of the respiratory tract. Isocyanates are well known to cause direct toxic and irritant effects, such as irritation of the nose, throat, and upper airways and also eye and skin irritation. In animal and human studies, it has been found that isocyanates cause skin sensitization and sensitization of the lung. The sensitization mechanism and metabolism of isocyanates is not fully understood. Concurrent reactions are often seen between different isocyanates and their different corresponding amines. It is not always evident whether the 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.<br/>    The aim of the first two papers included in this thesis was to study the dermal uptake and metabolism of isocyanates by dermal provocation of volunteers with different doses of 4,4′-MDI. This was done by the tape-stripping technique and studies on plasma and urine over time. The aim of papers three, four, and five was 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. In order to do so, the guinea pig maximization test (GPMT) was used. The aim of paper six was to investigate the cause behind the rapid decrease in 4,4′-MDI in patch test preparations.<br/>    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 GPMT. Aged, pure 4,4′-MDI is instable, even when stored in the freezer. The outcome of 4,4ʹ-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). <br/>},
  author       = {Hamada, Haneen},
  isbn         = {978-91-7619-492-8},
  keyword      = {4,4′-MDI,freund's complete adjuvant,Guinea pig maximization test,4,4'-MDA,4,4'-DMDA,4,4'-DMDI,PPD,p-phenylenediamine,2,4-TDI,Toluene diisocyanate,trimer,FCA,Cross-reactivity,dermal uptake,contact allergy,contact dermatitis},
  language     = {eng},
  pages        = {82},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Experimental and Clinical Studies on Contact Allergy to Diphenylmethane-4,4′-diisocyanate and Related Substances},
  year         = {2017},
}