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Sensitizing aspects of preservatives
Journal
of Biological
Standardization
1975 3, 241-245
Sensitizing aspectsof preservatives* Halvor Mdler,
M. D.t
The effect in man of small quantities of chemicals used as preservatives in vaccines in both allergic and non-allergic subjects has been studied. Some substances, though given in minute quantities may give rise to allergic reactions.
It is presumed that preservatives should combine a high effectiveness with a negligible toxicity. Even the low concentrations used may, however, provoke allergic reactions. As preservatives they are administered to the human body in amounts far below those used in clinical therapy and, consequently, one can usually disregard the possibility of sensitization. This means that the allergic reactions observed are usually elicited in subjects already sensitized by other means. However, sensitization even with minute amounts of allergen may occur if special circumstances are at hand. Thus, the possibility of experimental sensitization is much greater if the allergen is deposited epicutaneously and intracutaneously than if it is given subcutaneously, or-still less-intramuscularly (Storck, 1962). To induce sensitization experimentally by the epicutaneous route the following circumstances have been found to enhance greatly the possibilities: chemical or thermal injury, repeated application and occlusion. It is interesting that similar conditions prevail in certain clinical situations (Hjorth, 1970). Thus, the disease often starts with a slight trauma, bum or eczema which is treated repeatedly with an antipruritic, anti-inflammatory or antibiotic topical, often with an occlusive dressing. We have now vast clinical experience, particularly from patients with hypostatic dermatitis, of the high frequency of sensitization to a * Received for publication 4 December 1974. Paper read at the International Symposium on Preservatives in Biological Products, San Francisco, 1973. t Department of Dermatology, University of Lund, Malma General Hospital, S-214 01 Malmij, Sweden.
241
HALVOR
MOLLER
variety of topicals, not only to the so-called active agents but also to preservatives and other additives (Bandmann, Calnan, Cronin, Fregert, Hjorth, Magnusson, Maibach, Malten, Meneghini, Pirila & Wilkinson, 1972). If we now turn to the possibilities of eliciting an allergic reaction in the previously sensitized subject the requirements are much lower with regard to the amount of allergen, mode of application, specificity of molecular structure, etc. Furthermore, there are certain problems in detecting the allergy. For instance, it is not necessary that the patient has been sensitized by the same route as that by which he is now getting the challenge reaction. He may have been sensitized by epicutaneous application and he will later have an allergic reaction by oral or parenteral administration (Ekelund & Moller, 1969; Cronin, 1972). Examples of this are sensitization during topical treatment of a stasis dermatitis with neomycin, tetracycline or hydroxyquinoline, followed by a generalized rash after taking the corresponding tablets. Another principle to bear in mind is that of cross-sensitization (Hjorth & Fregert, 1972). The patient may have been sensitized to one compound and is now having a challenge reaction to another which, however, is chemically similar (Fig. 1). An example of this is the ‘para-group’ of substances in which the individual compounds are built up of an aromatic ring containing COOCH,
COOCzH5
SO2 NH2
I
I
I
6H
NH*
NH2
Methylporaben
Benzocaine
Sulfanilamide
Fig. 1. Cross-sensitivity among related allergens. an amino group or an hydroxyl group in the para-position, with varying chains in the opposite position. The patient may have been sensitized epicutaneously with benzocaine which is a very common clinical occurrence in hypostatic eczema and he, or she, is later exposed to, for example, parabens, a common group of preservatives. There are also technical aspects of importance. When testing epicutaneously the patch test concentration may be crucial. With benzalkonium and other quarternary ammonium bases even low concentrations may be irritant (Kleinhans, 1972). Also the choice of test vehicle is of utmost importance since the standard vehicle, petrolatum, is not always working. For example, for disclosing contact allergy to chlorhexidine a water or an alcoholic solution is required (Ljunggren & MBller, 1972). The presence of delayed allergy may also be checked by intradermal injection (Fregert & Rorsman, 1966). It is then necessary to ascertain that the patient does not react to a preservative added to the test solution. We have found merthiolate (thimerosal) to be an excellent example of this. With merthiolate quite special conditions are at hand. In an unspecified group of patients with suspect contact allergy we have found a certain number of positive cutaneous reactions to this preservative (Hansson & Moller, 1970). In our department in southern Sweden it comprises 4-S% of all tested patients, in a recent American report it was 8%. This may be demonstrated epicutaneously as well as intradermally. The compound is used as a preservative in several countries throughout the world, usually in vaccines, gammaglobulins, intradermal test reagents, etc. In certain countries, such as the U.S.A., 242
SENSITIZIKG
ASPECTS
OF PRESERVATIVES
it is also used as a disinfectant, but not so in Sweden. Thus, the high figure for positive reactions to merthiolate in the U.S.A. may be explained by the patients having had contact with merthiolate externally but this cannot explain the figure in our country. Furthermore, we were surprised to find an even higher frequency in healthy subjects, up to 20%, but only if the test subjects were selected by age (Hansson & Moller, 1970). It was found that young adults had the highest frequency of positive cutaneous tests for merthiolate while old people did not react, even to higher concentrations. It was also found that our eczema patients reacting to merthiolate had a much lower mean age than eczema patients reacting to other compounds. For several reasons we have concluded that these reactions are not of an allergic nature but should be considered as some type of idiosyncrasy demonstrable mainly in young people. The theoretical implications of these findings are naturally interesting but there are also practical consequences of importance. Thus, merthiolate when added as a preservative to intradermal test agents may give rise to false positive reactions when looking for delayed allergy (Hansson & Miiller, 1971). In Sweden, and probably in other countries as well, old tuberculin contains merthiolate as a preservative. Swedish children are actively immunized against tuberculosis and the fight against this disease includes maintaining a certain immunity state in the population. This is confirmed by a positive tuberculin reaction. It was, however, found in our study on many hundreds of recruits that a good deal of the so-called positive tuberculin reactions were due, not to the tuberculin itself, but to the additive merthiolate. This meant of course that the state of tuberculosis immunity could not be established. A consequence of this is of course that when using a battery of intradermal allergens to study the presence or absence of delayed allergy in, for example, Hodgkin’s disease or in the atopic state it should be ascertained that the positive reactions recorded are not due to this additive. Finally, some words on the frequency of patch test reactions to some preservatives. In Table 1 results are compared with those obtained with the most common epicutaneous TABLE 1. Frequency of positive patch test reactions in per cent of tested patients : (a) Department of Dermatology, Malmij, 1972; (b) North American Contact Dermatitis Group, 1971-72 (Maibach, personal communication)
Merthiolate Formaldehyde Parabens Ethylenediamine Hydroxyquinolines (Nickel sulfate
(4
(b)
4.6 2.1 o-4 0.5
8 4 3 7
1.2-l .4 8.5
11)
allergen, nickel sulphate. There are some interesting discrepancies. As mentioned earlier, it may be presumed that cutaneous reactions to merthiolate in Sweden are nonallergic but that in, for example, the U.S.A. some of them may be of an allergic nature. Formaldehyde reactions are probably obtained through sensitization by textiles. Since formaldehyde is now seldom used as a preservative it should not play a role even as a challenger. Parabens are overwhelming in creams and topical solutions. Reactions are scarce in Scandinavia, but are more frequent in the U.S.A. They are important for maintaining cross-sensitivity. Reactions to ethylenediamine are frequent in the U.S.A., but scarce in Scandinavia. This is probably a question of exposure possibilities. 243
HALVOR
MOLLER
Chlorhexidine, hexachlorophene and triclosan constitute a group of chemically related compounds that are now widely used as disinfectants and preservatives. Only a few allergic reactions have been reported. However, if water or ethanol is used as a test vehicle instead of petrolatum some positive reactions may be obtained, at least with chlorhexidine and hexachlorophene (Table 2). TABLE
2. Results of epicutaneous testing with disinfectants (1 y0 in ethanol) in patients with suspected contact dermatitis
Chlorhexidine Hexachlorophene Triclosan (Irgasan DP 300)
Patients tested (No.)
Positive tests (No.1
Positive tests (%>
513 312 200
16 7 0
3.1 2.2 0
The conclusions to be drawn should be that preservatives, although administered to man in minute quantities, may cause side-effects, mainly of an allergic nature (see also Schorr, 1970; Fisher, Pascher & Kanof, 1971; Meneghini, Rantuccio & Lomuto, 1971; Wilkinson, 1972).
REFERENCES Bandmann, H.-J., Calnan, C. D., Cronin, E., Fregert, S., Hjorth, N., Magnusson, B., Maibach, H., Malten, K. E., Meneghini, C. L., PirilZ, V. & Wilkinson, D. S. (1972). Dermatitis from applied medicaments. Archives of Dermatology 106, 335-337. Cronin, E. (1972). Contact dermatitis. XVII. Reactions to contact allergens given orally or systemically. Bn’tish Journal of Dermatology 86, 104-107. Ekelund, A.-G. & Moller, H. (1969). Oral provocation in eczematous contact allergy to neomycin and hydroxy-quinolines. Acta Dermato-Venereologica 49, 422-426. Fisher, A. A., Pascher, F. & Kanof, N. B. (1971). Allergic contact dermatitis due to ingredients of vehicles. A ‘vehicle tray’ for patch testing. Archives of Dermatology 104, 286290. Fregert, S. & Rorsman, H. (1966). Allergy to chromium, nickel and cobalt. Acta DermatoVenereologica 46, 144-148. Hansson, H. & Moller, H. (1970). Patch test reactions to merthiolate in healthy young subjects. BritishJournal of Dermatology 83, 349-356. Hansson, H. & Moller, H. (1971). Intracutaneous test reactions to tuberculin containing mertbiolate as a preservative. ScandinavianJournal of Infectious Diseases 3, 169-172. Hjorth, N. (1970). HIufige Allergene in der dermatologischen Praxis. Fortschritte der praktischen Dermatologie und Venereologie 6, 75-84. In Textbook of Dermatology (edited Hjorth, N. & Fregert, S. (1972). Contact dermatitis. by A. Rook, D. S. Wilkinson & F. J. G. Ebling), 2nd edition, Vol. I, 14, pp. 314-324. Oxford, London, Edinburgh and Melbourne: Blackwell Scientific Publications. Kleinbans, D. (1972). Epikutantestungen mit Cetylpyridiniumcblorid. Berufsdermatosen 20, 217-222. Ljunggren, B. & Mdller, H. (1972). Eczematous contact allergy to chlorhexidine. Acta Dermato- Venereologica 52, 308-3 10. Menegbini, C. L., Rantuccio, F. & Lomuto, M. (1971). Additives, vehicles and active drugs of topical medicaments as causes of delayed-type allergic dermatitis. Dermatologica 143, 137-147. Schorr, W. (1970). Allergic skin reactions from cosmetic preservatives. Documentary Issue, American Perfumer and Cosmetics. 244
SENSITIZING
ASPECTS
OF PRESERVATIVES
Storck, H. (1962). Das experimentelle Ekzem. In Handbuch der Huut- und Gescklecktskrunkkeiten. ~.~adussohn. Ergiinzungswerk (edited by G. Miescher 8z H. Storck), Vol. II, 1, pp. 120-121. Berlin, G&tingen and Heidelberg: Springer-VerIag. Wilkinson, D. S. (1972). Sensitivity to pharmaceutical additives. In Meckamhs in Drug Allergy. A Glaxo Symposium (edited by C. H. Dash & H. E. H. Jones), pp. 75-92. Edinburgh and London: ChurchiU Livingstone.
245
of Biological
Standardization
1975 3, 241-245
Sensitizing aspectsof preservatives* Halvor Mdler,
M. D.t
The effect in man of small quantities of chemicals used as preservatives in vaccines in both allergic and non-allergic subjects has been studied. Some substances, though given in minute quantities may give rise to allergic reactions.
It is presumed that preservatives should combine a high effectiveness with a negligible toxicity. Even the low concentrations used may, however, provoke allergic reactions. As preservatives they are administered to the human body in amounts far below those used in clinical therapy and, consequently, one can usually disregard the possibility of sensitization. This means that the allergic reactions observed are usually elicited in subjects already sensitized by other means. However, sensitization even with minute amounts of allergen may occur if special circumstances are at hand. Thus, the possibility of experimental sensitization is much greater if the allergen is deposited epicutaneously and intracutaneously than if it is given subcutaneously, or-still less-intramuscularly (Storck, 1962). To induce sensitization experimentally by the epicutaneous route the following circumstances have been found to enhance greatly the possibilities: chemical or thermal injury, repeated application and occlusion. It is interesting that similar conditions prevail in certain clinical situations (Hjorth, 1970). Thus, the disease often starts with a slight trauma, bum or eczema which is treated repeatedly with an antipruritic, anti-inflammatory or antibiotic topical, often with an occlusive dressing. We have now vast clinical experience, particularly from patients with hypostatic dermatitis, of the high frequency of sensitization to a * Received for publication 4 December 1974. Paper read at the International Symposium on Preservatives in Biological Products, San Francisco, 1973. t Department of Dermatology, University of Lund, Malma General Hospital, S-214 01 Malmij, Sweden.
241
HALVOR
MOLLER
variety of topicals, not only to the so-called active agents but also to preservatives and other additives (Bandmann, Calnan, Cronin, Fregert, Hjorth, Magnusson, Maibach, Malten, Meneghini, Pirila & Wilkinson, 1972). If we now turn to the possibilities of eliciting an allergic reaction in the previously sensitized subject the requirements are much lower with regard to the amount of allergen, mode of application, specificity of molecular structure, etc. Furthermore, there are certain problems in detecting the allergy. For instance, it is not necessary that the patient has been sensitized by the same route as that by which he is now getting the challenge reaction. He may have been sensitized by epicutaneous application and he will later have an allergic reaction by oral or parenteral administration (Ekelund & Moller, 1969; Cronin, 1972). Examples of this are sensitization during topical treatment of a stasis dermatitis with neomycin, tetracycline or hydroxyquinoline, followed by a generalized rash after taking the corresponding tablets. Another principle to bear in mind is that of cross-sensitization (Hjorth & Fregert, 1972). The patient may have been sensitized to one compound and is now having a challenge reaction to another which, however, is chemically similar (Fig. 1). An example of this is the ‘para-group’ of substances in which the individual compounds are built up of an aromatic ring containing COOCH,
COOCzH5
SO2 NH2
I
I
I
6H
NH*
NH2
Methylporaben
Benzocaine
Sulfanilamide
Fig. 1. Cross-sensitivity among related allergens. an amino group or an hydroxyl group in the para-position, with varying chains in the opposite position. The patient may have been sensitized epicutaneously with benzocaine which is a very common clinical occurrence in hypostatic eczema and he, or she, is later exposed to, for example, parabens, a common group of preservatives. There are also technical aspects of importance. When testing epicutaneously the patch test concentration may be crucial. With benzalkonium and other quarternary ammonium bases even low concentrations may be irritant (Kleinhans, 1972). Also the choice of test vehicle is of utmost importance since the standard vehicle, petrolatum, is not always working. For example, for disclosing contact allergy to chlorhexidine a water or an alcoholic solution is required (Ljunggren & MBller, 1972). The presence of delayed allergy may also be checked by intradermal injection (Fregert & Rorsman, 1966). It is then necessary to ascertain that the patient does not react to a preservative added to the test solution. We have found merthiolate (thimerosal) to be an excellent example of this. With merthiolate quite special conditions are at hand. In an unspecified group of patients with suspect contact allergy we have found a certain number of positive cutaneous reactions to this preservative (Hansson & Moller, 1970). In our department in southern Sweden it comprises 4-S% of all tested patients, in a recent American report it was 8%. This may be demonstrated epicutaneously as well as intradermally. The compound is used as a preservative in several countries throughout the world, usually in vaccines, gammaglobulins, intradermal test reagents, etc. In certain countries, such as the U.S.A., 242
SENSITIZIKG
ASPECTS
OF PRESERVATIVES
it is also used as a disinfectant, but not so in Sweden. Thus, the high figure for positive reactions to merthiolate in the U.S.A. may be explained by the patients having had contact with merthiolate externally but this cannot explain the figure in our country. Furthermore, we were surprised to find an even higher frequency in healthy subjects, up to 20%, but only if the test subjects were selected by age (Hansson & Moller, 1970). It was found that young adults had the highest frequency of positive cutaneous tests for merthiolate while old people did not react, even to higher concentrations. It was also found that our eczema patients reacting to merthiolate had a much lower mean age than eczema patients reacting to other compounds. For several reasons we have concluded that these reactions are not of an allergic nature but should be considered as some type of idiosyncrasy demonstrable mainly in young people. The theoretical implications of these findings are naturally interesting but there are also practical consequences of importance. Thus, merthiolate when added as a preservative to intradermal test agents may give rise to false positive reactions when looking for delayed allergy (Hansson & Miiller, 1971). In Sweden, and probably in other countries as well, old tuberculin contains merthiolate as a preservative. Swedish children are actively immunized against tuberculosis and the fight against this disease includes maintaining a certain immunity state in the population. This is confirmed by a positive tuberculin reaction. It was, however, found in our study on many hundreds of recruits that a good deal of the so-called positive tuberculin reactions were due, not to the tuberculin itself, but to the additive merthiolate. This meant of course that the state of tuberculosis immunity could not be established. A consequence of this is of course that when using a battery of intradermal allergens to study the presence or absence of delayed allergy in, for example, Hodgkin’s disease or in the atopic state it should be ascertained that the positive reactions recorded are not due to this additive. Finally, some words on the frequency of patch test reactions to some preservatives. In Table 1 results are compared with those obtained with the most common epicutaneous TABLE 1. Frequency of positive patch test reactions in per cent of tested patients : (a) Department of Dermatology, Malmij, 1972; (b) North American Contact Dermatitis Group, 1971-72 (Maibach, personal communication)
Merthiolate Formaldehyde Parabens Ethylenediamine Hydroxyquinolines (Nickel sulfate
(4
(b)
4.6 2.1 o-4 0.5
8 4 3 7
1.2-l .4 8.5
11)
allergen, nickel sulphate. There are some interesting discrepancies. As mentioned earlier, it may be presumed that cutaneous reactions to merthiolate in Sweden are nonallergic but that in, for example, the U.S.A. some of them may be of an allergic nature. Formaldehyde reactions are probably obtained through sensitization by textiles. Since formaldehyde is now seldom used as a preservative it should not play a role even as a challenger. Parabens are overwhelming in creams and topical solutions. Reactions are scarce in Scandinavia, but are more frequent in the U.S.A. They are important for maintaining cross-sensitivity. Reactions to ethylenediamine are frequent in the U.S.A., but scarce in Scandinavia. This is probably a question of exposure possibilities. 243
HALVOR
MOLLER
Chlorhexidine, hexachlorophene and triclosan constitute a group of chemically related compounds that are now widely used as disinfectants and preservatives. Only a few allergic reactions have been reported. However, if water or ethanol is used as a test vehicle instead of petrolatum some positive reactions may be obtained, at least with chlorhexidine and hexachlorophene (Table 2). TABLE
2. Results of epicutaneous testing with disinfectants (1 y0 in ethanol) in patients with suspected contact dermatitis
Chlorhexidine Hexachlorophene Triclosan (Irgasan DP 300)
Patients tested (No.)
Positive tests (No.1
Positive tests (%>
513 312 200
16 7 0
3.1 2.2 0
The conclusions to be drawn should be that preservatives, although administered to man in minute quantities, may cause side-effects, mainly of an allergic nature (see also Schorr, 1970; Fisher, Pascher & Kanof, 1971; Meneghini, Rantuccio & Lomuto, 1971; Wilkinson, 1972).
REFERENCES Bandmann, H.-J., Calnan, C. D., Cronin, E., Fregert, S., Hjorth, N., Magnusson, B., Maibach, H., Malten, K. E., Meneghini, C. L., PirilZ, V. & Wilkinson, D. S. (1972). Dermatitis from applied medicaments. Archives of Dermatology 106, 335-337. Cronin, E. (1972). Contact dermatitis. XVII. Reactions to contact allergens given orally or systemically. Bn’tish Journal of Dermatology 86, 104-107. Ekelund, A.-G. & Moller, H. (1969). Oral provocation in eczematous contact allergy to neomycin and hydroxy-quinolines. Acta Dermato-Venereologica 49, 422-426. Fisher, A. A., Pascher, F. & Kanof, N. B. (1971). Allergic contact dermatitis due to ingredients of vehicles. A ‘vehicle tray’ for patch testing. Archives of Dermatology 104, 286290. Fregert, S. & Rorsman, H. (1966). Allergy to chromium, nickel and cobalt. Acta DermatoVenereologica 46, 144-148. Hansson, H. & Moller, H. (1970). Patch test reactions to merthiolate in healthy young subjects. BritishJournal of Dermatology 83, 349-356. Hansson, H. & Moller, H. (1971). Intracutaneous test reactions to tuberculin containing mertbiolate as a preservative. ScandinavianJournal of Infectious Diseases 3, 169-172. Hjorth, N. (1970). HIufige Allergene in der dermatologischen Praxis. Fortschritte der praktischen Dermatologie und Venereologie 6, 75-84. In Textbook of Dermatology (edited Hjorth, N. & Fregert, S. (1972). Contact dermatitis. by A. Rook, D. S. Wilkinson & F. J. G. Ebling), 2nd edition, Vol. I, 14, pp. 314-324. Oxford, London, Edinburgh and Melbourne: Blackwell Scientific Publications. Kleinbans, D. (1972). Epikutantestungen mit Cetylpyridiniumcblorid. Berufsdermatosen 20, 217-222. Ljunggren, B. & Mdller, H. (1972). Eczematous contact allergy to chlorhexidine. Acta Dermato- Venereologica 52, 308-3 10. Menegbini, C. L., Rantuccio, F. & Lomuto, M. (1971). Additives, vehicles and active drugs of topical medicaments as causes of delayed-type allergic dermatitis. Dermatologica 143, 137-147. Schorr, W. (1970). Allergic skin reactions from cosmetic preservatives. Documentary Issue, American Perfumer and Cosmetics. 244
SENSITIZING
ASPECTS
OF PRESERVATIVES
Storck, H. (1962). Das experimentelle Ekzem. In Handbuch der Huut- und Gescklecktskrunkkeiten. ~.~adussohn. Ergiinzungswerk (edited by G. Miescher 8z H. Storck), Vol. II, 1, pp. 120-121. Berlin, G&tingen and Heidelberg: Springer-VerIag. Wilkinson, D. S. (1972). Sensitivity to pharmaceutical additives. In Meckamhs in Drug Allergy. A Glaxo Symposium (edited by C. H. Dash & H. E. H. Jones), pp. 75-92. Edinburgh and London: ChurchiU Livingstone.
245