Contact allergens and prevention of contact dermatitis

Sigfrid Fregert, M.D. Lund, Sweden

Contact dermatitis is responsible for about 90% of the cases of occupational dermatoses and allergic mechanisms appear responsible for more than half of these. Knowledge of the properties of the allergens is therefore of utmost importance and should be made available to dermatologists and other health care practitioners responsible for preventing disease in the workplace.

CHARACTERISTICS OF ALLERGENS

There are about 2 million known chemicals, approxi- mately 100,000 of which are used in industry. In addition, about 2000 new chemicals are synthesized each year. How- ever, only a few of the new chemicals cause contact der- matitis, and these only in a few subjects. Chemicals that have been in use for some years are the ones responsible for allergies in most cases. Identification of the new chem- icals that arc sensitizers can be aided by predictive expcr- iments in animals. Industries primarily perform irritation predictive tests, and a distinction is often not made between the irritating and sensitizing capacity of the chemicals.

The molecular weight of sensitizers (haptens) that cause reactions of a delayed type (type IV) is commonly ~600 daltons.’ For example, the oligomer of epoxy resin of the bisphenol A type with a molecular weight of 340 daltons is a strong sensitizer, but the oligomer with a molecular weight of 624 daltons is a nonsensitizer.’ If the given mo- lecular weight is higher, a contaminant should be suspected to be the true allergen. The allergens that cause contact urticaria reactions of an immunologic nature (type I) com- monly have a molecular weight of 5000 to 20,000 daltons. Substances that cause contact urticaria of a nonallergic type commonly have a low molecular weight.’

Other chemical properties play a decisive role in the sen- sitization capacity of chemicals. There are many more sen- sitizers among the aromatic than among the aliphatic com- pounds. The polarity and presence of combining groups play an important role. Many sensitizers are aldehydges, alco- hols, amines, and nitro compounds. Penetration of chemi- cals into skin depends on the size and the lipid-water sol- ubility, as well as other properties. Penetration also varies depending on the skin area.4 Conjugation between the hapten and skin protein to a full antigen depends on the ability of the hapten to form covalent binding or binding by formation of free radicals.5 Sometimes a compound acts as a prohapten

From the Department of Occupational Dermatology, University Hospital.

Reprint requests: Sigfrid Fregert, M.D., Professor, Department of Occupational Demratology, University Hospital, S-221 85 Lund, Sweden.

and is transformed into a hapten. Styrene, for example, is transformed on the skin surface to styrene epoxide. During patch testing with styrene and styrene epoxide in equi- molar concentrations, the epoxide gives a stronger reaction. Unlike styrene, the epoxide can conjugate by covalent binding.6

Natural products often contain hundreds of substances, but the same substance is present in many kinds of products. Thus eugenol is present in most balsams, berries, spices, flavoring agents, and fragrances.7 Moreover, synthetic sub- stances are used in many products. Several types of thiuram sulfides, for instance, are found in rubber, pesticides, paints, glues, acrylics, and medicaments. Contaminants of varying amount and type can be responsible for the sensitizing ca- pacity of a product. The contaminant can be a residue of the raw material, such as epoxy resin oligomer with a mo- lecular weight of 340 daltons in epoxy acrylate* or multi- functional acrylics in polyfunctional azuridine, a polyure- thane hardener.’

Several products form degradation products during stor- age; for example, formaldehyde is formed from polyeth- ylene glycol (carbo wax) in cosmetics, topical medicaments, and even steroid creams. lo Ethylene thiourea, a rubber chem- ical, is formed from the pesticides Maneb and Zineb, the manganese and zinc salts of ethylene-biu-dithiocarbamate. ’ ’ Several substances can be degraded by heating. Thus heat formed at metal cutting operations can transform butylated hydroxytoluene in cutting oil into 44 new substances, and can transform isopropyl paraphenylene diamine into 27 dif- ferent substances. Carbohydrates in cutting oil can form aldehydes, mainly formaldehyde. The formation of many substances of unknown composition may be induced by welding iron coated with paint or plastic.

Cross-reactions occur between many chemically related substances and are important in the prevention of allergic contact dermatitis. For example, there are 600 sesquiter- penlactones in Asteruceae plants and many of these are cross-sensitizing.” Most of the investigations on cross-sen- sitization have not, however, been performed properly, as the purity is not commonly checked. The term “cross-sen- sitivity” is often misused. Thus there are reports of “cross- reactions” between balsams containing hundreds of sub- stances. Cross-sensitivity means that the person allergic to a primary allergen reacts to a chemically related secondary allergen to which he or she has not been sensitized.‘” Thus the patch substances must be pure and the subject must not have been in contact with the secondary allergen. It is some- times suggested that the secondary allergens be applied at tenfold or lOO-fold higher concentrations than the primary allergens. This might be to ensure that the secondary aller- gen test preparations contain a smaller part of the allergenic

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substance than the primary allergen test preparation; how- ever, the same allergen is present in both.

Patch testing is used to confirm contact allergy. It is necessary to know the chemistry and irritant effect of the test substances and their prevalence in the environment.‘j The term “relevance” is often misused; the expression “nonexplicable” is preferable.“, I4 Prick testing is used to confirm immediate-type reactions of an allergic or nonal- lergic nature. The reactions are often unspecific and not related to the skin condition.’

CONCLUSION

Allergic contact dermatitis can be prevented ,by elimi- nating allergenic chemicals in products and diminishing the allergenicity of chemicals by modifications. A prerequisite to prevention, however, is knowledge of the chemistry and occurrence of allergens. Many products are mixtures of several chemicals that often contain contaminants that act as allergens.

For this reason, methods need to be developed to identify allergens. A combination of patch testing, chemical anal- ysis, and predictive animal tests provides the basis for this type of prevention.

In several products that cause allergic contact dermatitis the allergen is not known (as in many rubber chemicals and in phenolformaldehyde resins). These allergens must he identified before preventive measures can be taken. More frequent chemical analysis in clinical practice would ex- pedite dermatologic treatment and prevention.

REFERENCES

1. Fregert S. Molecular weights of haptens. Acta Derm Venereol [Stockh] 1978;79(suppl):41.

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1986

Fregert S. Thorgeirsson A. Patch testing with low molecular oligomers of epoxy resins in humans. Contact Dermatitis 1977;3:301. von Krogh G, Maibach HJ. Contact urticaria syndrome: an expanding phenomenon. In: Moschella SL, Hurley HJ. eds. Dermatology. 2nd ed. Philadelphia: WB Saunders Co, 1984: 323-33. Wester RC, Maibach HJ. In vivo percutaneous absorption. In: Marzulli FN, Maibach HJ, eds. Advances in modem toxicol- ogy. Dermatotoxicology and pharmacology. vol 4. New York: Hemisphere Publishing Co, 1983: 13 1.

5. Dupuis G, Benezra C. Allergic contact dermatitis to simple chemicals. A molecular approach. New York: Marcel Dekker Inc, 1982.

6. Sjiiborg S, Fregert S, Trulsson L. Contact allergy to styrene and related chemicals. Contact Dermatitis 1984;10:94.

7. Hjorth N. Eczematous allergy to balsams. Allied perfumes and flavouring agents, with special reference to balsam of Peru. Copenhagen: Munksgaard, 1961.

8. Bjijrkner B, Niklasson B, Persson B. The sensitizing potential of di(meth)acrylates based on bisphenol A or epoxy resin in the guinea pig. Contact Dermatitis 1984;10:286.

9. Dahlquist I, Fregert S, Trulsson L. Contact allergy to tri- methylolpropane triacrylate (TMPTA) in an aziridine plastic hardener. Contact Dermatitis 1983;9: 122.

IO. Dahlquist I, Fregert S, Gruvberger B. Detection of formal- dehyde in corticoid creams. Contact Dermatitis 1980;6:494.

11. Bruze M, Fregert S. Allergic contact dermatitis from ethylene thiourea. Contact Dermatitis 1983;9:208.

12. Evans FJ, Schmidt RJ. Plants and plant products that induce contact dermatitis. PIanta Med 1980:38:289.

13. Wilkinson DS, Fregert S, Magnusson B, et al. Terminology of contact dermatitis. Acta Derm Venereol [Stockh] 1970;50:287.

14. Fregert S, Bandmann HJ. Patch testing. Berlin: Springer-Ver- lag, 1975.