Annals of Occupational Hygiene Advance Access originally published online on November 28, 2006
Annals of Occupational Hygiene 2007 51(2):219-226; doi:10.1093/annhyg/mel076
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Aniline—A ‘Historical’ Contact Allergen? Current Data from the IVDK and Review of the Literature
1 Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander University Erlangen-Nürnberg Erlangen, Germany
2 Bayer HealthCare AG, Toxicology Wuppertal, Germany
3 Information Network of Departments of Dermatology (IVDK) at the Georg August University Göttingen, Germany
*Author to whom correspondence should be addressed. E-mail: wolfgang.uter{at}rzmail.uni-erlangen.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTS OF THE IVDKDISCUSSION WITH REVIEW OF...CONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Objectives: To assess whether aniline should be regarded as potential cause of contact allergy (CA). Methods: Retrospective analysis of clinical data collected in a CA surveillance network (IVDK, www.ivdk.org) between 01/1992 and 06/2004 and review of pertinent literature. Results: In the above period, 25 of the 1119 patients patch tested with aniline had positive (allergic) reactions; in 24 of these 25 patients, CA to p-phenylenediamine, p-aminoazobenzene or (in one case) another para-amino compound was additionally diagnosed. Exposure to aniline could not be ascertained in any of the cases, based on the available data. Discussion: Previous clinical results, which have been summarized and tabulated, are partly difficult to evaluate, as they may lack detail, or test concentrations are higher than those currently recommended, possibly yielding false-positive reactions. In none of the studies had previous exposures to aniline been unequivocally identified. Conclusion: Based on clinical data it is unlikely that aniline is an independent sensitizer of current importance. However, it may elicit allergic reactions in subjects pre-sensitized to para-substituted amino compounds. In summary, supported by recent experimental evidence employing the local lymph node assay as a validated animal test system, it appears probable that aniline is a weak allergen.
Keywords: allergic contact • aniline • CAS 62-53-3 • clinical epidemiology • dermatitis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS OF THE IVDKDISCUSSION WITH REVIEW OF...CONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Aniline (CAS 62-53-3) is one of the hallmark compounds in the evolution of industrial chemistry. Its historical importance is illustrated by the fact that major companies included the term ‘aniline’ in their name, such as ‘Badische Anilin & Soda Fabrik AG’ (BASF) in 1865 or AGFA (‘Aktien-Gesellschaft für Anilin-Fabrikation’) in 1873. For the year 1996, the world aniline production capacity provided by more than 40 companies was estimated at about 2.3 billion tons (Kahl and Schröder, 2002). In Western Europe, the total industrial use of aniline was 555 000 tons in 1993, markedly increasing since then, with the synthesis of diphenylmethane-4,4'-diisocyanate (MDI) ranking top (74%), followed by processing to rubber chemicals (16%), dyes (5%), pesticides (3%), pharmaceuticals (1.2%), fibres (1%) and other products (3.7%) (Anonymous, 2004b). The following environmental releases, not necessarily involving skin contact, have been considered in the EU Risk Assessment Report: pesticides and rubber products where aniline can be formed as degradation product, microbial reduction to nitrobenzene, thermal degradation of polyurethanes, coal and oil industries, and landfills (Anonymous, 2004b).
Aniline is rather toxic, with formation of methaemoglobin dependent on exposure-dose. Secondary consequences due to hypoxaemia include seizures, weakness, possibly death and anaemia as symptom of chronic intoxication. In animal studies, spleen damage and hepatotoxicity and nephrotoxicity have been demonstrated. Moreover, aniline penetrates the skin (Anonymous, 1992). Consequently, due to such marked toxicity, exposure of workers has been strictly controlled for decades, e.g. via occupational exposure limits in a variety of European countries (Anonymous, 2004b). On the other hand, available information on aniline intoxication in humans in earlier years indicates that exposure had indeed occurred at least accidentally. As contact allergy (CA) and subsequent allergic contact dermatitis (ACD) require a certain minimum exposure dose to develop, depending on the sensitization potential of the substance, it could be expected that cases of ACD due to aniline should be an extreme rarity at least in the more recent years due to the control measurements in place. A notable frequency of positive patch test (PT) reactions to aniline, indicative of CA to this compound, was observed in older studies. To assess the current importance of aniline CA, taking cross-reactivity to para-substituted amino compounds (PAC) into account, we examined current PT results of a CA surveillance network and put these into the perspective of previous evidence regarding CA to aniline.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS OF THE IVDKDISCUSSION WITH REVIEW OF...CONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Since 1989, a network of initially 8, nowadays 40 departments of dermatology in Germany, also including 2 in Austria and 1 in Switzerland, cooperates as ‘Information Network of Departments of Dermatology’ (IVDK, www.ivdk.org) in the field of CA research. Aims and operational procedures have been described in detail (Uter et al., 1998). In brief, the PT results, along with a standardized set of demographic and clinical data, of all patients with suspected ACD attending one of the participating centres are collected. The PT procedure follows current international guidelines (most recently, Wahlberg and Lindberg, 2006) further amended by the German Contact Dermatitis Research Group (DKG) (Schnuch et al., 2001), of which all IVDK partners are members. All data are transmitted in an anonymous, electronic format to the data centre in Göttingen twice a year and quality controlled (Uter et al., 2005).
In this analysis, PT reactions to aniline, obtained between January 1992 and June 2004, are considered as outcome. Aniline has never been part of the test series recommended and used by the DKG, but has been tested by the centres listed above following special research interests. The most common PT concentration was 1%, in accordance with current recommendations (De Groot, 2000), tested in 1053 patients. Among these, 976 had been tested with aniline in petrolatum, 58 patients from one centre with Eucerinium anhydricum (Eucerin) as vehicle, and in another centre, 19 patients with 1% aniline in water. (Eucerinium anhydricum is a mixture of petrolatum (93.5%), cetearyl alcohol (0.5%) and EuceritTM (6%), the latter being a purified fraction of lanolin alcohols.) More rarely, higher PT concentrations were used (n = 66 patients). Overall, 1119 patients were identified as having been patch tested with aniline. Results obtained at the third day reading after start of the PT were considered as standard outcome, partly supplemented by late reactions. Concomitant reactions to other allergens, especially PAC, were additionally analysed. p-Phenylenediamine, p-aminodiphenyl amine and p-aminoazobenzene were tested 1% in petrolatum.
Previous reports regarding the sensitization potential of aniline were identified by literature search in common databases, e.g. Medline. Moreover, a manual search of the older literature and references in German, respectively, was performed.
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RESULTS OF THE IVDK |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS OF THE IVDKDISCUSSION WITH REVIEW OF...CONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Altogether 25 of the 1119 patients (2.2%, exact 95% CI = 1.5–3.3%) reacted positively to aniline; all these reactions were observed to a test concentration of 1% (n = 8 using EucerinTM as vehicle, n = 17 using petrolatum as vehicle); see Table 2. A comparison of the proportions of CA to aniline between patients tested with aniline in EucerinTM and those tested with aniline in petrolatum yielded no evidence of a significant difference (P = 0.30, Fisher's exact test, 2-sided). In addition, 1 reaction regarded as irritant, and 7 doubtful reactions were noted. The median age of the 25 patients testing positive was 57, compared to a median age of 43 in those patients who tested negative. The proportion of females was almost identical in the two subgroups (12/25 and 48.2%, respectively); for further details regarding important demographic and clinical characteristics (Schnuch et al., 1997) see Table 1.
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Collapsing the contingency table (Table 2) to dichotomized outcomes (positive versus non-positive), yielding a 2*2 table, a highly asymmetrical distribution can be noted (P < 0.0001, McNemar test), i.e. significantly more patients had positive reactions to p-phenylenediamine or p-aminoazobenzene and negative reactions to aniline, than vice versa. Cohen's kappa value was 0.27 (95% CI = 0.18–0.36), indicating only ‘fair’ agreement (Uter et al., 2004) between reactions to aniline and either of the two PAC.
The anamnestic profile of the 25 patients exhibiting a positive PT reaction to aniline was unremarkable: occupations comprised old-age pensioners (n = 7), office workers (n = 6), ‘housewives’, farmers, painters (n = 2 each) and a number of singular job titles. In 18/25 ACD had eventually been diagnosed. The sites most commonly affected were the hands (n = 10), and (lower) legs and face (n = 5 each). In none of the 25 patients unequivocal evidence of past contact to aniline could be traced in the IVDK routine documentation. Hence, no clinical relevance, determined along the lines of an algorithm proposed by Ale and Maibach (1995), could be ascertained.
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DISCUSSION WITH REVIEW OF THE LITERATURE |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS OF THE IVDKDISCUSSION WITH REVIEW OF...CONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Human data
The present analysis of a large collection of routine PT data is the first study addressing aniline CA for 20 years (the previous studies of PT results in patients, consulting for suspected ACD, are summarized in Table 3). Before addressing human data in general, a few particular aspects of the IVDK study will be discussed.
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First of all, the test concentration of 1% which is recommended nowadays (De Groot, 2000) yielded all the positive reactions we observed—higher concentrations previously often used [like 10% in Olive oil (Rietschel and Fowler, 1995)] did not cause positive reactions in the few cases they had been applied presently. The impact of the vehicle, in particular the differential interaction between aniline and petrolatum versus EucerinTM, which consists of 93.5% petrolatum, with two emulsifying agents added, is probably less relevant, albeit not yet formally studied. Our study does not allow for a proper comparison, as aniline in EucerinTM had not been tested in addition to a petrolatum-based preparation in the same patients. Still, the comparison presented above supports this notion to some extent. The observation of a higher age in patients testing positive to aniline (versus testing negative) indicates a positive age gradient, similar to the observation of an
60% increased risk in persons aged 45 and above noted with p-phenylenediamine (Uter et al., 2002). The limited number of patients testing positive to aniline does not allow drawing firm conclusions from the differential distribution of the characteristics shown in Table 1. However, it is evident that aniline had often been tested in cases with hand dermatitis, partly with occupational background, but eventually it was leg dermatitis which was over-represented in the patients testing positive. Evidently, the degree of detail is very limited in several studies: partly, the test concentration (or vehicle) is not given (see Table 3), partly aniline had obviously been tested in consecutive patients [e.g. (Moriearty et al., 1978; Schwarz and Gottmann-Luckerath, 1982)], whereas in other studies aniline had been tested in an aimed fashion, e.g. in patients with lower leg dermatitis, e.g. (Angelini et al., 1975; Ebner and Lindemayr, 1977) (the latter will usually produce a higher yield of positive reactions). A major drawback of virtually any study—including our most recent analysis—is the lack of valid information on past (probable) exposure to aniline which may have caused CA, even though the job titles partly mentioned such as ‘painters’ or ‘leather industry’ (Meneghini et al., 1963), or the use of aniline in occupation-related PT series (Enders, 1986) seem to suggest an occupational context. Similar difficulties in determining the clinical relevance of positive PT reactions have been noted with other allergens as well (Ale and Maibach, 1995). A number of reports include PT results with aniline in patients who had been diagnosed with CA to PAC such as p-phenylenediamine. Although concordance has not formally been quantified by these studies, often the majority of patients with aniline CA tested positive to PAC as well. Nevertheless, in some previous studies positive reactions to aniline have been observed without a notable proportion of concomitant reactions to PAC, indicating the possibility of primary sensitization to aniline: in some of the patch tested groups Meneghini found only one third of patients to react positively to p-phenylenediamine as well positive to aniline (Meneghini et al., 1963). Schultheiss found only 28 of 737 tested patients with a positive reaction to 2% p-phenylenediamine, whereas 5% aniline tested positive in 62 of 737 patients (Schultheiss, 1959).
Results of one human maximization test are available. In this study, 25 persons were induced with 20% aniline solution (no information on purity given) and challenged with 10% aniline in petrolatum, yielding positive results in 7 persons (Kligman, 1966). However, due to limited documentation it remains unclear whether these persons had possibly been exposed to PAC as well, either previously or synchronously.
Experimental data (animal studies)
The skin sensitizing potential of aniline was assessed in three different guinea pig models (Goodwin et al., 1981). The maximization test according to Magnusson and Kligman, employing 1.5% intracutaneous and 25% dermal induction concentration, followed by an epicutaneous challenge using 10% aniline, yielded a positive reaction in 1 of 10 animals. Following the protocol of the Single Injection Adjuvant test (SIAT), 1.5% aniline in physiologic saline was injected intracutaneously in 10 guinea pigs. Elicitation followed after 12–14 days by 6 h occluded chamber application of 20% aniline, yielding positive results in 5 of 10 animals. In a modified Draize test induction was achieved by 4 simultaneous intracutaneous injections in the axilla and into the inguinal lymph nodes of a 2.5% aniline solution. Fourteen days later, an intra- and epicutaneous challenge was performed on the opposite flanks using 1% concentration. In this study, no evidence of a sensitizing potential was found. In a further maximization test with intradermal (0.5% aniline in physiologic saline) and epicutaneous (undiluted) induction, elicitation with undiluted aniline yielded 90% positive reactions in Dunkin–Hartley guinea pigs (Basketter and Scholes, 1992). The discrepancy between the results of these studies can not be fully explained. Test methods in guinea pigs using adjuvant are regarded as very sensitive, but it is also recognized that Freund's complete adjuvant can cause non-specific hypersensitivity (Kligman and Basketter, 1995; Buehler, 1996). Comparing the two available maximizations tests (Goodwin et al., 1981; Basketter and Scholes, 1992) different test substance concentrations could be a reason for the discrepancy, as the study using higher epicutaneous induction and elicitation concentrations found the higher number of animals reacting.
Assessment of aniline in the local lymph node assay (LLNA) yielded negative (Haneke et al., 2001) and doubtful or weak positive reactions (Basketter and Scholes, 1992; Basketter et al., 2003), respectively. The observation that the concentration of aniline necessary to induce a threefold increase in lymphocyte proliferation (EC3 value) ranges from 50 to 89% (in acetone/olive oil) is indicative of a very low sensitization potential (Basketter et al., 2003; Gerberick et al., 2005). A popliteal lymph node test in mice yielded negative results for aniline. Interestingly, this test identified the reactive metabolites nitrosobenzene and phenyl hydroxylamine as possible haptens (Wulferink et al., 2001). However, the role of these or other metabolites in the pathogenesis of human CA/ACD to aniline is yet unclear.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS OF THE IVDKDISCUSSION WITH REVIEW OF...CONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The judgment on aniline being a ‘historical’ or a ‘current’ allergen is based on data which are partly hard to interpret and difficult to integrate:
- In virtually all clinical PT studies, including the most recent one presented here, valid information on previous exposure of aniline sensitive patients to aniline is lacking.
- Considering the apparent strong coupling of aniline CA to CA against some PAC especially in our recent analysis of IVDK data, it appears possible that aniline is not a primary sensitizer, but an allergen eliciting allergic (cross) reactions only in individuals pre-sensitized to PAC—who need not have been exposed to aniline itself.
- On the other hand, in some older studies a notable proportion of patients apparently tested positive only to aniline, but not to those PAC tested. Thus, notwithstanding the general lack of unequivocally proven exposure, it cannot be excluded that aniline may be a primary sensitizer, or may have been one under past exposure conditions.
- The one human maximization study (Kligman, 1966) suggesting that aniline is a contact sensitizer has (i) not been reproduced (and will probably not be reproduced, under current bioethical standards) and (ii) leaves traces of doubt regarding whether aniline has indeed been the primary sensitizer.
- In this situation, the most recent experimental animal studies, with their controlled exposure, seem to provide the best evidence suggesting that aniline is indeed an allergen, albeit a very weak one.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS OF THE IVDKDISCUSSION WITH REVIEW OF...CONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The members of the Information Network of Departments of Dermatology (IVDK) contributed data to this analysis are as follows: Dortmund (P.J. Frosch, B. Pilz, C. Pirker, R. Herbst, K. Kügler), Erlangen (K.-P. Peters, T.L. Diepgen, M. Fartasch, M. Hertl, V. Mahler), Essen (J. Schaller, H.-M. Ockenfels, U. Hillen), Hamburg (M. Kiehn, D. Vieluf, R. Weßbecher), Homburg/Saar (F.A. Bahmer, P. Koch, C. Pföhler), Kiel (J. Brasch), Mainz (D. Becker), München LMU (F. Enders, F. Rueff, B. Przybilla, P. Thomas, T. Oppel), München TU (J. Rakoski, U. Darsow), Tübingen (G. Lischka, M. Röcken, T. Biedermann), Ulm (H. Gall [deceased], P. Gottlöber, R. Hinrichs, G. Staib, H. Pillekamp).
Received July 3, 2006; in final form October 18, 2006
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