Chemical contact allergens

For effective sensitization, a chemical must therefore be inherently protein-reactive or must be converted in the skin to a protein-reactive metabolite. Chemicals that are unable to associate effectively with proteins will fail to stimulate a cutaneous immune response. For those chemical contact allergens that require metabolism to a protein reactive species, it is possible that genetic differences in metabolism may play a role in the differential susceptibility of individuals to the development of contact hypersensitivity responses to these materials. 

Over the past decade, there have been considerable advances in our understanding of the immunobiological mechanisms that result in the quality of immune response necessary for the induction of chemical respiratory allergy. Experiments designed to characterize immune responses in mice to chemical sensitizers have demonstrated that different classes of chemical allergen stimulate the development of qualitatively discrete immune responses consistent with the selective emergence of functional subpopulations of T lymphocytes [16]. Thus, topical exposure of BALB/c strain mice to chemical contact allergens such as 2,4-dinitrochlorobenzene (DNCB) results in the induction of... 

Sources of Information on the Occurrence of Chemical Contact Allergens... 

The different sources of information each have their advantages and limitations, and are thus more or less adequate in different situations (Flyvholm et al. 1995 Flyvholm 1996). This chapter gives a presentation of the different methods used to obtain information on the occurrence of chemical contact allergens with a short discussion on each method followed by a general discussion. 

Chap. 58 (Computerised Product Database. Registered Chemical Contact Allergens) and Flyvholm et al. (1992). 

Formaldehyde is an example of a contact allergen which can occur in products from various origins, each of which requires different sources of information to be detected (Flyvholm 1997). Thus, formaldehyde is used below to illustrate advantages and limitations of the different sources of information on occurrence of chemical contact allergens. 

For each concentration of chemical tested in the LLNA, a stimulation index (SI) is derived using the value obtained with the concurrent vehicle control as the denominator. Chemicals that induce an SI of three or more are defined as skin sensitizers. This threshold for positivity was based initially on empirical observations in investigations of both contact allergens and non-sensitizing chemicals [5], Subsequently, a retrospective statistical analysis of results obtained in the LLNA with a wider range of chemicals (130) confirmed that an SI value of 3 does indeed provide the most appropriate basis... 

Basketter, D.A., Scholes, E.W. and Kimber, I., The performance of the local lymph node assay with chemicals identified as contact allergens in the human maximization test, Fd. Chem. Toxic., 32, 543, 1994. 

Dearman, R J. et al., Differential ability of occupational chemical contact and respiratory allergens to cause immediate and delayed dermal hypersensitivity reactions in mice. Int. Arch. Allergy Immunol., 97, 315, 1992. 

Warbrick, E.V. et al., Analysis of cytokine mRN A expression following repeated exposure of mice to chemical contact and respiratory allergens. J. Appl. Toxicol., 18, 205, 1998. 

Whether or not chlorothalonil is a true dermal sensitizer in humans or strictly a skin irritant remains controversial. Some investigators suggest that repeated exposure results in an enhanced irritant response, whereas others suggest that it is a potent contact allergen. It is noted that relatively few cases of allergy to chlorothalonil have been reported despite widespread use for over 20 years. Furthermore, at a plant that produces the chemical cases of work-related contact dermatitis have not been reported for years after adoption of good hygienic practices. ... 

A study in mice examined immune responses following topical exposure to three allergenic diisocyanates diphenylmethane-4,4 -diisocyanate (MDI), dicyclohexyl-methane-4,4 -diisocyanate (HMDI), and isophorone diisocyanate (IPDI). Contact and respiratory sensitizers induce differential immune responses in mice characteristic of Thl and Th2 T helper cell activation, respectively. All three chemicals are contact allergens. MDI is, in addition, a known human respiratory allergen. HMDI and IPDI did not produce an immunologic response in the mouse similar to MDI. These findings suggest that HMDI has much less potential to cause respiratory sensitization in humans than does MDI ... 

Toxicology. Zinc dithiocarbamates (ZDC) are contact allergens and are one of the chemical groups in rubber that cause the type IV delayed-type hypersensitivity skin reaction (DTH). ... 

Based on the kno vledge of the processes of T cell sensitization by chemicals and the importance of T cells in induction of autoimmune diseases a number of key indicators of autoimmunogenic compounds can be defined. These include the possibility to be subject of metabolic conversion (either intra- or extra-hepatically), the capacity to activate dendritic cells, to induce cytokine production (in any cell type), or the potency to cause cell stress or cell death. Most of these processes can be studied in vitro, but none of the available methods have been tested for this purpose and often chemicals may behave completely different in vitro than in vivo. However, much can be learned from initiatives to design alternative methods for contact allergens, as many of these basic processes that lead to T cell sensitization are similar for allergenic and autoimmunogenic chemicals. 

Gerberick, G.F., Vassallo, J.D., Foertsch, L.M., Price, B.B., Chaney, J.G. and Lepoittevin, J.P. (2007) Quantification of chemical peptide reactivity for screening contact allergens a classification tree model approach. Toocicological Sciences, 97, 417 27. 

Zinke, S., Gerner, I., and Schlede, E., Evaluation of a rule base for identifying contact allergens by using a regulatory database comparison of data on chemicals notified in the European union with "structural alerts" used in the DEREK expert system, Alt. Lab. Anim. (ATLA), 30, 285-298, 2002. 

Maurer T, Thomann P, Weirich EG, Hess R (1975) The optimization test in the guinea-pig. A method for the predictive evaluation of the contact allergenicity of chemicals. Agents Actions. 5(2) 174-179... 

Thus, when faced with a chemical of unknown activity, the program uses the presence or absence of toxicophores and of modulators to predict its toxicity (Figs. 19.1-19.3). Thus, the presence of the toxicophore OH—0= (a phenol) endows a chemical with an 87.5% probability of being a contact allergen and a potency of 51 (moderate activity, see Table... 

Figure 19.2. Prediction of the contact allergenicity of 4-chloro-l,3-benzenediol. In addition to the probability of activity and the basal potency derived from the toxicophore (shown in bold in A), the chemical also contains an activating modulator (shown in bold in B), which further augments the potency. A potency of 64 units indicates a very strong potency (Table 19.3).

Figure 19.3. Predictionof the lack of contact allergenicity of zingerone-Whereasthepresenceofthe toxicophore (A) is associated with a probability of activity and a potency, the presence of the inactivating modulator (B) abohshes the potency. Moreover, the presence of a deactivating moiety (C), which is presentin five chemicals in thedatabasethat are devoid of allergenicity (Tablel9.2,No. 19), further decreases the likelihood that the zigerone is a contact allergen.

Figure 19.4. Prediction of the lack of contact allergenicity of of dehydroalantolactone. The chemical contains no toxicophore therefore, it is presumed to be inactive. However, it contains two structures (shownin bold)that are "unknown" to the model. That introduces an element of uncertainity in the prediction.

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