Relationship between allergic contact dermatitis and electrophilicity.

Rosenkranz, Herbert S.; Klopman, Gilles; Zhang, Ying Ping; Graham, Cynthia; Karol, Meryl H.

doi:10.1289/ehp.99107129

Cited by 23 publications

(17 citation statements)

References 21 publications

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“…Our estimate that 32% of contact sensitizers, in the widespread use category, are mutagenic corroborates the analysis by Rosenkranz, Klopman, Zhang, Graham, and Karol, who obtained a figure of 30-40% of contact sensitizers that were electrophiles as judged by SAR analyses of contact sensitizers for mutagenesis. (13) It also agrees with the previous value of 36% based on the more limited analysis of contact sensitizers among the NTP chemicals. (2) The complexity of the response patterns shown in Table III could be reasonably surmised from what is known about the chemical and biological behavior of mutagens and contact sensitizers.…”

Section: Discussionsupporting

confidence: 91%

The Tumorigenicity of Mutagenic Contact‐Sensitizing Chemicals

Albert

Magee²

2000

Risk Analysis

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The electrophilic nature of some contact sensitizers, that is, chemicals that cause allergic contact dermatitis (ACD), is also characteristic of genotoxic tumorigens. Electrophiles can adduct protein, which is the basis for ACD, as well as DNA, which is the basis for mutagenicity and carcinogenicity. This suggests that some electrophilic contact sensitizers may be genotoxic tumorigens. To further investigate this matter, we evaluated 146 chemicals that had been bioassayed for tumorigenicity and mutagenicity in the National Toxicology Program, with an analysis of structure-activity relationships for contact sensitization. Using the data from this analysis and from other sources, the proportion of the contact sensitizers that were both mutagenic and tumorigenic was found to range from 20% to 28%. This finding suggests that there may be in the order of 90 genotoxic tumorigens for rodents among the approximately 384 chemicals that have been validated as contact sensitizers for humans.

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Section: Discussionsupporting

confidence: 91%

The Tumorigenicity of Mutagenic Contact‐Sensitizing Chemicals

Albert

Magee²

2000

Risk Analysis

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“…Early evidence demonstrating chemical reactivity as underpinning the sensitizing potency of a chemical was reported by Landsteiner and Jacobs in 1936. 14 The rationalization of skin sensitizer properties in terms of electrophilicity or proelectrophilicity of the chemicals, enabling them to bind to proteins is supported by observations from Rosenkranz et al 15 where 30–40% out of 355 randomly chosen chemicals that are human sensitizers were electrophilic. While the majority of electrophilic chemicals are known to exist within the five common mechanistic applicability domains (i.e.…”

Section: Introductionmentioning

confidence: 98%

Substituent Effects on the Reactivity of Benzoquinone Derivatives with Thiols

Mbiya

Chipinda

Siegel

et al. 2012

Chem. Res. Toxicol.

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Benzoquinone (BQ) is an extremely potent electrophilic contact allergen that haptenates endogenous proteins through Michael addition (MA). It is also hypothesized that BQ may haptenate proteins via free radical formation. The objective of this study was to assess the inductive effects (activating and deactivating) of substituents on BQ reactivity and mechanistic pathway of covalent binding to a nucleophilic thiol. The BQ binding of Cys34 on human serum albumin was studied and for reactivity studies, nitrobenzenethiol (NBT) was used as a surrogate for protein binding of the BQ and benzoquinone derivatives (BQD). Stopped flow techniques were used to determine pseudo-first order rate constants (k) of methyl, t-butyl and chlorine substituted BQD reactions with NBT whereas electron pair resonance (EPR) studies were performed to investigate the presence a free radical mediated binding mechanism of BQD. Characterization of adducts was performed using mass spectrometry and nuclear magnetic resonance spectroscopy (NMR). The rate constant values demonstrated the chlorine substituted (activated) BQD to be more reactive toward NBT than the methyl and t-butyl substituted (deactivated) BQD, and this correlated with the respective EPR intensities. The EPR signal, however, was quenched in the presence of NBT suggesting MA as the dominant reaction pathway. MS and NMR results confirmed adduct formation to be a result of MA onto the BQ ring with vinylic substitution also occurring for chlorine substituted derivatives. The binding positions on BQ and NBT:BQ(D) stoichiometric ratios were affected by whether the inductive effects of the substituents on the ring were positive or negative. The reactivity of BQ and BQD is discussed in terms of the potential relationship to potential allergenic potency.

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“…This RAI model has been used in order to evaluate data on various sets of skin‐sensitizing chemicals, including sultones, p ‐nitrobenzyl halides, acrylates, sulfonate esters and substituted gamma butyrolactones (15, 16). Other approaches include the development of empirical QSARs by means of the application of statistical methods to sets of biological data and structural descriptors (17, 18). Despite the complexities and the still‐limited understanding of some of the processes leading to skin sensitization, it is possible to describe some of the relationships between chemical structures and the ability to form covalent conjugates with proteins.…”

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confidence: 99%

Ranking of hair dye substances according to predicted sensitization potency: quantitative structure–activity relationships

et al. 2004

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Allergic contact dermatitis following the use of hair dyes is well known. Many chemicals are used in hair dyes and it is unlikely that all cases of hair dye allergy can be diagnosed by means of patch testing with p-phenylenediamine (PPD). The objectives of this study are to identify all hair dye substances registered in Europe and to provide their tonnage data. The sensitization potential of each substance was then estimated by using a quantitative structure-activity relationship (QSAR) model and the substances were ranked according to their predicted potency. A cluster analysis was performed in order to help select a number of chemically diverse hair dye substances that could be used in subsequent clinical work. Various information sources, including the Inventory of Cosmetics Ingredients, new regulations on cosmetics, data on total use and ChemId (the Chemical Search Input website provided by the National Library of Medicine), were used in order to identify the names and structures of the hair dyes. A QSAR model, developed with the help of experimental local lymph node assay data and topological sub-structural molecular descriptors (TOPS-MODE), was used in order to predict the likely sensitization potential. Predictions for sensitization potential were made for the 229 substances that could be identified by means of a chemical structure, the majority of these hair dyes (75%) being predicted to be strong/moderate sensitizers. Only 22% were predicted to be weak sensitizers and 3% were predicted to be extremely weak or non-sensitizing. Eight of the most widely used hair dye substances were predicted to be strong/moderate sensitizers, including PPD - which is the most commonly used hair dye allergy marker in patch testing. A cluster analysis by using TOPS-MODE descriptors as inputs helped us group the hair dye substances according to their chemical similarity. This would facilitate the selection of potential substances for clinical patch testing. A patch-test series with potent, frequently used, substances representing various chemical clusters is suggested. This may prove useful in diagnosing PPD-negative patients with symptoms of hair dye allergy and would provide some clinical validation of the QSAR predictions.

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Relationship between allergic contact dermatitis and electrophilicity.

Cited by 23 publications

References 21 publications

The Tumorigenicity of Mutagenic Contact‐Sensitizing Chemicals

The Tumorigenicity of Mutagenic Contact‐Sensitizing Chemicals

Substituent Effects on the Reactivity of Benzoquinone Derivatives with Thiols

Ranking of hair dye substances according to predicted sensitization potency: quantitative structure–activity relationships

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