Analysis of real-time mixture cytotoxicity data following repeated exposure using BK/TD models.
Cosmetic products generally consist of multiple ingredients. Thus, cosmetic risk assessment has to deal with mixture toxicity on a long-term scale which means it has to be assessed in the context of repeated exposure. Given that animal testing has been banned for cosmetics risk assessment, in vitro assays allowing long-term repeated exposure and adapted for in vitro - in vivo extrapolation need to be developed. However, most in vitro tests only assess short-term effects and consider static endpoints which hinder extrapolation to realistic human exposure scenarios where concentration in target organs is varies over time. Thanks to impedance metrics, real-time cell viability monitoring for repeated exposure has become possible. We recently constructed biokinetic/toxicodynamic models (BK/TD) to analyze such data (Teng et al., 2015) for three hepatotoxic cosmetic ingredients: coumarin, isoeugenol and benzophenone-2. In the present study, we aim to apply these models to analyze the dynamics of mixture impedance data using the concepts of concentration addition and independent action. Metabolic interactions between the mixture components were investigated, characterized and implemented in the models, as they impacted the actual cellular exposure. Indeed, cellular metabolism following mixture exposure induced a quick disappearance of the compounds from the exposure system. We showed that isoeugenol substantially decreased the metabolism of benzophenone-2, reducing the disappearance of this compound and enhancing its in vitro toxicity. Apart from this metabolic interaction, no mixtures showed any interaction, and all binary mixtures were successfully modeled by at least one model based on exposure to the individual compounds.
Models for Toxicology and Ecotoxicology Unit, INERIS, Parc Technologique Alata, BP 2, 60550 Verneuil-en-Halatte, France.
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Teng
Models for Toxicology and Ecotoxicology Unit, INERIS, Parc Technologique Alata, BP 2, 60550 Verneuil-en-Halatte, France.
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Tebby
ODESIA Neosciences, Sophia Antipolis, 400 route des chappes, 06903 Sophia Antipolis, France.
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Barcellini-Couget
INRA, ToxAlim, 400 route des Chappes, BP, 167 06903 Sophia Antipolis, Cedex, France.
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De Sousa
Models for Toxicology and Ecotoxicology Unit, INERIS, Parc Technologique Alata, BP 2, 60550 Verneuil-en-Halatte, France.
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Brochot
INRA, ToxAlim, 400 route des Chappes, BP, 167 06903 Sophia Antipolis, Cedex, France.
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Rahmani
AgroParisTech, UMR 1402 INRA-AgroParisTech Ecosys, 78850 Thiverval Grignon, France; INRA, UMR 1402 INRA-AgroParisTech Ecosys, 78850 Thiverval Grignon, France. Electronic address: alexandre.pery@agroparistech.fr.
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Pery
D001577:Benzophenones / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003358:Cosmetics / Q000493:pharmacokinetics* / Q000633:toxicity*; D003374:Coumarins / Q000493:pharmacokinetics / Q000633:toxicity; D004347:Drug Interactions; D005054:Eugenol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D008954:Models, Biological
D001577:Benzophenones; D003358:Cosmetics; D003374:Coumarins; D005054:Eugenol; C036643:isoeugenol; C030123:coumarin; C035476:2,2',4,4'-tetrahydroxybenzophenone
Cell viability; Hepatotoxicity; Impedance; Mixture; Repeated dose toxicity; TK/TD models