Different DNA damage response of cis and trans isomers of commonly used UV filter after the exposure on adult human liver stem cells and human lymphoblastoid cells

2-ethylhexyl 4-methoxycinnamate (EHMC), used in many categories of personal care products (PCPs), is one of the most discussed ultraviolet filters because of its endocrine-disrupting effects. EHMC is unstable in sunlight and can be transformed from trans-EHMC to emergent cis-EHMC. Toxicological studies are focusing only on transEHMC; thus the toxicological data for cis-EHMC are missing. In this study, the in vitro genotoxic effects of trans- and cis-EHMC on adult human liver stem cells HL1-hT1 and human-derived lymphoblastoid cells TK-6 using a high-throughput comet assay were studied. TK-6 cells treated with cis-EHMC showed a high level of DNA damage when compared to untreated cells in concentrations 1.56 to 25 mu g mL(-1). trans-EHMC showed genotoxicity after exposure to the two highest concentrations 12.5 and 25 mu g mL(-1). The increase in DNA damage on HL1-hT1 cells induced by cis-EHMC and transEHMC was detected at the concentration 25 pg mL-1. The No observed adverse effect level (NOAEL, mg kg lbw day I) was determined using a Quantitative in vitro to in vivo extrapolation (QIVIVE) approach: NOAEL(trans-EHMC) = 3.07, NOAEL(cis-EHMC) = 0.30 for TK-6 and NOAEL(trans-EHMC) = 26.46, NOAEL(cis-EHMC) = 20.36 for HL1-hT1. The hazard index (HI) was evaluated by comparing the reference dose (RID, mg kg(-1) bw day(-1)) obtained from our experimental data with the chronic daily intake (CDI) of the female population. Using comet assay experimental data with the more sensitive TK-6 cells, HIcis-EHMC was 7 times higher than HItrans-EHMC In terms of CDI, relative contributions were; dermal exposure route > oral > inhalation. According to our results we recommend the RfD(trans-EHMC) = 0.20 and RfD(cis-EHMC) = 0.02 for trans-EHMC and cis-EHMC, respectively, to use for human health risk assessment. The significant difference in trans-EHMC and cis-EHMC response points to the need for toxicological reevaluation and application reassessment of both isomers in PCPs. (C) 2017 Elsevier B.V. All rights reserved.