Molecular Evaluation of Vitamin D3 Receptor Agonists Designed for Topical Treatment of Skin Diseases11The authors declared not to have conflict of interest

MC903 (calcipotriol) is a synthetic, low calcemic analog of the nuclear hormone 1α,25-dihydroxyvitamin D3 and used in the treatment of psoriasis. The beneficial effects of MC903 on psoriasis are based on gene regulatory events. The genomic actions of 1α,25-dihydroxyvitamin D3 and its analogs are primarily mediated by a complex of the vitamin D3 receptor and the retinoid X receptor bound to a 1α,25-dihydroxyvitamin D3 response element that can be considered as the molecular switch of 1α,25-dihydroxyvitamin D3 signaling. In this study, the interaction of MC903 and two new analogs, GS1500 and EB1213, with this molecular switch was compared with that of 1α,25-dihydroxyvitamin D3. In DNA-dependent limited protease digestion assays, ligand-dependent gel shift assays and mammalian-one-hybrid assays, all four ligands appeared to be equally sensitive VDR agonists that activated vitamin D3 receptor–retinoid X receptor-1α,25-dihydroxyvitamin D3 response element complexes at a concentration of approximately 0.2 nM. The analyzed VDR agonists, however, also showed individual molecular properties, such as a reduced sensitivity in HaCaT cells (MC903), a selectivity for DNA-bound vitamin D3 receptor–retinoid X receptor heterodimers (GS1500) and a long-lasting stabilization of vitamin D3 receptor–retinoid X receptor-1α,25-dihydroxyvitamin D3 response element complexes (EB1213). This molecular evaluation demonstrated that the sensitivity in activating the vitamin D3 receptor is already optimal for MC903, but the analog may not be ideal in keeping the receptor active and in selectively triggering 1α,25-dihydroxyvitamin D3 signaling pathways

Assessment of dermal absorption of aluminium from a representative antiperspirant formulation using a (26A1)A1 microtracer approach: A follow-up study in humans

A follow-up study was performed in 12 healthy women to evaluate systemic exposure to aluminium following topical application of a representative antiperspirant formulation under real-life use conditions (part A) and to assess the local fate of topically applied aluminium by taking additional tape strips and skin biopsies (Part B). A simple roll-on formulation, containing the maximal possible radioactive dose, was prepared with [26A1] aluminium-labeled chlorohydrate (ACH). The microtracer of [26A1] was used to distinguish aluminium from the natural background, using accelerator mass spectrometry. [26A1] aluminiumcitrate was administered intravenously to estimate the dermal fraction absorbed. Despite the 25-fold increase of the topical dose compared with the previous study, only 12 blood samples gave results above the lower limit of quantitation (0.118 fg/mL). The most reliable estimates of the dermal fraction absorbed are derived from noncompartmental analysis with the urine data. By using the intravenous dose to normalize the urinary excretion to 100% bioavailability, the best estimate of the fraction absorbed of [26A1] from a topical application of [26A1]- aluminium-labeled chlorohydrate in an antiperspirant formulation was 0.00052%. Part B of the study demonstrated that the majority of the aluminium in the formulation remained associated with the external layers of the skin without penetration through the skin. copy 2022 The Author(s) 2022

Read-across and new approach methodologies applied in a 10-step framework for cosmetics safety assessment – A case study with parabens

International audienceParabens are esters of para-hydroxybenzoic acid that have been used as preservatives in many types of products for decades including agrochemicals, pharmaceuticals, food and cosmetics. This illustrative case study with propylparaben (PP) demonstrates a 10-step read-across (RAX) framework in practice. It aims at establishing a proof-of-concept for the value added by new approach methodologies (NAMs) in read-across (RAX) for use in a next-generation risk assessment (NGRA) in order to assess consumer safety after exposure to PP-containing cosmetics. In addition to structural and physico-chemical properties, in silico information, toxicogenomics, in vitro toxicodynamic, toxicokinetic data from PBK models, and bioactivity data are used to provide evidence of the chemical and biological similarity of PP and analogues and to establish potency trends for observed effects in vitro. The chemical category under consideration is short (C1–C4) linear chain n-alkyl parabens: methylparaben, ethylparaben, propylparaben and butylparaben. The goal of this case study is to illustrate how a practical framework for RAX can be used to fill a hypothetical data gap for reproductive toxicity of the target chemical PP