Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy.

BACKGROUND AND PURPOSE: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated. EXPERIMENTAL APPROACH: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg-1·day-1 elexacaftor + 3.5 mg·kg-1·day-1 tezacaftor + 25 mg·kg-1·day-1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed. KEY RESULTS: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development. CONCLUSION AND IMPLICATION: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.

Mechanisms of adverse mammary effect induced by olanzapine and therapeutic interventions in rat model.

BACKGROUND: Olanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented. METHODS: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed. RESULTS: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen. CONCLUSIONS: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.

The Effect of Quinolones on Common Duckweed Lemna minor L., a Hydrophyte Bioindicator of Environmental Pollution.

Plant growth and the development of morphological traits in plants are inhibited under exposure to pharmaceuticals that are present in soil and water. The present study revealed that moxifloxacin (MOXI), nalidixic acid (NAL), levofloxacin (LVF) and pefloxacin (PEF) at concentrations of >0.29, >0.48, >0.62 and >1.45 mg × L-1, respectively, inhibited the growth (Ir) of duckweed plants and decreased their yield (Iy). In the current study, none of the tested quinolones (QNs) at any of the examined concentrations were lethal for common duckweed plants. However, at the highest concentration (12.8 mg × L-1), LVF increased Ir and Iy values by 82% on average and increased the values of NAL, PEF and MOXI by 62% on average. All tested QNs led to the loss of assimilation pigments. In consequence, all QNs, except for LVF, induced changes in chlorophyll fluorescence (Fv/Fm), without any effect on phaeophytinization quotient (PQ) values. The uptake of NAL, MOXI, LVF by Lemna minor during the 7-day chronic toxicity test was directly proportional to drug concentrations in the growth medium. Nalidixic acid was absorbed in the largest quantities, whereas in the group of fluoroquinolones (FQNs), MOXI, LVF and PEF were less effectively absorbed by common duckweed. This study demonstrated that biosorption by L. minor occurs regardless of the plants' condition. These findings indicate that L. minor can be used as an effective biological method to remove QNs from wastewater and water and that biosorption should be a mandatory process in conventional water and wastewater treatment.

Validation and inhibition study for toxic expression of quinolone antibiotic resistance genes in agricultural soils of eastern China.

With the extensive use of antibiotics, the problem of antibiotic resistance genes (ARGs) has gradually emerged. As agricultural soil is an important enrichment media of antibiotics and ARGs, it is particularly important to study the toxicity of ARGs, the effects of various nutrients and pollutants, and how to control them through source modification and process regulation. In this study, a combination of source modification and process regulation was used to weaken the toxic expression of Quinolones' (QNs') ARGs in soils from different agricultural areas. And the influence of soil nutrients and pollutants on this process will be explored. Protein-protein docking and molecular docking were used to construct a target protein complex for the toxic expression of QNs' ARGs and characterize the toxicity of QNs' ARGs. The two-dimensional and three-dimensional quantitative structure-activity relationships model construction and sensitivity analysis were used to molecular modification and related validation. Molecular dynamics simulations assisted by sampling survey method based on agricultural soils in Northeast China and the lower-middle reaches of the Yangtze River were carried out to generate four scenarios. The main results are: (a) A functionally improved and environmentally friendly quinolone derivative (ORB-19) was designed. It can effectively inhibit the expression of QNs' ARGs and weaken the antibiotic selection pressure risk. The application of ORB-19 in agricultural areas could significantly inhibit the toxic expression of QNs' ARGs (112.75%~169.59%); (b) QNs' ARGs have a stronger toxic expression in agricultural areas of Northeast China, which have higher nutrient elements; (c) The contribution of different types of agricultural pollution to suppressing the toxic expression of QNs' ARGs in agricultural soils varies; (d) The options of applied field measures given for the inhibition of QNs' ARG toxic expression varied between plots with different agricultural pollution types. This study provides theoretical support for inhibiting the toxic expression of QNs' ARGs in the soil environment, reducing the spread of ARGs in microbial populations, replacing green QNs derivatives, and sustainable development of agricultural soils.

Detection, dietary exposure assessment and risk evaluation of quinolones and pyrrolizidine alkaloids in commercial honey from Brazil.

Pyrrolizidine alkaloids are secondary plant metabolites that have already been designated as a potential health risk due to their toxicity. Quinolones are antimicrobials related to bacterial resistance, one of the world's largest contemporary public health problems. This study searched for 22 pyrrolizidine alkaloids and 7 quinolones in honey available for sale in the state of Rio de Janeiro - Brazil - employing an analytical method based on LC-Q-TOF-HRMS. No quinolones were identified, while pyrrolizidine alkaloids were found in 39 out of 80 samples, mainly erucifoline (detected in 17% of the samples) and intermedine/lycopsamine (quantified in 27% of the samples). Considering the highest value found, 141.8 µg kg-1 for senecionine and a consumption of 20 g of honey per person per day, the dietary exposure reached 47.3 ng kg-1, resulting in a MOE value of 5.010, that might lead to a risk for human health.

Early antitumor activity of oral Langerhans cells is compromised by a carcinogen.

Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here, we define the Langerhans cells (LCs) of the tongue and demonstrate that LCs protect the epithelium from carcinogen-induced OSCC by rapidly priming αßT cells capable of eliminating γH2AX+ epithelial cells, whereas γδT and natural killer cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies, while dendritic cells (DCs), macrophages, and plasmacytoid DCs (pDCs) populate the epithelium. Single-cell RNA-sequencing analysis indicates that these newly differentiated cells display an immunosuppressive phenotype accompanied by an expansion of T regulatory (Treg) cells. Accumulation of the Treg cells was regulated, in part, by pDCs and precedes the formation of visible tumors. This suggests LCs play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis.

Strengthened rebamipide ocular nanoformulation to effectively treat corneal alkali burns in mice through the HMGB1 signaling pathway.

Corneal alkali burns are a major ophthalmic emergency, as current therapeutic treatments are limited. Novel treatment targets and new potential agents are required to combat this severe ocular injury. Glycyrrhizin and rebamipide (RBM) are both FDA-approved drugs with potential effects against corneal alkali burns, but RBM is limited by its low aqueous solubility and low bioavailability. This study aimed to utilize dipotassium glycyrrhizinate (DG, a dipotassium salt of glycyrrhizin) as a nanocarrier encapsulating RBM to formulate an ophthalmic solution (marked DG-RBM) with strengthened activities to treat corneal alkali burns. Results showed that an easy DG-RBM preparative process generated particles with high encapsulation efficacy and ultra-small micellar size. The solubility of RBM in DG-RBM in aqueous solution was 3.1 × 105-fold enhanced than its free solution. DG-RBM exhibited excellent storage stability. In vitro cytotoxicity, ex vivo conjunctival responses, and rabbit eye tolerance tests showed that DG-RBM possessed good ocular safety profiles. DG-RBM exhibited improved in vivo corneal permeation profiles and demonstrated a strong effect against H2O2-induced oxidative damage, with a significant effect on promoting epithelial wound healing in corneal cells in vitro. As expected, in a mouse model of corneal alkali burns, the topical administration of DG-RBM achieved a strengthened efficacy against alkali burn damages. The mechanism of this therapeutic effect involved regulating high-mobility group box 1 (HMGB1) signaling and its related angiogenic and proinflammatory cytokines. These findings demonstrate the ease of preparing DG-RBM and its great potential as a novel ocular topical formulation to treat corneal alkali burns by regulating HMGB1 signaling.

Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp.

P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4-7 and 12 is required for inhibition.

Cytotoxicity of Amino-BODIPY Modulated via Conjugation with 2-Phenyl-3-Hydroxy-4(1H)-Quinolinones.

The combination of cytotoxic amino-BODIPY dye and 2-phenyl-3-hydroxy-4(1H)-quinolinone (3-HQ) derivatives into one molecule gave rise to selective activity against lymphoblastic or myeloid leukemia and the simultaneous disappearance of the cytotoxicity against normal cells. Both species' conjugation can be realized via a disulfide linker cleavable in the presence of glutathione characteristic for cancer cells. The cleavage liberating the free amino-BODIPY dye and 3-HQ derivative can be monitored by ratiometric fluorescence or by the OFF-ON effect of the amino-BODIPY dye. A similar cytotoxic activity is observed when the amino-BODIPY dye and 3-HQ derivative are connected through a non-cleavable maleimide linker. The work reports the synthesis of several conjugates, the study of their cleavage inside cells, and cytotoxic screening.

In vivo and in silico evaluations of survival and cardiac developmental toxicity of quinolone antibiotics in zebrafish embryos (Danio rerio).

Quinolones are ranked as the second most commonly used class of antibiotics in China, despite their adverse clinical and environmental effects. However, information on their cardiac developmental toxicity to zebrafish is limited. This study investigates the relationships between different quinolone structures and toxicity in zebrafish embryos using in vivo and in silico methods. All of the experimentally tested quinolones show cardiac developmental toxicity potential and present mortality and teratogenic effects in a dose-dependent manner. Theoretically, the acute toxicity values predicted using quantitative structure-toxicity relationship (QSTR) modeling based on previously reported LC50 values are in good agreement with the in vivo results. Further investigation demonstrates that the hormetic concentration response of some quinolones may be related to methylation on the piperazine ring at the C-7 position. The amino group at the C-5 position, the methylated or ethylated piperazine group at the C-7 position, halogens at the C-8 position and a cyclopropyl ring at N1 position may be responsible for cardiac developmental toxicity. In terms of survival (key ecological endpoint), the naridine ring is more toxic than the quinoline ring. This combined approach can predict the acute and cardiac developmental toxicity of other quinolones and impurities.

Second-, third- and fourth-generation quinolones: Ecotoxicity effects on Daphnia and Ceriodaphnia species.

We conducted the first complete toxicological study of six quinolones, including acute, chronic, and recovery assays on Daphnia magna and Ceriodaphnia dubia. The assayed quinolones were second-generation ciprofloxacin (CIP), norfloxacin (NOR), enrofloxacin (ENR), and marbofloxacin (MAR); third-generation levofloxacin (LEV), and fourth-generation moxifloxacin (MOX). The median lethal concentrations (LC50) obtained for both species by acute ecotoxicity assay ranged from 14 to 73 mg L-1 and from 3 to 23 mg L-1 at 48 and 72 h, respectively; while the median effective concentration (EC50) ranged from 4 to 28 mg L-1 in the chronic ecotoxicity assays. C. dubia surviving the chronic exposure assay was monitored in recovery assays free of quinolones. A fluorometric method was used to confirm that there was no significant loss of quinolone concentrations during the acute assays. We also used this method to show that quinolone concentrations fell below 80% of the nominal value after 9-11 d if exposure solutions were not renewed. This study on the ecotoxicological and chemical behavior of quinolones in two cladoceran species fills a data gap about how these emerging contaminants affect nontarget aquatic organisms and how long they persist in the environment.

Combined toxicity characteristics and regulation of residual quinolone antibiotics in water environment.

In this study, the mixture toxicity index method was used to evaluate the combined toxicity of residual Quinolones (QNs) on algae in twelve groups of water environment reported in the literature. The selected three sets of data (II, Ⅺ, and Ⅻ) combined with full factorial design method were used to analyze the significance of the combined toxicity. Subsequently, molecular docking was used to reveal the significant mechanism of the primary effect of the combined toxicity. Finally, based on the sensitivity analysis method, the acid-base conditions affecting the combined toxicity were screened, and molecular dynamics simulation was used to control the combined toxicity in the water environment. The results of the mixture toxicity index method showed that the combined toxicity in all the twelve groups of water environments was synergistic. The full factorial design method revealed that ciprofloxacin, norfloxacin, enrofloxacin, lomefloxacin, and their binary combinations from the combined toxicity system of QNs, were the significant factors that caused the synergistic toxicity of QNS on algae. Molecular docking confirmed that the total number of amino acids, the number of significant amino acids, and hydrogen bonds of QNs toxic targets were significantly related to the synergistic effect of the combined toxicity. In addition, the molecular dynamics simulation showed that the binding energy of residual QNs and toxic targets changes with the acid-base conditions of the water environment. Thus, the combined toxicity can be slowed down or reduced by adequately adjusting the acid-base condition of the water.

Environmentally Friendly Quinolones Design for a Two-Way Choice between Biotoxicity and Genotoxicity through Double-Activity 3D-QSAR Model Coupled with the Variation Weighting Method.

Quinolone (QN) antibiotics are widely used, which lead to their accumulation in soil and toxic effects on ryegrass in pasture. In this study, we employed ryegrass as the research object and selected the total scores of 29 QN molecules docked with two resistant enzyme structures, superoxide dismutase (SOD, PDB ID: 1B06) and proline (Pro, PPEP-2, PDB ID: 6FPC), as dependent variables. The structural parameters of QNs were used as independent variables to construct a QN double-activity 3D-QSAR model for determining the biotoxicity on ryegrass by employing the variation weighting method. This model was constructed to determine modification sites and groups for designing QNs molecules. According to the 3D contour map of the model, by considering enrofloxacin (ENR) and sparfloxacin (SPA) as examples, 23 QN derivatives with low biotoxicity were designed, respectively. The functional properties and environmental friendliness of the QN derivatives were predicted through a two-way selection between biotoxicity and genotoxicity before and after modification; four environmentally friendly derivatives with low biotoxicity and high genotoxicity were screened out. Mixed toxicity index and molecular dynamics methods were used to verify the combined toxicity mechanism of QNs on ryegrass before and after modification. By simulating the combined pollution of ENR and its derivatives in different soils (farmland, garden, and woodland), the types of combined toxicity were determined as partial additive and synergistic. Binding energies were calculated using molecular dynamics. The designed QN derivatives with low biotoxicity, high genotoxicity, and environmental friendliness can highly reduce the combined toxicity on ryegrass and can be used as theoretic reserves to replace QN antibiotics.

Absence of Mal/TIRAP Results in Abrogated Imidazoquinolinones-Dependent Activation of IRF7 and Suppressed IFNß and IFN-I Activated Gene Production.

Activation of TLR7 by small imidazoquinoline molecules such as R848 or R837 initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-κB, and interferon regulatory factors (IRFs) and afterward to the induction of cytokines and anti-viral Type I IFNs. In general, TLRs mediate these effects by utilizing different intracellular signaling molecules, one of them is Mal. Mal is a protein closely related to the antibacterial response, and its role in the TLR7 pathways remains poorly understood. In this study, we show that Mal determines the expression and secretion of IFNß following activation of TLR7, a receptor that recognizes ssRNA and imidazoquinolines. Moreover, we observed that R848 induces Mal-dependent IFNß production via ERK1/2 activation as well as the transcription factor IRF7 activation. Although activation of TLR7 leads to NF-κB-dependent expression of IRF7, this process is independent of Mal. We also demonstrate that secretion of IFNß regulated by TLR7 and Mal in macrophages and dendritic cells leads to the IP-10 chemokine expression. In conclusion, our data demonstrate that Mal is a critical regulator of the imidazoquinolinones-dependent IFNß production via ERK1/2/IRF7 signaling cascade which brings us closer to understanding the molecular mechanism's regulation of innate immune response.

PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts.

Stalled replication forks can be restarted and repaired by RAD51-mediated homologous recombination (HR), but HR can also perform post-replicative repair after bypass of the obstacle. Bulky DNA adducts are important replication-blocking lesions, but it is unknown whether they activate HR at stalled forks or behind ongoing forks. Using mainly BPDE-DNA adducts as model lesions, we show that HR induced by bulky adducts in mammalian cells predominantly occurs at post-replicative gaps formed by the DNA/RNA primase PrimPol. RAD51 recruitment under these conditions does not result from fork stalling, but rather occurs at gaps formed by PrimPol re-priming and resection by MRE11 and EXO1. In contrast, RAD51 loading at double-strand breaks does not require PrimPol. At bulky adducts, PrimPol promotes sister chromatid exchange and genetic recombination. Our data support that HR at bulky adducts in mammalian cells involves post-replicative gap repair and define a role for PrimPol in HR-mediated DNA damage tolerance.

Integrative, genome-wide association study identifies chemicals associated with common women's malignancies.

BACKGROUND: Breast cancer, cervical cancer, and ovarian cancer are three of the most commonly diagnosed malignancies in women, and more cancer prevention research is urgently needed. METHODS: Summary data of a large genome-wide association study of female cancers were derived from the UK biobank. We performed a transcriptome-wide association study and a gene set enrichment analysis to identify correlations between chemical exposure and aberrant expression, repression, or mutation of genes related to cancer using the Comparative Toxicogenomics Database. RESULTS: We identified five chemicals (NSC668394, glafenine, methylnitronitrosoguanidine, fenofibrate, and methylparaben) that were associated with the incidence of both breast cancer and cervical cancer. CONCLUSION: Using a transcriptome-wide association study and gene set enrichment analysis we identified environmental chemicals that are associated with an increased risk of breast cancer, cervical cancer, and ovarian cancer.

Drug efficacy and toxicity prediction: an innovative application of transcriptomic data.

Drug toxicity and efficacy are difficult to predict partly because they are both poorly defined, which I aim to remedy here from a transcriptomic perspective. There are two major categories of drugs: (1) restorative drugs aiming to restore an abnormal cell, tissue, or organ to normal function (e.g., restoring normal membrane function of epithelial cells in cystic fibrosis), and (2) disruptive drugs aiming to kill pathogens or malignant cells. These two types of drugs require different definition of efficacy and toxicity. I outlined rationales for defining transcriptomic efficacy and toxicity and illustrated numerically their application with two sets of transcriptomic data, one for restorative drugs (treating cystic fibrosis with lumacaftor/ivacaftor aiming to restore the cellular function of epithelial cells) and the other for disruptive drugs (treating acute myeloid leukemia with prexasertib). The conceptual framework presented will help and sensitize researchers to collect data required for determining drug toxicity.

Design, synthesis and discovery of 2(1H)-quinolone derivatives for the treatment of pulmonary fibrosis through inhibition of TGF-ß/smad dependent and independent pathway.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening and interstitial lung disease with the median survival of only 3-5 years. However, due to the unclear etiology and problems in accurate diagnosis, up to now only two drugs were approved by FDA for the treatment of IPF and their outcome responses are limited. Numerous studies have shown that TGF-ß is the most important cytokine in the development of pulmonary fibrosis and plays a role through its downstream signaling molecule TGF-binding receptor Smads protein. In this paper, compounds bearing 2(1H)-quinolone scaffold were designed and their anti-fibrosis effects were evaluated. Of these compounds, 20f was identified as the most active one and could inhibit TGF-ß-induced collagen deposition of NRK-49F cells and mouse fibroblasts migration with comparable activity and lower cytotoxicity than nintedanib in vitro. Further mechanism studies indicated that 20f reduced the expression of fibrogenic phenotypic protein α-SMA and collagen Ⅰ by inhibiting the TGF-ß/Smad dependent pathways and ERK1/2 and p38 pathways. Moreover, compared with the nintedanib, 20f (100 mg/kg/day, p.o) more effectively alleviated collagen deposition in lung tissue and delayed the destruction of lung tissue structure both in bleomycin-induced prevention and treatment mice pulmonary fibrosis models. The immunohistochemical experiments further showed that 20f could block the expression level of phosphorylated Smad3 in the lung tissue cells, which resulted in its anti-fibrosis effects in vivo. In addition, 20f demonstrated good bioavailability (F = 41.55% vs 12%, compare with nintedanib) and an appropriate elimination half-life (T1/2 = 3.5 h), suggesting that 20f may be a potential drug candidate for the treatment of pulmonary fibrosis.

Strategic photosafety screening system consisting of in chemico photoreactivity and in vitro skin exposure for quinolone derivatives.

The main objective of this study was to verify the applicable domain of a proposed photosafety screening system, consisting of a reactive oxygen species (ROS) assay and in vitro skin permeation test, for dermally-applied chemicals. Quinolones (QNLs) were selected as test compounds, including enoxacin, flumequine, moxifloxacin, nalidixic acid, orbifloxacin, and oxolinic acid. The ROS assay and in vitro skin permeation test were employed to evaluate photoreactivity and skin deposition of QNLs, respectively. All QNLs exhibited significant ROS generation on exposure to simulated sunlight; in particular, enoxacin was indicative of potent photoreactivity compared with the other 5 QNLs. Steady-state concentration values of flumequine and nalidixic acid were calculated to be 5.0 and 8.2 µg/mL, respectively, and higher than those of the other QNLs. Based on the photoreactivity and skin exposure of QNLs, the phototoxic risk was ranked, and the predicted phototoxic risk by the proposed system was mostly in agreement with observed in vivo phototoxicity, suggesting the applicability of the proposed strategy to photosafety assessment of QNLs. The proposed screening would be efficacious to predict phototoxic risk of dermally-applied chemicals.