Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro-In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment.

High-throughput in vitro assays combined with in vitro-in vivo extrapolation (IVIVE) leverage in vitro responses to predict the corresponding in vivo exposures and thresholds of concern. The integrated approach is also expected to offer the potential for efficient tools to provide estimates of chemical toxicity to various wildlife species instead of animal testing. However, developing fish physiologically based toxicokinetic (PBTK) models for IVIVE in ecological applications is challenging, especially for plausible estimation of an internal effective dose, such as fish equivalent concentration (FEC). Here, a fish PBTK model linked with the IVIVE approach was established, with parameter optimization of chemical unbound fraction, pH-dependent ionization and hepatic clearance, and integration of temperature effect and growth dilution. The fish PBTK-IVIVE approach provides not only a more precise estimation of tissue-specific concentrations but also a reasonable approximation of FEC targeting the estrogenic potency of endocrine-disrupting chemicals. Both predictions were compared with in vivo data and were accurate for most indissociable/dissociable chemicals. Furthermore, the model can help determine cross-species variability and sensitivity among the five fish species. Using the available IVIVE-derived FEC with target pathways is helpful to develop predicted no-effect concentration for chemicals with similar mode of action and support screening-level ecological risk assessment.

First metabolic profiling of 4-n-nonylphenol in human liver microsomes by integrated approaches to testing and assessment: Metabolites, pathways, and biological effects.

4-n-nonylphenol (4-n-NP), a typical endocrine disrupting chemical, has been so far frequently detected in various environmental mediums and editable food. However, the specific metabolic pathways in human and potential adverse effects of metabolites have not been elucidated yet. Here, metabolic profiling of 4-n-NP in human liver microsome (HLM) was comprehensively characterized by integrated approaches of testing and assessment. A total of 21 metabolites were identified using nontarget analysis with high-resolution mass spectrum, including three groups of unique phase I metabolites first determined in HLM. Seven various metabolic pathways of 4-n-NP were identified by both in silico and in vitro, and CYP1A2, 2C19, and 2D6 were the mainly participating enzymes. Two secondary metabolites with carbonyl groups on side chains (M4, M7) presented most abundant in HLM, which were also predicted to have high binding affinities towards HPG-axis-related receptors (AR, ER, and PR). ESRs (estrogen receptors) were shared core protein targets for all metabolites revealed by protein-protein interaction networks. Biological functions enrichment analysis indicated that 4-n-NP metabolites might primarily involve in ESR-mediated signaling, GPCR ligand binding, Class A/1 (Rhodopsin-like receptors) and metabolism-related pathways. These findings of 4-n-NP metabolites, pathways, and biological effects provide insightful information for its environmental exposure and risk assessment.

Assessment of Thigh MRI Radiomics and Clinical Characteristics for Assisting in Discrimination of Juvenile Dermatomyositis.

Magnetic resonance imaging (MRI) is an important non-invasive examination in the early diagnosis of juvenile dermatomyositis (JDM). We aimed to evaluate the feasibility of radiomics to establish a quantitative analysis of MRI images. Radiomics and machine learning were used to retrospectively analyze MRI T2 fat suppression sequences and relevant clinical data. The model associated with radiomics features was established using a cohort of patients who underwent thigh MRI at the children's hospital from June 2014 to September 2021. In total, 75 patients with JDM and 75 control children were included in the training cohort (n = 102) and validation cohort (n = 48). The independent factors including lower muscle strength (OR, 0.75; 95% CI, 0.59-0.90), higher creatine kinase (CK) level (OR, 1.65; 95% CI, 1.20-2.38), and higher radiomics score (OR, 2.30; 95% CI, 1.63-3.62) were associated with a clinical diagnosis of JDM. The combined model achieved good discrimination performance compared the radiomics score model under linear discriminant analyses in the training cohort (AUC, 0.949; 95% CI, 0.912-0.986 vs. AUC, 0.912; 95% CI, 0.858-0.967; p = 0.02) and in the validation cohort (AUC, 0.945; 95% CI, 0.878-1 vs. AUC, 0.905; 95% CI, 0.812-0.998; p = 0.03). The combined model showed the diagnostic value was not weaker than the biopsy (AUC, 0.950; 95% CI, 0.919-0.981, n = 150 vs. AUC, 0.952; 95% CI, 0.889-1, n = 72; p = 0.95) and electromyogram (EMG) (AUC, 0.950; 95% CI, 0.919-0.981 vs. AUC, 0.900; 95% CI, 0.852-0.948; p = 0.10) among all the patients. The combination of radiomics features extracted from the MRI and non-invasive clinical characteristics obtained a pronounced discriminative performance to assist in discriminating JDM.

Occurrence, bioaccumulation, fate, and risk assessment of novel brominated flame retardants (NBFRs) in aquatic environments - A critical review.

Novel brominated flame retardants (NBFRs), which have been developed as replacements for legacy flame retardants such as polybrominated diphenyl ethers (PBDEs), are a class of alternative flame retardants with emerging and widespread applications. The ubiquitous occurrence of NBFRs in the aquatic environments and the potential adverse effects on aquatic organisms have initiated intense global concerns. The present article, therefore, identifies and analyzes the current state of knowledge on the occurrence, bioaccumulation, fates, and environmental and health risks of NBFRs in aquatic environments. The key findings from this review are that (1) the distribution of NBFRs are source-dependent in the global aquatic environments, and several NBFRs have been reported at higher concentrations than that of the legacy flame retardants; (2) high bioaccumulative properties have been found for all of the discussed NBFRs due to their strong hydrophobic characteristics and weak metabolic rates; (3) the limited information available suggests that NBFRs are resistant to biotic and abiotic degradation processes and that sorption to sludge and sediments are the main fate of NBFRs in the aquatic environments; (4) the results of ecological risk assessments have indicated the potential risks of NBFRs and have suggested that source areas are the most vulnerable environmental compartments. Knowledge gaps and perspectives for future research regarding the monitoring, toxicokinetics, transformation processes, and development of ecological risk assessments of NBFRs in aquatic environments are proposed.

Pharmacokinetics and bioavailability comparison of generic and branded citalopram 20 mg tablets: an open-label, randomized-sequence, two-period crossover study in healthy Chinese CYP2C19 extensive metabolizers.

BACKGROUND: Citalopram is a selective serotonin reuptake inhibitor (SSRI) mainly prescribed to treat major depression. OBJECTIVE: The aim of this study was to compare the pharmacokinetic characteristics of a new and a branded citalopram 20 mg formulation to support the marketing authorization of the test formulation in China. METHODS: A single-dose, open-label, randomized-sequence, two-period crossover design was used in this study. Healthy Chinese male cytochrome P450 (CYP) 2C19 extensive metabolizers, aged 18-40 years, were eligible to participate. CYP2C19 poor metabolizers were excluded, based on genotyping of genomic DNA from blood samples. Twenty-four subjects were randomly assigned to receive the test formulation followed by the reference formulation, and then vice versa. A 2-week washout occurred between study periods. Blood samples were collected for up to 144 h post-dose. Quantification was carried out using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated and analysed statistically. The two formulations were considered pharmacokinetically equivalent if the 90 % confidence intervals (CIs) of the log-transformed ratios (test/reference) of the maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC(last)), and area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were within the predetermined acceptance range (70-143 % for C(max); 80-125 % for AUC(last) and AUC(∞)) according to China State Food and Drug Administration bioequivalence guidelines. Tolerability was monitored by clinical assessment, vital signs, laboratory analysis and interviews with participants about adverse events. RESULTS: A total of 24 participants, with a mean (SD) age of 26 (3) years (range 22-32 years), body weight of 65.2 (5.0) kg (range 53-73 kg), and height of 172.7 (4.9) cm (range 159-182 cm), were enrolled in this study. Both formulations showed similar pharmacokinetic profiles. Mean (SD) AUC(last), AUC(∞) and C(max) were 1436 (341) ng · h/mL, 1595 (381) ng · h/mL and 32.3 (5.9) ng/mL, respectively, for the test formulation, and 1444 (388) ng · h/mL, 1648 (504) ng · h/mL, 33.1 (7.4) ng/mL, respectively, for the reference formulation. Median (range) time to reach C(max) (t(max)) was 2 (1-12) hours (test) and 3 (1-6) hours (reference). The 90 % CIs of the treatment ratios for the ln-transformed values of C(max), AUC(last) and AUC(∞) were 92.5-103.6, 95.2-100.6 and 96.4-105.4, respectively. No significant difference was found between treatments with regard to pharmacokinetic parameters. Fifteen adverse events were reported during the study but none were considered serious. CONCLUSION: This single-dose study found that the test and reference citalopram 20 mg tablets met the regulatory criteria for assuming bioequivalence in the selected healthy Chinese male subjects. Both formulations were well tolerated.

A tiered ecological risk assessment of three chlorophenols in Chinese surface waters.

INTRODUCTION: The ecological risks posed by three chlorophenols (CPs), 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP), and pentachlorophenol (PCP) in Chinese surface waters were assessed. MATERIALS AND METHODS: This was achieved by applying a tiered ecological risk assessment (ERA) approach ranging from deterministic methods to probabilistic options to measured concentrations of CPs in surface water of seven major watersheds and three drainage regions in China and the chronic toxicity data for indigenous Chinese species. RESULTS AND DISCUSSION: The results show that the risks of three chlorophenols are ranked PCP>2,4-DCP≈2,4,6-TCP. PCP posed little ecological risk while 2,4-DCP and 2,4,6-TCP posed negligible or de minimis risk in Chinese surface water. However, the risks varied with different river basins, for example, PCP posed some ecological risk in the Yangtze, Huaihe, and Pearl Rivers. The magnitude of 2,4-DCP and 2,4,6-TCP pollution in North China was more serious than that in South China. CONCLUSION: The probabilistic risk assessment approach, which can provide more information for risk managers and decision makers, was favored over the screening-level single-value estimate method. However, the results from all tiers of the ERA methods in the framework were consistent with each other.

Simultaneous determination of citalopram and its metabolite in human plasma by LC-MS/MS applied to pharmacokinetic study.

A simple sensitive and robust method for simultaneous determination of citalopram and desmethylcitalopram was developed using liquid chromatography tandem mass spectrometry (LC-MS/MS). A 200 microL aliquot of plasma sample was employed and deproteinized with methanol and desipramine was used as the internal standard. After vortex mixing and centrifugation, the supernatant was diluted with water (1:1, v/v) and then directly injected to analysis. Analytes were separated by a Zorbax XDB C(18) column with the mobile phase composed of acetonitrile and water (30:70, v/v) with 0.25% formic acid and monitored in MRM mode using a positive electrospray source with tandem mass spectrometry detection. The total run time was 3.5 min. The dynamic range was 0.2-100 ng/mL for citalopram and 0.25-50 ng/mL for desmethylcitalopram, respectively. Compared to the best existing literatures for plasma samples, the same LOQ for CIT (0.5 ng/mL) and lower LOQ for DCIT (0.25 vs 5 ng/mL) were reached, and less sample preparation steps and runtime (3.5 vs 10 min) were taken for our method. Accuracy and precision was lower than 8% and lower than 11.5% for either target. Validation results and its application to the analysis of plasma samples after oral administration of citalopram in healthy Chinese volunteers demonstrated the method was applicable to pharmacokinetic studies.