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Human biomonitoring studies typically capture only a small and unknown fraction of the entire chemical universe. We combined chemical analysis with a high-throughput in vitro assay for neurotoxicity to capture complex mixtures of organic chemicals in blood. Plasma samples of 624 pregnant women from the German LiNA cohort were extracted with a nonselective extraction method for organic chemicals. 294 of >1000 target analytes were detected and quantified. Many of the detected chemicals as well as the whole extracts interfered with neurite development. Experimental testing of simulated complex mixtures of detected chemicals in the neurotoxicity assay confirmed additive mixture effects at concentrations less than individual chemicals' effect thresholds. The use of high-throughput target screening combined with bioassays has the potential to improve human biomonitoring and provide a new approach to including mixture effects in epidemiological studies.

Background and Objective: Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin)., Methods: In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism. In addition, two open-label, fixed-treatment period, phase I studies in healthy male volunteers are described. Period 1: participants received oral BI 425809 25 mg (single dose) on day 1; period 2: participants received multiple doses, across 10 days, of oral itraconazole or rifampicin combined with a single dose of oral BI 425809 25 mg on day 4/7 of the itraconazole/rifampicin treatment, respectively. Pharmacokinetic and safety endpoints were assessed in the absence/presence of itraconazole/rifampicin and included area under the concentration-time curve (AUC) over the time interval 0-167 h (AUC 0‒167 ; itraconazole), 0-168 h (AUC 0‒168 ; rifampicin), or 0-infinity (AUC 0-∞ ; rifampicin and itraconazole), maximum measured concentration (C max ) of BI 425809, and adverse events., Results: In vitro results suggested that CYP3A4 accounted for ≥ 90% of the metabolism of BI 425809. BI 425809 exposure (adjusted geometric mean ratio [%]) was higher in the presence of itraconazole (AUC 0‒167 : 265.3; AUC 0-∞ : 597.0; C max : 116.1) and lower in the presence of rifampicin (AUC 0‒168 : 10.3; AUC 0-∞ : 9.8; C max : 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated., Conclusions: Systemic exposure of BI 425809 was altered in the presence of strong CYP3A4 modulators, corroborating in vitro results that CYP3A4 mediates a major metabolic pathway for BI 425809., Trial Registration Number: NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017)., (© 2021. The Author(s).)

Rationale: Low-molecular-weight organic acids that generally contain one to three carboxyl groups are involved in many important biological processes; therefore, it is important to develop a quantitative method for analyzing organic acids in serum in order to allow an evaluation of metabolic changes. In this study, we evaluated a protocol for detecting 26 organic acids in serum based on ultrasound-assisted derivatization by gas chromatography/mass spectrometry (GC/MS)., Methods: Serum samples were prepared using ultrasound-assisted silane derivatization before GC/MS analysis to quantify concentrations of organic acids. Additionally, we investigated the variables affecting derivatization yields, including the extraction solvent, derivatization reagents, and derivatization conditions (reaction temperature, duration, and sonication parameters). The protocol was ultimately applied to detect organic acid profiles related to obesity., Results: We used acetone as the extraction solvent and determined suitable derivatization conditions, as follows: BSTFA + 1% TMCS, 50°C, 10 min, and 100% ultrasound power. The protocol showed satisfactory linearity (r = 0.9958-0.9996), a low limit of detection (0.04-0.42 μmol/L), good reproducibility (coefficient of variation (CV) %: 0.32-13.76%), acceptable accuracy (recovery: 82.97-114.96%), and good stability within 5 days (CV%: 1.35-12.01% at room temperature, 1.24-14.09% at 4°C, and 1.01-11.67% at -20°C). Moreover, the protocol was successfully applied to obtain the organic acid profiles from obese and healthy control subjects., Conclusions: We identified and validated a protocol for ultrasound-assisted derivatization prior to GC/MS analysis for detecting 26 kinds of organic acids in serum. The results suggest the efficacy of this protocol for clinical applications to determine metabolic changes related to fluctuations in organic acid profiles., (© 2021 John Wiley & Sons Ltd.)

Non-targeted analysis (NTA), including both suspect screening analysis (SSA) and unknown compound analysis, has gained increasing popularity in various fields for its capability in identifying new compounds of interests. Current major challenges for NTA SSA are that (1) tremendous effort and resources are needed for large-scale identification and confirmation of suspect chemicals and (2) suspect chemicals generally show low matching rates during identification and confirmation processes. To narrow the gap between these challenges and smooth implementation of NTA SSA methodology in the biomonitoring field, we present a thorough SSA workflow for the large-scale screen, identification, and confirmation of industrial chemicals that may pose adverse health effects in pregnant women and newborns. The workflow was established in a study of 30 paired maternal and umbilical cord serum samples collected at delivery in the San Francisco Bay area. By analyzing LC-HRMS and MS/MS data, together with the assistance of a combination of resources including online MS/MS spectra libraries, online in silico fragmentation tools, and the EPA CompTox Chemicals Dashboard, we confirmed the identities of 17 chemicals, among which monoethylhexyl phthalate, 4-nitrophenol, tridecanedioic acid, and octadecanedioic acid are especially interesting due to possible toxicities and their high-volume use in industrial manufacturing. Similar to other previous studies in the SSA field, the suspect compounds show relatively low MS/MS identification (16%) and standard confirmation (8%) rates. Therefore, we also investigated origins of false positive features and unidentifiable suspected features, as well as technical obstacles encountered during the confirmation process, which would promote a better understanding of the flaw of low confirmation rate and encourage gaining more effective tools for tackling this issue in NTA SSA.

The adipose tissue:blood partition coefficient is a key-endpoint to predict the pharmacokinetics of chemicals in humans and animals, since other organ:blood affinities can be estimated as a function of this parameter. We performed a search in the literature to select all the available rat in vivo data. This approach resulted into two improvements to existing models: a homogeneous definition of the endpoint and an expanded data collection. The resulting dataset was used to develop QSAR models as a function of linear and non-linear algorithms. Several applicability domain definitions were assessed and the definition corresponding to a good balance between performance and coverage was retained. We assessed the pertinence of combining single models into integrated approaches to increase the accuracy in predictions. The best integrated model outperformed the single models and it was characterized by an external mean absolute error (MAE) equal to 0.26, while preserving an adequate coverage (84 %). This performance is comparable to experimental variability and it highlights the pertinence of the integrated model., (© 2020 Wiley-VCH GmbH.)

Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden., (Copyright © 2020. Published by Elsevier Inc.)

Capillary zone electrophoresis-mass spectrometry (CE-MS) is a mature analytical tool for the efficient profiling of (highly) polar and ionizable compounds. However, the use of CE-MS in comparison to other separation techniques remains underrepresented in metabolomics, as this analytical approach is still perceived as technically challenging and less reproducible, notably for migration time. The latter is key for a reliable comparison of metabolic profiles and for unknown biomarker identification that is complementary to high resolution MS/MS. In this work, we present the results of a Metabo-ring trial involving 16 CE-MS platforms among 13 different laboratories spanning two continents. The goal was to assess the reproducibility and identification capability of CE-MS by employing effective electrophoretic mobility (μ eff ) as the key parameter in comparison to the relative migration time (RMT) approach. For this purpose, a representative cationic metabolite mixture in water, pretreated human plasma, and urine samples spiked with the same metabolite mixture were used and distributed for analysis by all laboratories. The μ eff was determined for all metabolites spiked into each sample. The background electrolyte (BGE) was prepared and employed by each participating lab following the same protocol. All other parameters (capillary, interface, injection volume, voltage ramp, temperature, capillary conditioning, and rinsing procedure, etc.) were left to the discretion of the contributing laboratories. The results revealed that the reproducibility of the μ eff for 20 out of the 21 model compounds was below 3.1% vs 10.9% for RMT, regardless of the huge heterogeneity in experimental conditions and platforms across the 13 laboratories. Overall, this Metabo-ring trial demonstrated that CE-MS is a viable and reproducible approach for metabolomics.

Solvent extracts of mammalian tissues and blood contain a large amount of co-extracted matrix components, in particular lipids, which can adversely affect instrumental analysis. Clean-up typically degrades non-persistent chemicals. Alternatively, passive sampling with the polymer polydimethylsiloxane (PDMS) has been used for a comprehensive extraction from tissue without altering the mixture composition. Despite a smaller fraction of matrix being co-extracted by PDMS than by solvent extraction, direct analysis of PDMS extracts was only possible with direct sample introduction (DSI) GC-MS/MS, which prevented co-extracted matrix components entering the system. Limits of quantitation (LOQ) ranged from 4 to 20 pg μL -1 ethyl acetate (PDMS extract) for pesticides and persistent organic pollutants (POPs). The group of organophosphorus flame retardants showed higher LOQs up to 107 pg μL -1 due to sorption to active sites at the injection system. Intraday precision ranged between 1 and 10%, while the range of interday precision was between 1 and 18% depending on the analyte. The method was developed using pork liver, brain, and fat as well as blood and was then applied to analyze human post-mortem tissues where polychlorinated biphenyls (PCBs) as well as dichlorodiphenyltrichloroethane (DDT) and DDT metabolites were detected. Graphical abstract.

Unidentified peaks remain a major problem in untargeted metabolomics by LC-MS/MS. Confidence in peak annotations increases by combining MS/MS matching and retention time. We here show how retention times can be predicted from molecular structures. Two large, publicly available data sets were used for model training in machine learning: the Fiehn hydrophilic interaction liquid chromatography data set (HILIC) of 981 primary metabolites and biogenic amines,and the RIKEN plant specialized metabolome annotation (PlaSMA) database of 852 secondary metabolites that uses reversed-phase liquid chromatography (RPLC). Five different machine learning algorithms have been integrated into the Retip R package: the random forest, Bayesian-regularized neural network, XGBoost, light gradient-boosting machine (LightGBM), and Keras algorithms for building the retention time prediction models. A complete workflow for retention time prediction was developed in R. It can be freely downloaded from the GitHub repository (https://www.retip.app). Keras outperformed other machine learning algorithms in the test set with minimum overfitting, verified by small error differences between training, test, and validation sets. Keras yielded a mean absolute error of 0.78 min for HILIC and 0.57 min for RPLC. Retip is integrated into the mass spectrometry software tools MS-DIAL and MS-FINDER, allowing a complete compound annotation workflow. In a test application on mouse blood plasma samples, we found a 68% reduction in the number of candidate structures when searching all isomers in MS-FINDER compound identification software. Retention time prediction increases the identification rate in liquid chromatography and subsequently leads to an improved biological interpretation of metabolomics data.

The Canadian Health Measures Survey (CHMS), an ongoing national health survey conducted in two-year cycles, collects extensive biomonitoring data that is used to assess the exposure of Canadians to environmental chemicals of concern. Combining data from multiple cycles of the CHMS allows for the calculation of robust regional estimates of chemical concentrations in blood and urine. The objective of this work was to compare biomarkers of exposure to several environmental chemicals for the provinces of Quebec and Ontario, two major CHMS regions, as well as the entire CHMS (representing Canada) minus Quebec (CMQ), and the entire CHMS minus Ontario (CMO), and to interpret differences between regions. Geometric means and 95th percentiles of blood and/or urinary concentrations of 45 environmental chemicals or their metabolites for Ontario, Quebec, CMQ, and CMO were calculated by combining the two most recent cycles of data available for a chemical (cycles 1 and 2, or cycles 2 and 3) from the first three cycles of the CHMS (2007-2013). Weighted one-way ANOVA was used to test the differences between regional estimates. After applying a Bonferonni-Holm adjustment for multiple comparisons, the following measures were significantly higher in Quebec as compared to Ontario and CMQ: blood lead, urinary lead and the urinary polyaromatic hydrocarbon (PAH) metabolites, 9-hydroxyfluorene, 1-hydroxyphenanthrene, 2- hydroxyphenanthrene and 3-hydroxyphenanthrene. In Quebec compared to CMQ only, urinary 2-hydroxfluorene, 3-hydroxyfluorene, 2-hydroxynaphthalene, and 4-hydroxyphenanthrene were higher. The concentration of urinary fluoride was significantly higher in Ontario as compared to Quebec and CMO. Blood manganese and urinary fluoride were significantly lower in Quebec compared to CMQ, and blood and urinary selenium were significantly lower in Ontario compared to CMO. Regional differences in tobacco use, age of dwellings and drinking water fluoridation are among the possible contributing factors to some of the observed differences. In conclusion, this is the first study where biomonitoring data from multiple cycles of CHMS were combined in order to generate robust estimates for subsets of the Canadian population. Such assessments can contribute to a regional-level prioritization of control measures to reduce the exposure of Canadians to chemicals in their environment., (Crown Copyright © 2020. Published by Elsevier GmbH. All rights reserved.)

Background and Aims: While excess energy intake and physical inactivity constitute the obvious causes of body fat accumulation, persistent organic pollutants (POPs) are novel factors that have been linked to cardiometabolic disorders. Major sources of POPs are animal fats including fatty fish. Given the putative protective effects of fish on cardiovascular disease, we explored whether high consumption of fatty fish increased serum concentrations of POPs., Methods and Results: Men and women aged 35-70 years with body mass index between 25 and 38 kg/m 2 and at least 1 cardiometabolic component were randomized to high intakes of fatty fish (mostly farmed salmon, ∼630 g/week; n = 45), high intakes of nuts (∼200 g/week; n = 42) or a control group following their usual diet but restricting fatty fish and nuts for 6 months (n = 44). Concentrations of 15 POPs (5 organochlorinated compounds, 2 dioxin-like polychlorinated biphenyls and 8 non-dioxin-like polychlorinated biphenyls) and cardiometabolic risk factors were measured at baseline and end of the study. Results showed that changes in concentrations of individual and classes of POPs did not differ between the dietary groups and controls (p > 0.05). Among cardiometabolic risk factors HDL-cholesterol increased in the fatty fish group compared to controls (+0.10 mmol/L, CI (0.05-0.20); p = 0.005) while no changes were observed in the group consuming nuts., Conclusion: Fatty fish consumption for 6 months did not increase the serum concentrations of POPs in individuals with overweight or obesity and metabolic risk. While this finding appears reassuring regarding short-term intakes of farmed salmon, long term variations in POPs in adipose stores require further study., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare. All authors had access to the data and have seen and approved the final submitted manuscript., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Accurate and rapid analysis of complex microsamples are challenging tasks in translational research. Nanoelectrospray ionization (nESI) is the method of choice for analyzing small sample volumes by mass spectrometry (MS), but this technique works well only for polar analytes. Herein, we describe a versatile dual noncontact nESI/nAPCI (nanoatmospheric pressure chemical ionization) source that allows simultaneous detection of both polar and nonpolar analytes in microliter quantities of samples under ambient conditions and without pretreatment. The same device can be activated to enable electrophoretic separation. The noncontact nESI/nAPCI MS platform was applied to analyze different samples, including high sensitive direct analysis of biofluids and the efficient detection of proteins in buffers with high concentration of nonvolatile salts. Excellent linearity, accuracy and limits of detection were achieved for compounds with different chemical properties in different matrices. The high sensitivity, universality, simplicity, and ease of operation make this MS technique promising for use in clinical and forensic applications.

Chemical ionization of organic compounds with negligible vapor pressures (VP) is achieved at atmospheric pressure when the proximal sample is exposed to corona discharge. The vapor-phase analyte is produced through a reactive olfaction process, which is determined to include electrostatic charge induction in the proximal condensed-phase sample, resulting in the liberation of free particles. With no requirement for physical contact, a new contained nano-atmospheric pressure chemical ionization (nAPCI) source was developed that allowed direct mass spectrometry analysis of complex mixtures at a sample consumption rate less than nmol/min. The contained nAPCI source was applied to analyze a wide range of samples including the detection of 1 ng/mL cocaine in serum and 200 pg/mL caffeine in raw urine, as well as the differentiation of chemical composition of perfumes and beverages. Polar (e.g., carminic acid; estimated VP 5.1 × 10 -25 kPa) and nonpolar (e.g., vitamin D2; VP 8.5 × 10 -11 kPa) compounds were successfully ionized by the contained nAPCI ion source under ambient conditions, with the corresponding ion types of 78 other organic compounds characterized.

This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61 × 10 -2 and 9 × 10 -4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55 × 10 -1 and 8.5 × 10 -3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r 2 = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework.

Background: Puerto Rico has over 200 hazardous waste sites, as well as higher rates of several adverse health outcomes compared to the mainland US. In response to concerns of potential links between environmental contaminant exposure and preterm birth, the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort was formed. Biomarkers of exposure for several contaminants have been found to be elevated in this cohort compared to women of child-bearing age in the National Health and Nutrition Examination Survey (NHANES). However, exposure to persistent organic pollutants (POPs) has not been evaluated., Methods: In this preliminary analysis, we measured four classes of POPs, including perfluoroalkyl substances (PFASs), polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and several persistent pesticides in serum samples collected at 16-20 weeks gestation from the first 48 women enrolled in PROTECT. We performed descriptive analyses for each analyte, assessed correlations between analytes using Spearman correlations, and compared serum levels in PROTECT women to levels in NHANES women aged 18-40., Results: Several PFASs were detected in 96-100% of samples, with moderate to strong correlations between most PFASs (range r = 0.44-0.88). BDE47, BDE153, PCB 138-158, PCB153 and p,p'-dichlorodiphenyldichloroethene (p,p'-DDE) were detected in the majority of samples, with strong correlations between PCBs and p,p'-DDE (range r = 0.59-0.74). The median concentration for each analyte was lower than, sometimes by a factor of 4 (e.g. BDE47, p,p'-DDE), the median concentration reported in NHANES women aged 18-40., Conclusion: Although participants in the ongoing PROTECT birth cohort have higher exposure to many environmental contaminants, this preliminary study suggests that they have lower exposure to several POPS, specifically PCBs, OCPs, PFASs, and PBDEs., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Persistent organic pollutants (POPs) are man-made compounds with metabolic disruption impact. We investigated the effect of POP exposure in the cardiometabolic and inflammatory profile in a population of women with obesity and hypertension. In 43 premenopausal women (22 treated vs. 21 nontreated) undergoing bariatric surgery, blood and adipose tissue samples (visceral (vAT) and abdominal subcutaneous (scAT)) were collected. Median concentrations of ∑HCH and ∑POPs in vAT were significantly higher in treated women. VAT ∑HCH and scAT ∑HCH and ∑POPs concentrations were positively correlated with systolic blood pressure in the non-treated group. Our findings suggest that exposure to POPs and its accumulation in vAT and circulating in plasma may be associated to a higher cardiovascular risk in women with obesity and hypertension, with or without antihypertensive treatment.

Background In 2011, the IFCC Committee on Reference Intervals and Decision Limits (C-RIDL) initiated a worldwide multicenter study on references values facilitating the implementation of country-specific reference intervals (RIs). There has been no well-designed RI study in India. This study aims to derive RIs for 33 major biochemical analytes in carefully selected healthy Indians as defined in C-RIDL protocol. Methods A total of 512 healthy Indians were recruited. Sera collected from overnight fasting blood samples were measured collectively for the analytes. Multiple regression analysis (MRA) and nested analysis of variance (ANOVA) were used to identify the potential sources of variation (SV) of test results. RI were derived by both parametric and non-parametric methods for comparison. The need for secondary exclusion by latent abnormal values exclusion (LAVE) method was examined. Results MRA results indicated that both age and BMI were apparent SV for many analytes in both sexes. ANOVA revealed that partition of RIs by gender and age was required for 17 analytes (TC, HDL-C, TG, hsCRP, ALB, AST, ALT, ALP, GGT, TBil, Urea, CRE, UA, Fe, TTR, CK and IgM) and 5 (Glu, ALB, TC, ALP and Urea), respectively. RIs by parametric method were generally narrower than by non-parametric method, reflecting distorted peripheral distributions of test results. The LAVE method had no appreciable effect on RIs possibly due to inconsistency among abnormal values of related analytes. Conclusions This study has for the first time provided comprehensive RIs information in healthy Indians. The final RIs adopted were those derived by parametric method without LAVE procedure.

Background and Objective: RP5063 is a novel multimodal dopamine (D)-serotonin (5-HT) stabilizer possessing partial agonist activity for D 2/3/4 and 5-HT 1A/2A , antagonist activity for 5-HT 2B/2C/7, and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships., Methods: Pharmacokinetic sample data (175 patients on RP5063; 28 doses/patient) were analyzed, utilized one- and two-compartment models, and evaluated the impact of covariates. Pharmacodynamic analysis involved development of an E max model., Results: The pharmacokinetic analysis identified a one-compartment model incorporating body mass index influence on volume as the optimum construct, with fixed-effect parameters: (1) oral clearance (Cl/F), 5.11 ± 0.11 L/h; (2) volume of distribution (V c /F), 328.00 ± 31.40 L; (3) absorption constant (ka) 0.42 ± 0.17 h -1 ; (4) lag time (t lag) of 0.41 ± 0.02 h; and (5) a calculated half-life of 44.5 h. Pharmacokinetics were linear related to dose. An E max model for total Positive and Negative Syndrome Scale (PANSS) scores as the response factor against cumulative area under the curve (AUC) provided fixed-effect estimates: (1) E o  = 87.3 ± 0.71 (PANSS Units; pu); (2) E max  = - 31.60 ± 4.05 (pu); and (3) AUC 50  = 89.60 ± 30.10 (µg·h/mL). The predicted PANSS improvement reflected a clinical dose range of 5-30 mg., Conclusions: Pharmacokinetics of RP5063 behaved predictably and consistently. Pharmacodynamics were characterized using an E max model, reflecting total PANSS score as a function of cumulative AUC, that showed high predictability and low variability when correlated with actual observations.

The first Arctic Monitoring and Assessment Programme (AMAP) report was published in 1998 and followed by three assessment reports of human health (AMAP 2003, 2009 and 2015). The focus area of the AMAP reports was to monitor levels of environmental contaminants in the Arctic and to assess the health effects connected with detected levels in Arctic countries. This review gives an overview of temporal trends of contaminants and their health effects in humans of the Arctic based on data published by AMAP, as well as Russian scientific literature. Several time series of 31 contaminants in humans of the Arctic from different cohorts are reported. The lengths of time series and periods covered differ from each other. International restrictions have decreased the levels of most persistent organic pollutants in humans and food webs. Percentage changes for contaminants in human biological matrices (blood samples from children, mothers and males and breast milk samples) for the period of sampling showed declining trends in most of the monitored Arctic locations, with the exception of oxychlordane, hexachlorobenzene (HCB), 2,2',4,4',5,5'-hexabromodiphenyl ether (PBDE153) and perfluorinated compounds (PFCs).

Objective: Yimitasvir phosphate, an inhibitor of nonstructural protein 5A (NS5A) replication complex of hepatitis C virus (HCV), was evaluated in a double-blind, placebo-controlled, parallel, multiple-dose study., Methods: Twenty-four patients with chronic HCV genotype 1 infection were randomized to receive a 7-day course of yimitasvir phosphate at daily doses of 30, 100 or 200 mg or placebo. Antiviral efficacy, resistance profile, pharmacokinetics (PK), safety and tolerability were assessed., Key Findings: The maximal reduction in HCV RNA from baseline was 5.17 log 10 IU/ml. However, most patients experienced viral rebound on or before day 3 after yimitasvir treatment was initiated. The PK profile revealed median peak plasma concentrations at 4-12 h postdose and a mean terminal half-life of 14.47-17.09 h, the basis for daily dosing. Steady drug state was achieved following 5 days of daily dosing. The accumulation rate was low (1.29-1.73). There were no significant alterations in vital signs and laboratory findings among all participants., Conclusions: This study shows that yimitasvir phosphate was well tolerated, and the PK profile supported daily dosing regimens. A 1-week (7-day) treatment course led to a quick and significant reduction in HCV RNA level in this cohort with HCV GT-1 infection., (© 2018 Royal Pharmaceutical Society.)

Background and Aims: Persons with "metabolically healthy" obesity may develop cardiometabolic complications at a lower rate than equally obese persons with evident metabolic syndrome. Even morbidly obese individuals vary in risk profile. Persistent organic pollutants (POPs) are widespread environmental chemicals that impair metabolic homeostasis. We explored whether prevalence of metabolic syndrome in morbidly obese individuals is associated with serum concentrations of POPs., Methods and Results: A cross-sectional study among 161 men and 270 women with BMI >35 kg/m 2 and comorbidity, or >40 kg/m 2 . Circulating concentrations of 15 POPs were stratified by number of metabolic syndrome components. In multiple logistic regression analysis odds ratios between top quartile POPs and metabolic risk factors versus POPs below the top quartile were calculated adjusting for age, gender, body mass index, smoking status, alcohol consumption and cholesterol concentrations. Age-adjusted concentrations of trans-nonachlor and dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs) increased with number of metabolic syndrome components in both genders (p < 0.001), while the organochlorine pesticides HCB, β-HCH and p,p'DDE increased only in women (p < 0.008). Organochlorine pesticides in the top quartile were associated with metabolic syndrome as were dioxin-like and non-dioxin-like PCBs (OR 2.3 [95% CI 1.3-4.0]; OR 2.5 [95% CI 1.3-4.8] and 2.0 [95% CI 1.1-3.8], respectively). Organochlorine pesticides were associated with HDL cholesterol and glucose (OR = 2.0 [95% CI = 1.1-3.4]; 2.4 [95% CI = 1.4-4.0], respectively). Dioxin-like PCBs were associated with diastolic blood pressure, glucose and homeostatic model assessment-insulin resistance index (OR = 2.0 [95% CI = 1.1-3.6], 2.1 [95% CI = 1.2-3.6] and 2.1 [95% CI = 1.0-4.3], respectively)., Conclusion: In subjects with morbid obesity, metabolic syndrome was related to circulating levels of organochlorine pesticides and PCBs suggesting that these compounds aggravate clinically relevant complications of obesity., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man., Methods: The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3-30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg., Results: MIV-711 was a potent inhibitor of human cathepsin K (K i : 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC 50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data., Conclusions: MIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA. Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011.

Background: With the growing prevalence of obesity, an increased number of bariatric surgeries are being performed. Lipophilic persistent organic pollutants (POPs) are stored in adipose tissue, and an increased release of lipophilic POPs into the blood circulation may occur following rapid weight loss such as after bariatric surgery., Objectives: To evaluate and compare POP levels in serum before and after bariatric surgery, and to assess if the POP levels exceeded health based guideline values, with particular focus on women of childbearing age (WCBA)., Methods: Serum samples from 63 patients before and one year after bariatric surgery were analysed for organochlorine pesticides (OCPs); polychlorinated biphenyls (PCBs); and brominated flame retardants (BFRs)., Results: Mean weight loss one year after surgery was 32.1kg. The levels of all the analysed POPs in serum increased during the study period. Median levels of dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzen (HCB) and PCB-153 increased from 90.2ng/g lipid weight (lw) to 158.5ng/glw, from 21.1ng/glw to 36.4ng/glw and from 48.7ng/glw to 71.5ng/glw, respectively. The highest percentage increase was observed for PCB -138, with 83.1%. BFRs were detected in low sample numbers and at low levels. Guideline values for ΣPCB 6 in serum were exceeded for 5% of the participants., Conclusions: Weight loss after bariatric surgery resulted in increases of POPs levels in serum between 46.7%-83.1%. Guideline values for ΣPCB 6 in serum were exceeded for 5% of the participants. For WCBA, the possible transfer of comparable levels to infants warrants further attention., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The objective of this study was to develop and validate a 96-well plate solid phase extraction method for analysis of 23 lipophilic persistent organic pollutants (POPs) in low-volume plasma and serum samples which is applicable for biomonitoring and epidemiological studies. The analysis of selected markers for internal exposure: 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and polybrominated diphenylether 47 (BDE 47) was evaluated by comparing two SPE sorbents and GC-HRMS or GC-MS/MS detection. The final method extracted 23 POPs from 150 μL of serum and plasma using a 96-well extraction plate containing 60 mg Oasis HLB sorbent per well prior to GC-HRMS magnetic sector analysis. The extraction method was applied to 40 plasma samples collected for an epidemiological study. The recovery of selected POPs ranged from 31% to 63% (n = 48), and detection limits ranged from 2.2 to 45 pg/mL for PCBs, 4.2 to 167 pg/mL for OCPs, 7.8 pg/mL for OCDD and 6.1 pg/mL for BDE 47. This method showed good precision with relative standard deviations of selected POP concentrations in quality control samples (n = 48) ranging from 11% to 25%. The trueness was determined with standard reference material serum (n = 48) and the deviation from certified values ranged from 1 to 27%. Of the 23 POPs analyzed, 18 were detected in 43% to 100% of plasma samples collected for the epidemiological study. The method showed good robustness with low inter-well plate variation (11-31%) determined by twelve 96-well plate extractions, and can extract 96 samples, including quality controls and procedural blanks in 2-3 days. Comparison with GC-MS/MS analysis showed that similar concentrations (within 0.5% to 30%) of most POPs could be obtained with GC-APCI-MS/MS. Larger deviations were observed for PCB 194 (60%) and trans-nonachlor (43%). The developed method produces accurate concentrations of low-level marker POPs in plasma and serum, providing a suitable high-throughput sample preparation procedure for biomonitoring and epidemiological studies involving large sample size and limited sample volume. GC-HRMS was chosen over GC-MS/MS, however the latter showed promising results, and could be used as an alternative to GC-HRMS analysis for most POPs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Although centrifugation is performed in almost every blood sample, recommendations on duration and g-force are heterogeneous and mostly based on expert opinions. In order to unify this step in a fully automated laboratory, we aimed to evaluate different centrifugation settings and their influence on the results of routine clinical chemistry analytes., Materials and Methods: We collected blood from 41 healthy volunteers into BD Vacutainer PST II-heparin-gel- (LiHepGel), BD Vacutainer SST II-serum-, and BD Vacutainer Barricor heparin-tubes with a mechanical separator (LiHepBar). Tubes were centrifuged at 2000xg for 10 minutes and 3000xg for 7 and 5 minutes, respectively. Subsequently 60 and 21 clinical chemistry analytes were measured in plasma and serum samples, respectively, using a Roche COBAS instrument., Results: High sensitive Troponin T, pregnancy-associated plasma protein A, ß human chorionic gonadotropin and rheumatoid factor had to be excluded from statistical evaluation as many of the respective results were below the measuring range. Except of free haemoglobin (fHb) measurements, no analyte result was altered by the use of shorter centrifugation times at higher g-forces. Comparing LiHepBar to LiHepGel tubes at different centrifugation setting, we found higher lactate-dehydrogenase (LD) (P = 0.003 to < 0.001) and lower bicarbonate values (P = 0.049 to 0.008) in the latter., Conclusions: Serum and heparin samples may be centrifuged at higher speed (3000xg) for a shorter amount of time (5 minutes) without alteration of the analytes tested in this study. When using LiHepBar tubes for blood collection, a separate LD reference value might be needed., Competing Interests: Potential conflict of interest: Janne Cadamuro received a personal fee as guest member of a Becton Dickinson Advisory board meeting.

Background: Environmental Persistent Organic Pollutants (POPs) can alter the hormone homeostasis by mimicking, interfering or blocking the function of hormones; moreover POPs are hypothesized to modify the risk of breast cancer. The association between POPs and breast cancer has been widely studied but the conclusions are inconsistent. The present study examined the associations between serum levels of POPs and breast cancer with focus on the highly exposed Greenlandic Inuit population., Methods: The study design was a case-control study of Inuit women from Greenland. The participants were asked to complete a questionnaire with information on reproductive history and lifestyle and to provide a blood sample. The sampling was carried out in two time periods (2000-2003 and 2011-2014). The serum levels were determined of 14 polychlorinated biphenyls (PCBs), 11 organochlorine pesticides (OCPs), 16 perfluoroalkyl acids (PFAAs), 1 polybrominated biphenyl (PBB), and 9 polybrominated diphenyl ethers (PBDEs). Independent samples t-test was used to compare differences between cases and controls and odds ratios (OR) adjusted for identified confounders were obtained using logistic regression., Results: The study population included 77 breast cancer cases and 84 controls. The majority of the measured compounds declined significantly from 2000 - 2003 to 2011-2014. However, for the perfluorinated carboxylic acids (PFCAs) an increase was observed. The serum levels were significantly higher in cases compared to controls for the majority of the compounds, and after adjusting for age the difference was maintained for ∑OCP, dichlorodiphenyldichloroethylene (p,p'-DDE), ∑PFAA, ∑perfluorinated sulfonic acids (PFSA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS). For the lipophilic POPs, high serum levels (middel/highest vs. lowest tertile) of ∑PCB, ∑estrgoenicPCB, PCB99, PCB138, PCB153, PCB170, PCB170, and PCB183 was associated with breast cancer risk; for the amphiphilic PFAAs, high serum levels of ∑PFAA, ∑PFCA, ∑PFSA, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), PFHxS, and PFOS were associated with breast cancer risk., Conclusion: Significant, positive associations between breast cancer risk and PCBs and PFAAs were observed. The associations indicate that environmental exposure to POPs can be a factor increasing the risk for breast cancer in Inuit women.

Background: Current exposure assessment research does not sufficiently address multi-pollutant exposure and their correlations in human media. Understanding the extent of chemical exposure in reproductive-aged women is of particular concern due to the potential for in utero exposure and fetal susceptibility., Objectives: The objectives of this study were to characterize concentrations of chemical biomarkers during preconception and examine correlations between and within chemical classes., Methods: We examined concentrations of 135 biomarkers from 16 chemical classes in blood and urine from 73 women aged 18-40 enrolled in Snart Foraeldre/Milieu, a prospective cohort study of pregnancy planners in Denmark (2011-2014). We compared biomarker concentrations with United States similarly-aged, non-pregnant women who participated in the National Health and Nutrition Environmental Survey (NHANES) and with other international biomonitoring studies. We performed principal component analysis to examine biomarker correlations., Results: The mean number of biomarkers detected in the population was 92 (range: 60-108). The most commonly detected chemical classes were phthalates, metals, phytoestrogens and polycyclic aromatic hydrocarbons. Except blood mercury, urinary barium and enterolactone, geometric means were higher in women from NHANES. Chemical classes measured in urine generally did not load on a single component, suggesting high between-class correlation among urinary biomarkers, while there is high within-class correlation for biomarkers measured in serum and blood., Conclusions: We identified ubiquitous exposure to multiple chemical classes in reproductive-aged Danish women, supporting the need for more research on chemical mixtures during preconception and early pregnancy. Inter- and intra-class correlation between measured biomarkers may reflect common exposure sources, specific lifestyle factors or shared metabolism pathways., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The developing fetus and pregnant woman can be exposed to a variety of environmental chemicals that may adversely affect their health. Moreover, environmental exposure and risk disparities are associated with different social determinants, including socioeconomic status (SES) and demographic indicators. Our aim was to investigate whether and how maternal concentrations of a large panel of persistent and non-persistent environmental chemicals vary according to sociodemographic and lifestyle characteristics in a large pregnancy and birth cohort., Methods: Data were analyzed from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a cohort of pregnant women (N=2001) recruited over four years (2008-2011) in 10 cities across Canada. In all, 1890 urine and 1938 blood samples from the first trimester (1st and 3rd trimester for metals) were analysed and six sociodemographic and lifestyle indicators were assessed: maternal age, household income, parity, smoking status, country of birth and pre-pregnancy body mass index (BMI)., Results: We found these indicators to be significantly associated with many of the chemicals measured in maternal blood and urine. Women born outside Canada had significantly higher concentrations of di-2-ethylhexyl and diethyl phthalate metabolites, higher levels of all metals except cadmium (Cd), as well as higher levels of polychlorinated biphenyls (PCBs) and legacy organochlorine pesticides (OCPs). Nulliparity was associated with higher concentrations of dialkyl phosphates (DAPs), arsenic, dimethylarsinic acid (DMAA), perfluoroalkyl substances (PFASs) and many of the persistent organic pollutants. Smokers had higher levels of bisphenol A, Cd and perfluorohexane sulfonate, while those women who had never smoked had higher levels of triclosan, DMAA, manganese and some OCPs., Conclusion: Our results demonstrated that inequitable distribution of exposure to chemicals among populations within a country can occur. Sociodemographic and lifestyle factors are an important component of a thorough risk assessment as they can impact the degree of exposure and may modify the individual's susceptibility to potential health effects due to differences in lifestyle, cultural diets, and aging., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

This paper presents a progress report of the French human biomonitoring (HBM) program established in 2010. This program has been designed to provide a national representative estimation of the French population's exposure to various environmental chemicals and to study the determinants of exposure. This program currently consists in two surveys: a perinatal component related to a selection of 4145 pregnant women who have been enrolled in the Elfe cohort (the French Longitudinal Study since Childhood) in 2011, and a general population survey related to adults aged 18-74 years and children as from 6 years (Esteban). The aim of this manuscript is to present highlights of the French human biomonitoring program with particular focus on the prioritization of biomarkers to be analyzed in the program and the selection of biomarkers applied to both program components. The Delphi method was used to establish a consensual list of prioritized biomarkers in 2011. First results of the perinatal component of the French HBM program have shown that the biomarkers prioritized were relevant, as almost all pregnant women were exposed to them. However, for some biomarkers, levels' decreases have been observed which may partly be explained by measures taken to prohibit some of these chemicals (e.g. atrazine) and by industrial processes evolutions leading to the substitution of others (e.g. bisphenol A, di-2-ethylhexyl phthalate/DEHP, dialkyl phosphates). Therefore, the list of biomarkers to be monitored in the French HBM program has been implemented to include some substitutes of biomarkers prioritized in the first instance (e.g. bisphenol S, F). Finally, this method combines rigor and flexibility and helped us to build a prioritized list that will be shared and supported by many if not all actors., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Amongst the substances listed as persistent organic pollutants (POP) under the Stockholm Convention on Persistent Organic Pollutants (SCPOP) are chlorinated, brominated, and fluorinated compounds. Most experimental studies investigating effects of POP employ single compounds. Studies focusing on effects of POP mixtures are limited, and often conducted using extracts from collected specimens. Confounding effects of unmeasured substances in such extracts may bias the estimates of presumed causal relationships being examined. The aim of this investigation was to design a model of an environmentally relevant mixture of POP for use in experimental studies, containing 29 different chlorinated, brominated, and perfluorinated compounds. POP listed under the SCPOP and reported to occur at the highest levels in Scandinavian food, blood, or breast milk prior to 2012 were selected, and two different mixtures representing varying exposure scenarios constructed. The in vivo mixture contained POP concentrations based upon human estimated daily intakes (EDIs), whereas the in vitro mixture was based upon levels in human blood. In addition to total in vitro mixture, 6 submixtures containing the same concentration of chlorinated + brominated, chlorinated + perfluorinated, brominated + perfluorinated, or chlorinated, brominated or perfluorinated compounds only were constructed. Using submixtures enables investigating the effect of adding or removing one or more chemical groups. Concentrations of compounds included in feed and in vitro mixtures were verified by chemical analysis. It is suggested that this method may be utilized to construct realistic mixtures of environmental contaminants for toxicity studies based upon the relative levels of POP to which individuals are exposed.

The term "sample stacking" comprises a relatively broad spectrum of techniques that already form an almost inherent part of the methodology of CZE. Their principles are different but the effect is the same: concentration of a diluted analyte into a narrow zone and considerable increase of the method sensitivity. This review brings a survey of papers on electrophoretic sample stacking published approximately since the second quarter of 2014 till the first quarter of 2016. It is organized according to the principles of the stacking methods and includes chapters aimed at the concentration adjustment principle (Kohlrausch stacking), techniques based on pH changes, micellar methods, and other stacking techniques. Not reviewed are papers on transient ITP that are covered by another review in this issue., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Recent studies indicate that mineralo-organic nanoparticles form in various human body fluids, including blood and urine. These nanoparticles may form within renal tubules and increase in size in supersaturated urine, eventually leading to the formation of kidney stones. Here, we present observations suggesting that mineralo-organic nanoparticles found in blood may induce kidney stone formation via an alternative mechanism in which the particles translocate through endothelial and renal epithelial cells to reach urine. We propose that this alternative mechanism of kidney stone formation and the study of mineralo-organic nanoparticles in general may provide novel strategies for the early detection and treatment of ectopic calcifications and kidney stones.

Human exposure to environmental chemicals as persistent organic pollutants (POPs) is usually assessed considering each pollutant individually, with little attention to concentrations of mixtures in individuals or social groups. Yet, it may be relatively common for humans to have low and high concentrations of numerous POPs. The study objectives were to analyze the number of POPs detected per person at high concentrations in the U.S. population, and the associations between such type of indicators and socioeconomic factors as gender, race / ethnicity, education, and poverty level. From 91 POPs analyzed in serum samples of 4,739 individuals in three subsamples of the National Health and Nutrition Examination Survey (NHANES) 2003-2004 (the last period with valid updated individual data for the compounds considered in the present study), we computed the number of POPs whose serum concentrations were above selected cutoff points. POPs included were 13 organochlorine compounds (OCs), 10 polybrominated diphenyl ethers (PBDEs), the polybrominated biphenyl (PBB) 153, 38 polychlorinated biphenyls (PCBs), 17 polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs), and 12 perfluorinated compounds (PFCs). Over 13% of participants had ≥10 of the 37 most detected POPs each at a concentration in the top decile (P90). Over 30% of subjects with total toxic equivalency (TEQ) ≥P75, had ≥10 of 24 POPs not included in TEQ calculations at concentrations ≥P90. Compared to non-Hispanic whites, the adjusted odds ratio of having ≥10 of the 37 POPs at P90 was 9.2 for non-Hispanic blacks and 0.18 for Mexican Americans. Poverty, body mass index, age, and gender were also independently associated with having ≥10 POPs in the top decile. More than one tenth of the US population may have ≥10 POPs each at concentrations in the top decile. Such pattern is nine times more frequent in Non-Hispanic blacks and four times less frequent in Mexican Americans than in non-Hispanic whites.

Emerging evidence suggests that exposure to endocrine-disrupting chemicals including persistent organic pollutants (POPs) such as organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) has a long term impact on human health. The goal of this pilot study was to test whether antioxidant intervention by vitamin C supplementation may be a remedial approach to decrease body burden of POPs in humans. Using solid phase extraction coupled with a triple quadrupole mass spectrometer and a gas chromatography high resolution mass spectrometry, we measured 18 PCBs, 7 OCPs, and 5 PBDEs in the blood of 15 healthy California women (8 were obese/overweight and 7 had normal weight) before and after 2 months of vitamin C supplementation (1000 mg/day). We observed higher PBDE levels than PCBs and OCPs, but only PCB and OCP levels were strongly and positively correlated with participant's BMI and age. We also found statistically significant decreases in 6 PCBs (PCB-74, PCB-118, PCB-138, PCB-153, PCB-180, and PCB-187), and 2 OCPs (4,4'-DDE, and 4,4'-DDT), but not PBDEs after vitamin C supplementation. Pending confirmation of this pilot finding in a larger study of both sexes, vitamin C intervention may have important public health implications in protecting health by reducing body burdens of POPs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Self-rated health (SRH) is a powerful predictor of mortality, morbidity, and need for health services. SRH generally increases with educational level, and decreases with age, number of chronic conditions, and body mass index (BMI). Because human concentrations of most persistent organic pollutants (POPs) also vary by age, education, and BMI, and because of the physiological and clinical effects of POPs, we hypothesized that body concentrations of POPs are inversely associated with SRH., Objectives: To analyze the relation between serum concentrations of POPs and SRH in the general population of Catalonia, Spain, taking into account sociodemographic factors and BMI, as well as chronic health conditions and mental disorders, measured by the General Health Questionnaire-12 (GHQ-12)., Methods: POP serum concentrations were measured by gas chromatography with electron-capture detection in 919 participants of the Catalan Health Interview Survey., Results: Individuals with higher concentrations of POPs had significantly poorer SRH; e.g., the median concentration of HCB in subjects with poor SRH was twice as high as in subjects with excellent SRH (366 ng/g vs. 169 ng/g, respectively; p-value<0.001). In crude models and in models adjusted for sex and BMI, the POPs-SRH association was often dose-dependent, and the likelihood of poor or regular SRH was 2 to 4-times higher in subjects with POP concentrations in the top quartile. In models adjusted for age or for chronic conditions virtually all ORs were near unity. No associations were found between POP levels and GHQ-12., Conclusions: Individuals with higher concentrations of POPs had significantly poorer SRH, an association likely due to age and chronic conditions, but not to sex, education, social class, BMI, or mental disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The lethal toxicity values (log 1/LD(50)) of 527 aliphatic and aromatic compounds in oral, intravenous, intramuscular and intraperitoneal routes were used to investigate the relationships of log 1/LD(50) from different exposure routes. Regression analysis shows that the log 1/LD(50) values are well correlated between intravenous and intraperitoneal or intramuscular injections. However, the correlations between oral and intravenous or intraperitoneal routes are relatively poor. Comparison of the average residuals indicates that intravenous injection is the most sensitive exposure route and oral administration is the least sensitive exposure route. This is attributed to the difference in kinetic process of toxicity testing. The toxic effect of a chemical can be similar or significantly different between exposure routes, depending on the absorption rates of chemicals into blood. Inclusion of hydrophobic parameter and fractions of ionic forms can improve the correlations between intravenous and intraperitoneal or oral routes, but not between intraperitoneal and oral routes. This is due to the differences of absorption rate in different exposure environments from different routes. Several factors, such as experimental uncertainty, metabolism and toxic kinetics, can affect the correlations between intravenous and intraperitoneal or oral routes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We used PBPK (physiologically-based pharmacokinetic) modelling to investigate distribution, bioaccumulation and excretion of the seven POPs (persistent organic pollutants) CB-99, CB-153, HCB, oxychlordane, p,p'-DDE, BDE-47 and BDE-99 in 4 adult captive Greenland sledge dog (Canis familiaris) bitches fed minke whale (Balaenoptera acuterostrata) blubber for 500-635 days. The PBPK modelled POP concentrations in adipose tissue, liver, kidney and plasma were mostly within a factor 2 of actual measured tissue levels even for those at the lower concentration end. The excretion route for oxychlordane and CB-153 was modelled to be via faeces while lung alveolar excretion dominated for BDE-47, BDE-99, HCB, p,p'-DDE and CB-99. Furthermore the model suggested the retained mass of POPs after 500 and 635 days of exposure, respectively, to be relatively low despite these POPs being highly recalcitrant. The retention increased in the following order (% of total intake); p,p'-DDE (1%)

The aim of this study was to assess differences between two biological matrices (serum and breast adipose tissue) in the evaluation of persistent organic pollutant (POP) exposure in breast cancer patients. The study population consisted of 103 women undergoing surgery for newly diagnosed breast carcinoma in a public hospital in Granada, Southern Spain. Independent variables were gathered from questionnaires and clinical records. POP concentrations were quantified in breast adipose tissue and serum samples. Spearman correlation tests were performed between pairs of POP concentrations and stepwise multivariable linear regression analyses were conducted to assess predictors of concentrations in the two matrices. p,p'- Dichlorodiphenyldichloroethylene (p,p'-DDE) showed the the highest median concentration in both matrices (194.34 and 173.84 ng/g lipid in adipose tissue and serum, respectively). Median wet-basis adipose tissue:serum ratios ranged from 109.34 to 651.62, while lipid-basis ratios ranged from 0.88 to 4.34. In general, we found significant positive correlation coefficients between pairs of POPs in adipose tissue and in serum, which were always higher in adipose tissue. We found positive and statistically significant correlations between serum and adipose tissue concentrations of p,p'-DDE and hexachlorobenzene (HCB) but not of polychlorinated biphenyls (PCBs). Age was positively associated with most POPs in adipose tissue and serum, while the body mass index was positively associated with adipose tissue HCB concentrations and negatively associated with serum PCB-153 and PCB-138 concentrations. Recent weight loss was inversely associated with POP residues in adipose tissue and positively associated with POP residues in serum. Serum HCB and PCB-180 concentrations were lower in patients who had received preoperative chemotherapy. According to our results, serum and adipose tissue POP concentrations in breast cancer patients may be differentially affected by external predictors. Taken together, these findings indicate the need to take account of the individual POP(s) under study and the biological matrix used when relating internal POP exposure to breast cancer disease and to make a careful selection of covariates for adjusting the model., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The number of studies on persistent organic pollutants (POPs) and type 2 diabetes mellitus (T2DM) is growing steadily. Although concentrations of many POPs in humans have decreased substantially, only some studies consider temporal and inter-individual changes in POP concentrations when assessing exposure. Here we combined plasma measurements with mechanistic modeling to generate complementary exposure measures to our single blood draw after disease diagnosis. Blood was collected between 2003-2006 from 106 subjects with T2DM and 106 age-matched controls, and POP concentrations were compared after adjustment for relevant risk factors and multiple testing. Area under the curve (AUC) of PCB-153 from birth until age 18, representing early-life exposure, and AUC from birth until time of diagnosis were generated as well as examples of life-time exposure trajectories using a mechanistic exposure model. The rank sum of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs, OR=16.9 (95% CI: 3.05-93.6)) as well as β-hexachlorocyclohexane (β-HCH, OR=203.8 (95% CI: 11.5-3620)) and 1, 1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE, OR=11.3 (95% CI: 2.55-49.9)) were associated with T2DM. Neither of the AUCs reflecting early life exposure and total life-time exposure at the time of diagnosis were associated with the disease. The predicted life course trajectories display clear differences within and between individuals in the past and suggest that a single blood draw provide limited information on POP exposure earlier in life. The predicted AUCs for PCB-153 did not support the positive association between T2DM and measured blood concentration of certain POPs. This may suggest that the model is either too simplistic and/or that strength of the association may vary through life and with time to/past diagnosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aboriginal peoples in the Canadian Arctic are exposed to persistent organic pollutants (POPs) and metals mainly through their consumption of a traditional diet of wildlife items. Recent studies indicate that many human chemical levels have decreased in the north, likely due to a combination of reduced global chemical emissions, dietary shifts, and risk mitigation efforts by local health authorities. Body burdens for chemicals in mothers can be further offset by breastfeeding, parity, and other maternal characteristics. We have assessed the impact of several dietary and maternal covariates following a decade of awareness of the contaminant issue in northern Canada, by performing multiple stepwise linear regression analyses from blood concentrations and demographic variables for 176 mothers recruited from Nunavut and the Northwest Territories during the period 2005-2007. A significant aboriginal group effect was observed for the modeled chemicals, except for lead and cadmium, after adjusting for covariates. Further, blood concentrations for POPs and metals were significantly associated with at least one covariate of older age, fewer months spent breastfeeding, more frequent eating of traditional foods, or smoking during pregnancy. Cadmium had the highest explained variance (72.5%) from just two significant covariates (current smoking status and parity). Although Inuit participants from the Northwest Territories consumed more traditional foods in general, Inuit participants from coastal communities in Nunavut continued to demonstrate higher adjusted blood concentrations for POPs and metals examined here. While this is due in part to a higher prevalence of marine mammals in the eastern Arctic diet, it is possible that other aboriginal group effects unrelated to diet may also contribute to elevated chemical body burdens in Canadian Arctic populations., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)

We evaluated relationships between persistent organic pollutant (POP) levels in the blood of children with leukemia and POP levels in dust from their household vacuum cleaners. Blood and dust were collected from participants of the California Childhood Leukemia Study at various intervals from 1999 to 2007 and analyzed for two polybrominated diphenyl ethers (PBDEs), two polychlorinated biphenyls (PCBs), and two organochlorine pesticides using gas chromatography-mass spectrometry. Due to small blood sample volumes (100 μL), dichlorodiphenyldichloroethylene (DDE) and BDE-153 were the only analytes with detection frequencies above 70%. For each analyte, depending on its detection frequency, a multivariable linear or logistic regression model was used to evaluate the relationship between POP levels in blood and dust, adjusting for child's age, ethnicity, and breastfeeding duration; mother's country of origin; household annual income; and blood sampling date. In linear regression, concentrations of BDE-153 in blood and dust were positively associated; whereas, DDE concentrations in blood were positively associated with breastfeeding, maternal birth outside the U.S., and Hispanic ethnicity, but not with corresponding dust-DDE concentrations. The probability of PCB-153 detection in a child's blood was marginally associated with dust-PCB-153 concentrations (p = 0.08) in logistic regression and significantly associated with breastfeeding. Our findings suggest that dust ingestion is a source of children's exposure to certain POPs.

Heavy metals and persistent organic pollutants (POPs), including Pb, Cd, T-Hg, MeHg, PCDD/Fs, PCBs, PBDEs, PCNs, and PBDD/Fs, were analyzed in 20 paired samples of cord blood, maternal blood, maternal urine, and placenta. The samples were collected from pregnant mothers and neonates from South Korea in 2010. The distribution of heavy metals among the samples varied with their physicochemical characteristics. The concentrations of Pb and Hg in the maternal and the cord blood samples were significantly correlated each other, implying efficient transplacental transport (TPT). Cd and Hg were accumulated in the placenta, forming protein conjugates, and T-Hg was higher in the cord blood samples than the maternal blood samples due to the binding affinity of Hg with fetal proteins. POPs generally showed the highest concentrations in the maternal serum samples, and the POPs levels in the cord serum and the placenta samples were dependent on the degree of halogenation. The TPT of POPs was seemingly related to lipoprotein transportation. Some PBDE congeners, however, showed their highest concentrations in the cord serum samples, suggesting an additional TPT mechanism. This is the first study to detect PCNs and PBDD/Fs in the cord serum samples, showing that the PCN levels were comparable to other POPs. According to the principal component analysis (PCA) results of the contaminant levels, POPs and heavy metals showed significantly different characteristics, whereas PBDEs had an intermediate attribute. Despite the limited number of participants, the comprehensive analysis of trace contaminants in the paired sample sets enabled us to infer the distribution and TPT mechanism of various contaminants.

Atropisomerism can be a complex concept for those who have not encountered it before. This paper discusses the experiments for identification, isolation, thermal stability, toxicity and biotransformation of various species. The identified atropisomers are a series of rotational hindered biaryl, rotational hindered amide, ring flip, and macrocycles atropisomers identified using supercritical fluid chromatography (SFC) and high performance liquid chromatography (HPLC). These technologies offered the advantage of separating various atropoenantiomers, atropdiastereomers and mixed atropisomers with other forms of stereoisomers in both analytical and preparative scales. With ultra-performance convergence chromatography (UPC(2)), the detection of N-oxide atropisomer metabolites can be obtained at very low level thus enabling the observation of conversion in human plasma possible. As the resolution of atropisomers are related to the energy barriers on the rotational axis, a calculated computational protocol was developed to predict the formation. A threshold of 10kcal/mol was established for possible detection of the atropisomers' existence with chromatographic technologies at room temperature or above. The atropisomer with higher energy barrier (>20kcal/mol) were isolated via preparative chromatography and the isolates studied in vitro and in vivo for evaluation of their stability in human plasma. The detailed analytical method development to analyze the biotransformation of the atropisomers in human plasma are also discussed in this paper., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of the present study was to assess the relationship between serum concentrations of several persistent organic pollutants and insulin resistance markers in a cohort of women with a history of gestational diabetes mellitus. ∑POPs was computed as the sum of individual serum POP concentrations. No statistically significant associations were found between levels of any POP and fasting glucose. However, polychlorinated biphenyl (PCB) congeners 138 and 180 were positively associated with 2-h glucose levels and PCB 180 also with fasting immunoreactive insulin (IRI). We also found a positive association of p,p'- dichlorodiphenyldichloroethylene (p,p'- DDE), PCBs (138, 153, and 180), hexachlorobenzene, and ∑POPs with 2-h IRI. Serum concentrations of PCBs (138, 153, and 180), hexachlorobenzene, and ∑POPs were also positively associated with homeostasis model assessment (HOMA2-IR) levels. Moreover, p,p'- DDE, PCBs (138, 153 and 180), hexachlorobenzene, and ∑POPs were negatively associated with Insulin Sensitivity Index (ISI-gly) levels. No significant association was found between glycated hemoglobin and the concentrations of any POP. The removal of women under blood glucose lowering treatment from the models strengthened most of the associations previously found for the whole population. Our findings suggest that exposure to certain POPs is a modifiable risk factor contributing to insulin resistance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Humans are exposed to persistent organic pollutants (POPs) through various routes, including consumption of contaminated food and accidental ingestion of settled dust., Objectives: We aimed to identify key routes of exposure to organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) in California women of reproductive age., Methods: Blood was collected from 48 mothers participating in the California Childhood Leukemia Study from 2006 to 2007 and analyzed for POPs using gas chromatography-mass spectrometry. Multivariable linear regression models of natural-log transformed serum concentrations were used to identify determinants of exposure from available questionnaire information on dietary habits, reproductive history, and demographic characteristics, as well as vacuum cleaner dust-POP levels., Results: After adjusting for blood lipid levels, age, body mass index, cumulative lactation, and sampling date, serum concentrations of multiple major PCBs were positively associated with fish consumption, but not dust-PCB levels. After adjusting for blood lipid levels, Hispanic ethnicity, country of origin, and household annual income, serum concentrations of multiple major PBDEs were positively associated with dust-PBDE levels., Conclusions: Our findings suggest that the relative contribution of specific exposure routes to total POP intake varies by chemical class, with dust being a relatively important source of PBDEs and diet being a relatively important source of PCBs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Forensic and clinical toxicological screening procedures are employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques with information-dependent acquisition (IDA) approaches more and more often. It is known that the complexity of a sample and the IDA settings might prevent important compounds from being triggered. Therefore, data-independent acquisition (DIA) methods should be more suitable for systematic toxicological analysis (STA). The DIA method sequential window acquisition of all theoretical fragment-ion spectra (SWATH), which uses Q1 windows of 20-35 Da for data-independent fragmentation, was systematically investigated for its suitability for STA. Quality of SWATH-generated mass spectra were evaluated with regard to mass error, relative abundance of the fragments, and library hits. With the Q1 window set to 20-25 Da, several precursors pass Q1 at the same time and are fragmented, thus impairing the library search algorithms to a different extent: forward fit was less affected than reverse fit and purity fit. Mass error was not affected. The relative abundance of the fragments was concentration dependent for some analytes and was influenced by cofragmentation, especially of deuterated analogues. Also, the detection rate of IDA compared to SWATH was investigated in a forced coelution experiment (up to 20 analytes coeluting). Even using several different IDA settings, it was observed that IDA failed to trigger relevant compounds. Screening results of 382 authentic forensic cases revealed that SWATH's detection rate was superior to IDA, which failed to trigger ∼10% of the analytes.

Background: A nationwide multicenter study was organized to establish reference intervals (RIs) in the Turkish population for 25 commonly tested biochemical analytes and to explore sources of variation in reference values, including regionality., Methods: Blood samples were collected nationwide in 28 laboratories from the seven regions (≥400 samples/region, 3066 in all). The sera were collectively analyzed in Uludag University in Bursa using Abbott reagents and analyzer. Reference materials were used for standardization of test results. After secondary exclusion using the latent abnormal values exclusion method, RIs were derived by a parametric method employing the modified Box-Cox formula and compared with the RIs by the non-parametric method. Three-level nested ANOVA was used to evaluate variations among sexes, ages and regions. Associations between test results and age, body mass index (BMI) and region were determined by multiple regression analysis (MRA)., Results: By ANOVA, differences of reference values among seven regions were significant in none of the 25 analytes. Significant sex-related and age-related differences were observed for 10 and seven analytes, respectively. MRA revealed BMI-related changes in results for uric acid, glucose, triglycerides, high-density lipoprotein (HDL)-cholesterol, alanine aminotransferase, and γ-glutamyltransferase. Their RIs were thus derived by applying stricter criteria excluding individuals with BMI >28 kg/m2. Ranges of RIs by non-parametric method were wider than those by parametric method especially for those analytes affected by BMI., Conclusions: With the lack of regional differences and the well-standardized status of test results, the RIs derived from this nationwide study can be used for the entire Turkish population.

Wen-Xin-Formula (WXF), a famous traditional prescription, has been widely used to treat myocardial ischemia syndrome for thousands of years. However, the constituents absorbed into blood after oral administration of WXF remain unknown. Here, an integrative ultra performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) combined with the MetaboLynx approach was established to investigate the absorbed constituents in rats after oral administration of WXF. A hyphenated electrospray ionization and quadrupole-time-of-flight analyzer was used for the determination of accurate mass of the molecule and fragment ions. With this rapid and automated analysis method, a total of 32 peaks were tentatively characterized in vivo based on MS and MS/MS data and comparison with available databasess, 26 of which were parent components and six metabolites. These components mainly were ginsenosides, paeoniflorin, galloyl glucose, berberis alkaloids, phenolic, phenolic glycosides and unsaturated fatty acids, glucuronide products of original berberis alkaloids. The present study demonstrates that integrative UPLC-ESI-Q-TOF-MS technique and MetaboLynx data processing method were successfully applied for the rapid discovery of potentially bioactive components and metabolites from WXF, and proved that the established method could help to explore the effective substances for further research into WXF., (Copyright © 2014 John Wiley & Sons, Ltd.)

The potential of supercritical fluid extraction (SFE) as a preparation method for mass spectrometry of dried blood spots (DBS) was examined. SFE is generally used for the extraction of hydrophobic compounds, but hydrophilic metabolites such as amino acids, amines, and nucleic-acid-related metabolites could be extracted by adding a low level of methanol as a modifier. Under the optimized conditions, over 200 metabolites were detected from a dried serum spot, of which over 160 metabolites could be analyzed stably (RSD <20%). These results show that SFE is an effective extraction method of metabolites with a wide range of polarity in DBS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

When reporting circulating levels of persistent organic pollutants (POPs), usually lipid-normalized values are given. However, animal experiments and some human data indicate that exposure to POPs may change lipid values. The aim of the present study is to investigate if POP levels can predict future changes in levels of circulating lipids. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, lipids were measured at age 70 and at age 75 in 598 subjects without lipid-lowering medication. Twenty-three different POPs, including 16 polychlorinated biphenyls (PCBs), five organochlorine pesticides, one dioxin (OCDD) and one flame retardant brominated compound (BDE47) were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) at age 70. Strong relationships were seen among the baseline levels of the non-dioxin-like PCBs 194, 206 and 209 and the degree of increase in total serum cholesterol and LDL-cholesterol during the 5 year follow-up. These relationships were generally stronger when lipid-normalized levels were used compared to wet-weight based levels. On the contrary, for two of the pesticides, hexachlorobenzene and trans-nonachlordane, levels were inversely related to the change in LDL-cholesterol, with strongest associations found using wet-weight based levels. PCBs 194, 206 and 209 were inversely related to the change in HDL-cholesterol, in particular for wet-weight based levels. However, these relationships were only significant for wet-weight PCB 194 following adjustment for multiple testing. None of the POPs was related to the change in serum triglycerides. When investigating the association between the change in total serum cholesterol and LDL-cholesterol across different categories of change in BMI, we noted robust results especially in the group with stable BMI, suggesting that the observed relationships were not due to fluctuations in BMI over time. In conclusion, POPs are related to the change in lipids over time, especially LDL-cholesterol. This may explain why POP exposure previously has been linked to atherosclerosis and cardiovascular disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)