Dioxins are ubiquitous endocrine-disrupting substances,but determining the effects and benchmark doses in situations of coexposure is highly challenging.The objective of this study was to assess the relationship betwe...Dioxins are ubiquitous endocrine-disrupting substances,but determining the effects and benchmark doses in situations of coexposure is highly challenging.The objective of this study was to assess the relationship between dioxin andgestational diabetes mellitus(GDM),calculate the benchmark dose(BMD)of dioxin in coexposure scenarios,and derive a daily exposure threshold using an optimized physiologically based toxicokinetic(PBTK)model.Based on a nested casecontrol study including 77 cases with GDM and 154 controls,serum levels of 29 dioxin-like compounds(DLCs)along with 10 perfluoroalkyl acids(PFAAs),seven polybrominated diphenyl ethers(PBDEs),and five non-dioxin-like polychlorinated biphenyls(ndl-PCBs)were measured at 9−16 weeks of gestation.Bayesian machine kernel regression(BKMR)was employed to identify significant chemicals,and probit and logistic models were used to calculate BMD adjusted for significant chemicals.A physiologically based toxicokinetic(PBTK)model was optimized using polyfluorinated dibenzo-p-dioxins and dibenzofurans(PFDD/Fs)data by the Bayesian−Monte Carlo Markov chain method and was used to determine the daily dietary exposure threshold.The median serum level of total dioxin toxic equivalent(TEQ)was 7.72 pg TEQ/g fat.Logistic regression analysis revealed that individuals in the fifth quantile of total TEQ level had significantly higher odds of developing GDM compared to those in the first quantile(OR,8.87;95%CI 3.19,27.58).The BKMR analysis identified dioxin TEQ and BDE-153 as the compounds with the greatest influence.The binary logistic and probit models showed that the BMD10(benchmark dose corresponding to a 10%extra risk)and BMDL_(10)(lower bound on the BMD_(10))were 3.71 and 3.46 pg TEQ/g fat,respectively,when accounting for coexposure to BDE-153 up to the 80%level.Using the optimized PBTK model and modifying factor,it was estimated that daily exposure should be below 4.34 pg TEQ kg^(−1)bw week^(−1)in order to not reach a harmful serum concentration for GDM.Further studies should u展开更多
In this study,we conducted exposure experiments on egg-laying hens to explore the toxicokinetics and maternal transfer characteristics of lipophilic and proteinophilic halogenated organic pollutants(HOPs).The lipophil...In this study,we conducted exposure experiments on egg-laying hens to explore the toxicokinetics and maternal transfer characteristics of lipophilic and proteinophilic halogenated organic pollutants(HOPs).The lipophilic HOPs included polychlorinated biphenyls(PCBs),polybrominated diphenyl ethers(PBDEs),and dechlorane plus(DPs),while the proteinophilic HOPs included perfluorocarboxylic acids(PFCAs).The results revealed that most of lipophilic HOPs exhibit lower depuration rate(kd)than PFCAs.The kd of lipophilic HOPs correlated with the octanol−water partition coefficient(log KOW)values in a V-shaped curve,whereas that of PFCAs correlated with the protein−water partition coefficient(log KPW)values in an inverted V-shaped curve.The depuration rate,rather than the uptake rate,was a leading factor in determining the bioaccumulation potential of HOPs in hens.Although the dominant factors determining the tissue distribution of the two types of compounds were explicit(fats vs phospholipids),chemical-specific tissue distribution was still observed.The egg-maternal concentration ratio was dependent on the exposure status,concentration,and maternal tissue choice.Using a single maternal tissue may not be an appropriate method for assessing chemical maternal transfer potential.PFCAs have a greater maternal transfer potential(>80%of the total body burden)than lipophilic HOPs(approximately 30%for BDE209 and DPs,and less than 10%for the others).Their lipophilic and partly proteinophilic nature makes the toxicokinetics and maternal transfer characteristics of BDE209 and DPs different from those of other lipophilic HOPs.These findings are crucial for enhancing our understanding of the behavior and fate of HOPs in egg-laying hens.展开更多
As a key step in next-generation risk assessment(NGRA),in vitro to in vivo extrapolation(IVIVE)aims to mobilize a mechanism-based understanding of toxicology to translate bioactive chemical concentrations obtained fro...As a key step in next-generation risk assessment(NGRA),in vitro to in vivo extrapolation(IVIVE)aims to mobilize a mechanism-based understanding of toxicology to translate bioactive chemical concentrations obtained from in vitro assays to corresponding exposures likely to induce bioactivity in vivo.This conversion can be achieved via physiologically-based toxicokinetic(PBTK)models and machine learning(ML)algorithms.The last 5 years have witnessed a period of rapid development in IVIVE,with the number of IVIVE-related publications increasing annually.This Review aims to(1)provide a comprehensive overview of the origin of IVIVE and initiatives undertaken by multiple national agencies to promote its development;(2)compile and sort out IVIVE-related publications and perform a clustering analysis of their high-frequency keywords to capture key research hotspots;(3)comprehensively review PBTK and ML model-based IVIVE studies published in the last 5 years to understand the research directions and methodology developments;and(4)propose future perspectives for IVIVE from two aspects:expanding the scope of application and integrating new technologies.The former includes focusing on metabolite toxicity,conducting IVIVE studies on susceptible populations,advancing ML-based quantitative IVIVE models,and extending research to ecological effects.The latter includes combining systems biology,multiomics,and adverse outcome networks with IVIVE,aiming at a more microscopic,mechanistic,and comprehensive toxicity prediction.This Review highlights the important value of IVIVE in NGRA,with the goal of providing confidence for its routine use in chemical prioritization,hazard assessment,and regulatory decision making.展开更多
The toxicokinetic(TK)model‐derived kinetic bioconcentration factor(BCFk)provides a quantitatively comparable index to estimate the bioaccumulation potential of nanoparticles(NPs)that barely reach thermodynamic equili...The toxicokinetic(TK)model‐derived kinetic bioconcentration factor(BCFk)provides a quantitatively comparable index to estimate the bioaccumulation potential of nanoparticles(NPs)that barely reach thermodynamic equilibrium in aquatic organisms,but experimental data are limited for various NPs.In the present study,a machine learning model was applied to offer reliable in silico predictions for the dynamic body burden of diverse NPs to derive corresponding parameters for the TK model.The developed eXtreme Gradient Boosting‐derived TK(XGB‐TK)model was applied to predict BCFk results for a broad range of metallic or carbonaceous NPs,with an appreciable prediction R2 of 0.96.The BCFk values were predicted based on a random combination of selected variable features,revealing that their bioaccumulation potential showed an overall negative correlation with NP density or organism size.By applying importance analysis and partial dependence plots,NP density and organism size were revealed to be the top essential features that impact the bioaccumulation potential.The conjunctively used XGB‐TK model enabled a prior comparison for diverse NPs and straightforward derivation on the dependency of features,which could also guide the bioaccumulation mechanism exploration and experimental condition formulation.展开更多
Chlormequat is a quaternary ammonium and choline chlorinated derivated is used as plant growth regulating agent. There are very few documented cases of poisoning in humans. We reported a case of non-fatal suicide atte...Chlormequat is a quaternary ammonium and choline chlorinated derivated is used as plant growth regulating agent. There are very few documented cases of poisoning in humans. We reported a case of non-fatal suicide attempt by chlormequat in France. A 34-year-old woman was admitted to hospital after deliberate consumption of plant growth regulator, C5 SUN, containing chlormequat chloride (460 g/L) and choline chloride (320 g/L). Immediately, she developed symptoms of respiratory distress and a cardiac massage was begun by her father. In this case report, we described the method for an accurate and reliable screening of chlormequat which was based on the combination of Target Analysis powerful software and a high performance TOF-MS (Impact HD from Bruker). After forced diuresis, the kinetic of elimination of chlormequat is biphasic: vascular phase diffusion (half-life of 5.6 hr) followed by a phase of free elimination (half-life of 16.2 h). Although chlormequat poisoning is clinically similar to that observed with anticholinesterase compounds, chlormequat chloride is not an acetylcholinesterase inhibitor. Chlormequat seems to be a weak substrat competitor for cholinesterase leading to acetylcholine accumulation and prolonged depolarization in muscular junction. Cardiac massage, artificial respiration and forced diuresis have significantly improved the prognosis of our patient.展开更多
Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high...Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody(SHR-1222)in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the proposed method was 2.00-500μg/mL,and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods(ratios of drug exposure,0.8-1.0).Notably,two monkeys in the60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies(ADAs)in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.展开更多
基金funded by the National Natural Science Foundation of China,Grant 2017YFC1600504.
文摘Dioxins are ubiquitous endocrine-disrupting substances,but determining the effects and benchmark doses in situations of coexposure is highly challenging.The objective of this study was to assess the relationship between dioxin andgestational diabetes mellitus(GDM),calculate the benchmark dose(BMD)of dioxin in coexposure scenarios,and derive a daily exposure threshold using an optimized physiologically based toxicokinetic(PBTK)model.Based on a nested casecontrol study including 77 cases with GDM and 154 controls,serum levels of 29 dioxin-like compounds(DLCs)along with 10 perfluoroalkyl acids(PFAAs),seven polybrominated diphenyl ethers(PBDEs),and five non-dioxin-like polychlorinated biphenyls(ndl-PCBs)were measured at 9−16 weeks of gestation.Bayesian machine kernel regression(BKMR)was employed to identify significant chemicals,and probit and logistic models were used to calculate BMD adjusted for significant chemicals.A physiologically based toxicokinetic(PBTK)model was optimized using polyfluorinated dibenzo-p-dioxins and dibenzofurans(PFDD/Fs)data by the Bayesian−Monte Carlo Markov chain method and was used to determine the daily dietary exposure threshold.The median serum level of total dioxin toxic equivalent(TEQ)was 7.72 pg TEQ/g fat.Logistic regression analysis revealed that individuals in the fifth quantile of total TEQ level had significantly higher odds of developing GDM compared to those in the first quantile(OR,8.87;95%CI 3.19,27.58).The BKMR analysis identified dioxin TEQ and BDE-153 as the compounds with the greatest influence.The binary logistic and probit models showed that the BMD10(benchmark dose corresponding to a 10%extra risk)and BMDL_(10)(lower bound on the BMD_(10))were 3.71 and 3.46 pg TEQ/g fat,respectively,when accounting for coexposure to BDE-153 up to the 80%level.Using the optimized PBTK model and modifying factor,it was estimated that daily exposure should be below 4.34 pg TEQ kg^(−1)bw week^(−1)in order to not reach a harmful serum concentration for GDM.Further studies should u
基金funded by the National Nature Science Foundation of China(Nos.U23A2056,42277267,42321003)Guangdong Major Project of Basic and Applied Basic Research(2023B0303000007)+1 种基金Guangdong Foundation for the Program of Science and Technology Research(Nos.2023B1212060049)This is a contribution No.IS-3527 from GIGCAS.
文摘In this study,we conducted exposure experiments on egg-laying hens to explore the toxicokinetics and maternal transfer characteristics of lipophilic and proteinophilic halogenated organic pollutants(HOPs).The lipophilic HOPs included polychlorinated biphenyls(PCBs),polybrominated diphenyl ethers(PBDEs),and dechlorane plus(DPs),while the proteinophilic HOPs included perfluorocarboxylic acids(PFCAs).The results revealed that most of lipophilic HOPs exhibit lower depuration rate(kd)than PFCAs.The kd of lipophilic HOPs correlated with the octanol−water partition coefficient(log KOW)values in a V-shaped curve,whereas that of PFCAs correlated with the protein−water partition coefficient(log KPW)values in an inverted V-shaped curve.The depuration rate,rather than the uptake rate,was a leading factor in determining the bioaccumulation potential of HOPs in hens.Although the dominant factors determining the tissue distribution of the two types of compounds were explicit(fats vs phospholipids),chemical-specific tissue distribution was still observed.The egg-maternal concentration ratio was dependent on the exposure status,concentration,and maternal tissue choice.Using a single maternal tissue may not be an appropriate method for assessing chemical maternal transfer potential.PFCAs have a greater maternal transfer potential(>80%of the total body burden)than lipophilic HOPs(approximately 30%for BDE209 and DPs,and less than 10%for the others).Their lipophilic and partly proteinophilic nature makes the toxicokinetics and maternal transfer characteristics of BDE209 and DPs different from those of other lipophilic HOPs.These findings are crucial for enhancing our understanding of the behavior and fate of HOPs in egg-laying hens.
基金National Natural Science Foundation of China(grant no.2217060631)National Key Research and Development Program of China(grant no.2022YFC3902104).
文摘As a key step in next-generation risk assessment(NGRA),in vitro to in vivo extrapolation(IVIVE)aims to mobilize a mechanism-based understanding of toxicology to translate bioactive chemical concentrations obtained from in vitro assays to corresponding exposures likely to induce bioactivity in vivo.This conversion can be achieved via physiologically-based toxicokinetic(PBTK)models and machine learning(ML)algorithms.The last 5 years have witnessed a period of rapid development in IVIVE,with the number of IVIVE-related publications increasing annually.This Review aims to(1)provide a comprehensive overview of the origin of IVIVE and initiatives undertaken by multiple national agencies to promote its development;(2)compile and sort out IVIVE-related publications and perform a clustering analysis of their high-frequency keywords to capture key research hotspots;(3)comprehensively review PBTK and ML model-based IVIVE studies published in the last 5 years to understand the research directions and methodology developments;and(4)propose future perspectives for IVIVE from two aspects:expanding the scope of application and integrating new technologies.The former includes focusing on metabolite toxicity,conducting IVIVE studies on susceptible populations,advancing ML-based quantitative IVIVE models,and extending research to ecological effects.The latter includes combining systems biology,multiomics,and adverse outcome networks with IVIVE,aiming at a more microscopic,mechanistic,and comprehensive toxicity prediction.This Review highlights the important value of IVIVE in NGRA,with the goal of providing confidence for its routine use in chemical prioritization,hazard assessment,and regulatory decision making.
基金National Natural Science Foundation of China,Grant/Award Numbers:22125602,22206087,U2067215National Key R&D Program of China,Grant/Award Number:2020YFC1806703Fundamental Research Funds for the Central Universities,Grant/Award Number:XJ20222005501。
文摘The toxicokinetic(TK)model‐derived kinetic bioconcentration factor(BCFk)provides a quantitatively comparable index to estimate the bioaccumulation potential of nanoparticles(NPs)that barely reach thermodynamic equilibrium in aquatic organisms,but experimental data are limited for various NPs.In the present study,a machine learning model was applied to offer reliable in silico predictions for the dynamic body burden of diverse NPs to derive corresponding parameters for the TK model.The developed eXtreme Gradient Boosting‐derived TK(XGB‐TK)model was applied to predict BCFk results for a broad range of metallic or carbonaceous NPs,with an appreciable prediction R2 of 0.96.The BCFk values were predicted based on a random combination of selected variable features,revealing that their bioaccumulation potential showed an overall negative correlation with NP density or organism size.By applying importance analysis and partial dependence plots,NP density and organism size were revealed to be the top essential features that impact the bioaccumulation potential.The conjunctively used XGB‐TK model enabled a prior comparison for diverse NPs and straightforward derivation on the dependency of features,which could also guide the bioaccumulation mechanism exploration and experimental condition formulation.
文摘Chlormequat is a quaternary ammonium and choline chlorinated derivated is used as plant growth regulating agent. There are very few documented cases of poisoning in humans. We reported a case of non-fatal suicide attempt by chlormequat in France. A 34-year-old woman was admitted to hospital after deliberate consumption of plant growth regulator, C5 SUN, containing chlormequat chloride (460 g/L) and choline chloride (320 g/L). Immediately, she developed symptoms of respiratory distress and a cardiac massage was begun by her father. In this case report, we described the method for an accurate and reliable screening of chlormequat which was based on the combination of Target Analysis powerful software and a high performance TOF-MS (Impact HD from Bruker). After forced diuresis, the kinetic of elimination of chlormequat is biphasic: vascular phase diffusion (half-life of 5.6 hr) followed by a phase of free elimination (half-life of 16.2 h). Although chlormequat poisoning is clinically similar to that observed with anticholinesterase compounds, chlormequat chloride is not an acetylcholinesterase inhibitor. Chlormequat seems to be a weak substrat competitor for cholinesterase leading to acetylcholine accumulation and prolonged depolarization in muscular junction. Cardiac massage, artificial respiration and forced diuresis have significantly improved the prognosis of our patient.
基金supported by the National Natural Science Foundation of China(Grant No.81521005)the National Key Research Project of the Chinese Academy of Sciences(Grant No.XDA12050306)。
文摘Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody(SHR-1222)in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the proposed method was 2.00-500μg/mL,and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods(ratios of drug exposure,0.8-1.0).Notably,two monkeys in the60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies(ADAs)in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.
