Objective To estimate the biological exposure limit （BEL） using benchmark dose （BMD） based on two sets of data from occupational epidemiology. Methods Cadmium-exposed workers were selected from a cadmium smelting ...Objective To estimate the biological exposure limit （BEL） using benchmark dose （BMD） based on two sets of data from occupational epidemiology. Methods Cadmium-exposed workers were selected from a cadmium smelting factory and a zinc product factory. Doctors, nurses or shop assistants living in the same area served as a control group. Urinary cadmium （UCd） was used as an exposure biomarker and urinary D2-microgloburin （B2M）, N-acetyl-D-D-glucosaminidase （NAG） and albumin （ALB） as effect biomarkers. All urine parameters were adjusted by urinary creatinine. Software of BMDS （Version 1.3.2, EPA.U.S.A） was used to calculate BMD. Results The cut-off point （abnormal values） was determined based on the upper limit of 95% of effect biomarkers in control group. There was a significant dose response relationship between the effect biomarkers （urinary B2M, NAG9 and ALB） and exposure biomarker （UCd）. BEL value was 5 μg/g creatinine for UB2M as an effect biomarker, consistent with the recommendation of WHO. BEL could be estimated by using the method of BMD. BEL value was 3 μg/g creafinine for UNAG as an effect biomarker. The more sensitive the used biomarker is, the more occupational population will be protected. Conclusion BMD can be used in estimating the biological exposure limit （BEL）. UNAG is a sensitive biomarker for estimating BEL after cadmium exposure.展开更多
Objective The study aimed to estimate the benchmark dose(BMD)of coke oven emissions(COEs)exposure based on mitochondrial damage with the mitochondrial DNA copy number(mtDNAcn)as a biomarker.Methods A total of 782 subj...Objective The study aimed to estimate the benchmark dose(BMD)of coke oven emissions(COEs)exposure based on mitochondrial damage with the mitochondrial DNA copy number(mtDNAcn)as a biomarker.Methods A total of 782 subjects were recruited,including 238 controls and 544 exposed workers.The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction.Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95%confidence lower limit(BMDL).Results The mtDNAcn of the exposure group was lower than that of the control group(0.60±0.29 vs.1.03±0.31;P<0.001).A dose-response relationship was shown between the mtDNAcn damage and COEs.Using the Benchmark Dose Software,the occupational exposure limits(OELs)for COEs exposure in males was 0.00190 mg/m^(3).The OELs for COEs exposure using the BBMD were 0.00170 mg/m^(3)for the total population,0.00158 mg/m^(3)for males,and 0.00174 mg/m^(3)for females.In possible risk obtained from animal studies(PROAST),the OELs of the total population,males,and females were 0.00184,0.00178,and 0.00192 mg/m^(3),respectively.Conclusion Based on our conservative estimate,the BMDL of mitochondrial damage caused by COEs is0.002 mg/m^(3).This value will provide a benchmark for determining possible OELs.展开更多
A survey involving 6103 participants from five Chinese provinces was conducted to evaluate the threshold value of urinary cadmium （UCd） for renal dysfunction as benchmark dose low （BMDL）. The urinary N-acetyl-13-D...A survey involving 6103 participants from five Chinese provinces was conducted to evaluate the threshold value of urinary cadmium （UCd） for renal dysfunction as benchmark dose low （BMDL）. The urinary N-acetyl-13-D-glucosaminidase （UNAG） was chosen as an effect biomarker. The UCd BMDLs for UNAG ranged from 2.18μg/g creatinine （cr） to 4.26μg/g cr in the populations of different provinces. The selection of the sample population and area affect the evaluation of the BMDL. The reference level of UCd for renal effects was further evaluated based on the data of all 6103 subjects. With benchmark responses （BMR） of 10%/5%, the overall UCd BMDLs for males in the total population were 3.73/2.08 μg/g cr. The BMD was slightly lower in females, thereby indicating that females may be relatively more sensitive to Cd exposure than are males.展开更多
Eleven recently completed toxicological studies were critically reviewed to identify toxicologically significant endpoints and dose-response information. Dose-response data were compiled and entered into the USEPA＇s ...Eleven recently completed toxicological studies were critically reviewed to identify toxicologically significant endpoints and dose-response information. Dose-response data were compiled and entered into the USEPA＇s benchmark dose software （BMDS） for calculation of a benchmark dose （BMD） and a benchmark dose low （BMDL）. After assessing 91 endpoints across the nine studies, a total of 23 of these endpoints were identified for BMD modeling, and BMDL estimates corresponding to various dose-response models were compiled for these separate endpoints. Thyroid, neurobehavior and reproductive endpoints for BDE-47, -99, -209 were quantitatively evaluated. According to methods and feature of each study, different uncertainty factor （UF） value was decided and subsequently reference doses （RfDs） were proposed. Consistent with USEPA, the lowest BMDLs of 2.10, 81.77, and 1698 I^g/kg were used to develop RfDs for BDE-47, -99, and -209, respectively. RfDs for BDE-99 and BDE-209 were comparable to EPA results, and however, RfD of BDE-47 was much lower than that of EPA, which may result from that reproductive/developmental proves to be more sensitive than neurobehavior for BDE-47 and the principal study uses very-low-dose exposure.展开更多
Ionic liquids(ILs),traditionally considered environmentally benign solvents,have shown potential toxicity to organisms,raising concerns about their safety.Among them,1-octyl-3-methylimidazolium(M8OI)has been detected ...Ionic liquids(ILs),traditionally considered environmentally benign solvents,have shown potential toxicity to organisms,raising concerns about their safety.Among them,1-octyl-3-methylimidazolium(M8OI)has been detected at high concentrations in soils and exhibits hepatotoxic properties.To uncover the molecular mechanisms underlying this toxicity,wholetranscriptome sequencing was performed,coupled with benchmark dose(BMD)modeling,to derive transcriptomic points-of-departure(tPOD)through dose−response analysis.The transcriptomic analysis identified 425,667,and 567 differentially expressed genes(DEGs)following low(10μmol/L),medium(50μmol/L),and high(200μmol/L)doses of M8OI exposure,respectively.Enrichment analysis revealed significant perturbations in pathways related to cytokine−cytokine receptor interaction and IL-17 signaling.BMD modeling yielded tPOD values of 1.51μmol/L(median of the 20 most sensitive genes,omicBMD20),2.98μmol/L(tenth percentile of all genes,omicBMD10th),6.83μmol/L(mode of the first peak of all gene BMDs,omicBMDmode),and 5.9μmol/L for pathway-level analysis.These transcriptomics-derived tPODs were at least 105-fold lower than M8OI’s hepatotoxic concentration,as indicated by its EC_(50)of 723.6μmol/L in HepG2 cells.Functional analysis of the transcriptomic data identified legionellosis,rheumatoid arthritis,and transcriptional misregulation in cancer as the most sensitive pathways affected by M8OI.These findings highlight the molecular mechanisms driving M8OI-induced hepatotoxicity and underscore the utility of transcriptomics in deriving sensitive and quantitative toxicity thresholds.The results provide critical insights for guideline-driven toxicological evaluations and regulatory decision-making,supporting a more comprehensive assessment of IL safety.展开更多
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 utilize coexposure statistical methods and physiologically based pharmacokinetic(PBTK)models in reference dose calculation.展开更多
Objective The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level（NOAEL）,which is a critical factor in the establishment of an acceptab...Objective The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level（NOAEL）,which is a critical factor in the establishment of an acceptable dietary intake（ADI）.Methods In accordance with the Organization for Economic Co-operation and Development（OECD） testing guidelines,lanthanum nitrate was administered once daily by gavage to Sprague-Dawley（SD） rats at dose levels of 0,1.5,6.0,24.0,and 144.0 mg/kg body weight（BW） per day for 90 days,followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups.Outcome parameters were mortality,clinical symptoms,body and organ weights,serum chemistry,and food consumption,as well as ophthalmic,urinary,hematologic,and histopathologic indicators.The benchmark dose（BMD） approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum.Results Significant decreases were found in the 144.0 mg/kg BW group in the growth index,including body weight,organ weights,and food consumption.This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day.Importantly,the 95% lower confidence value of the benchmark dose（BMDL） was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males.Conclusion The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements（REEs）.展开更多
Objective The present study was undertaken to evaluate the subchronic oral toxicity of sodium dehydroacetate(DHA-Na)and to determine the point of departure(POD),which is a critical factor in the establishment of an ac...Objective The present study was undertaken to evaluate the subchronic oral toxicity of sodium dehydroacetate(DHA-Na)and to determine the point of departure(POD),which is a critical factor in the establishment of an acceptable dietary intake.Methods DHA-Na was administered once daily by gavage to Sprague–Dawley rats at dose levels of 0.0,31.0,62.0,and 124.0 mg/kg BW per day for 90 days,followed by a recovery period of 4 weeks in the control and 124.0 mg/kg BW per day groups.The outcome parameters were mortality,clinical observations,body weights,food consumption,hematology and clinical biochemistry,endocrine hormone levels,and ophthalmic,urinary,and histopathologic indicators.The benchmark dose(BMD)approach was applied to estimate the POD.Results Significant decreases were found in the 62.0 and 124.0 mg/kg BW groups in terms of the body weight and food utilization rate,whereas a significant increase was found in the thyroid stimulating hormone levels of the 124.0 mg/kg BW group.Importantly,the 95%lower confidence limit on the BMD of 51.7 mg/kg BW was modeled for a reduction in body weight.Conclusion The repeated-dose study indicated the slight systemic toxicity of DHA-Na at certain levels(62.0 and 124.0 mg/kg BW)after a 90-day oral exposure.展开更多
文摘Objective To estimate the biological exposure limit （BEL） using benchmark dose （BMD） based on two sets of data from occupational epidemiology. Methods Cadmium-exposed workers were selected from a cadmium smelting factory and a zinc product factory. Doctors, nurses or shop assistants living in the same area served as a control group. Urinary cadmium （UCd） was used as an exposure biomarker and urinary D2-microgloburin （B2M）, N-acetyl-D-D-glucosaminidase （NAG） and albumin （ALB） as effect biomarkers. All urine parameters were adjusted by urinary creatinine. Software of BMDS （Version 1.3.2, EPA.U.S.A） was used to calculate BMD. Results The cut-off point （abnormal values） was determined based on the upper limit of 95% of effect biomarkers in control group. There was a significant dose response relationship between the effect biomarkers （urinary B2M, NAG9 and ALB） and exposure biomarker （UCd）. BEL value was 5 μg/g creatinine for UB2M as an effect biomarker, consistent with the recommendation of WHO. BEL could be estimated by using the method of BMD. BEL value was 3 μg/g creafinine for UNAG as an effect biomarker. The more sensitive the used biomarker is, the more occupational population will be protected. Conclusion BMD can be used in estimating the biological exposure limit （BEL）. UNAG is a sensitive biomarker for estimating BEL after cadmium exposure.
基金supported by the National Natural Science Foundation of China[grant numbers:NSFC81872597,81001239]。
文摘Objective The study aimed to estimate the benchmark dose(BMD)of coke oven emissions(COEs)exposure based on mitochondrial damage with the mitochondrial DNA copy number(mtDNAcn)as a biomarker.Methods A total of 782 subjects were recruited,including 238 controls and 544 exposed workers.The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction.Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95%confidence lower limit(BMDL).Results The mtDNAcn of the exposure group was lower than that of the control group(0.60±0.29 vs.1.03±0.31;P<0.001).A dose-response relationship was shown between the mtDNAcn damage and COEs.Using the Benchmark Dose Software,the occupational exposure limits(OELs)for COEs exposure in males was 0.00190 mg/m^(3).The OELs for COEs exposure using the BBMD were 0.00170 mg/m^(3)for the total population,0.00158 mg/m^(3)for males,and 0.00174 mg/m^(3)for females.In possible risk obtained from animal studies(PROAST),the OELs of the total population,males,and females were 0.00184,0.00178,and 0.00192 mg/m^(3),respectively.Conclusion Based on our conservative estimate,the BMDL of mitochondrial damage caused by COEs is0.002 mg/m^(3).This value will provide a benchmark for determining possible OELs.
基金financially supported by Special Funds of the State Environmental Protection Public Welfare Industry(201009049201309049)+1 种基金National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2013BAI12B03)the Fundamental Research Funds for the Central Universities(2015JBM108)
文摘A survey involving 6103 participants from five Chinese provinces was conducted to evaluate the threshold value of urinary cadmium （UCd） for renal dysfunction as benchmark dose low （BMDL）. The urinary N-acetyl-13-D-glucosaminidase （UNAG） was chosen as an effect biomarker. The UCd BMDLs for UNAG ranged from 2.18μg/g creatinine （cr） to 4.26μg/g cr in the populations of different provinces. The selection of the sample population and area affect the evaluation of the BMDL. The reference level of UCd for renal effects was further evaluated based on the data of all 6103 subjects. With benchmark responses （BMR） of 10%/5%, the overall UCd BMDLs for males in the total population were 3.73/2.08 μg/g cr. The BMD was slightly lower in females, thereby indicating that females may be relatively more sensitive to Cd exposure than are males.
基金financially supported by the Natural Science Foundation of China(Grant 81072263,to Y.Z.)Chun Tsung Scholarship of Fudan University(to D.C.)
文摘Eleven recently completed toxicological studies were critically reviewed to identify toxicologically significant endpoints and dose-response information. Dose-response data were compiled and entered into the USEPA＇s benchmark dose software （BMDS） for calculation of a benchmark dose （BMD） and a benchmark dose low （BMDL）. After assessing 91 endpoints across the nine studies, a total of 23 of these endpoints were identified for BMD modeling, and BMDL estimates corresponding to various dose-response models were compiled for these separate endpoints. Thyroid, neurobehavior and reproductive endpoints for BDE-47, -99, -209 were quantitatively evaluated. According to methods and feature of each study, different uncertainty factor （UF） value was decided and subsequently reference doses （RfDs） were proposed. Consistent with USEPA, the lowest BMDLs of 2.10, 81.77, and 1698 I^g/kg were used to develop RfDs for BDE-47, -99, and -209, respectively. RfDs for BDE-99 and BDE-209 were comparable to EPA results, and however, RfD of BDE-47 was much lower than that of EPA, which may result from that reproductive/developmental proves to be more sensitive than neurobehavior for BDE-47 and the principal study uses very-low-dose exposure.
基金funded by the National Natural Science Foundation of China(No.22006118)the National Key R&D Program of China(No.2022YFF1102500).
文摘Ionic liquids(ILs),traditionally considered environmentally benign solvents,have shown potential toxicity to organisms,raising concerns about their safety.Among them,1-octyl-3-methylimidazolium(M8OI)has been detected at high concentrations in soils and exhibits hepatotoxic properties.To uncover the molecular mechanisms underlying this toxicity,wholetranscriptome sequencing was performed,coupled with benchmark dose(BMD)modeling,to derive transcriptomic points-of-departure(tPOD)through dose−response analysis.The transcriptomic analysis identified 425,667,and 567 differentially expressed genes(DEGs)following low(10μmol/L),medium(50μmol/L),and high(200μmol/L)doses of M8OI exposure,respectively.Enrichment analysis revealed significant perturbations in pathways related to cytokine−cytokine receptor interaction and IL-17 signaling.BMD modeling yielded tPOD values of 1.51μmol/L(median of the 20 most sensitive genes,omicBMD20),2.98μmol/L(tenth percentile of all genes,omicBMD10th),6.83μmol/L(mode of the first peak of all gene BMDs,omicBMDmode),and 5.9μmol/L for pathway-level analysis.These transcriptomics-derived tPODs were at least 105-fold lower than M8OI’s hepatotoxic concentration,as indicated by its EC_(50)of 723.6μmol/L in HepG2 cells.Functional analysis of the transcriptomic data identified legionellosis,rheumatoid arthritis,and transcriptional misregulation in cancer as the most sensitive pathways affected by M8OI.These findings highlight the molecular mechanisms driving M8OI-induced hepatotoxicity and underscore the utility of transcriptomics in deriving sensitive and quantitative toxicity thresholds.The results provide critical insights for guideline-driven toxicological evaluations and regulatory decision-making,supporting a more comprehensive assessment of IL safety.
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 utilize coexposure statistical methods and physiologically based pharmacokinetic(PBTK)models in reference dose calculation.
基金supported by China Food Safety Talent Competency Development Initiative:CFSA 523 Programthe National Natural Science Foundation of China[No.81402683]
文摘Objective The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level（NOAEL）,which is a critical factor in the establishment of an acceptable dietary intake（ADI）.Methods In accordance with the Organization for Economic Co-operation and Development（OECD） testing guidelines,lanthanum nitrate was administered once daily by gavage to Sprague-Dawley（SD） rats at dose levels of 0,1.5,6.0,24.0,and 144.0 mg/kg body weight（BW） per day for 90 days,followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups.Outcome parameters were mortality,clinical symptoms,body and organ weights,serum chemistry,and food consumption,as well as ophthalmic,urinary,hematologic,and histopathologic indicators.The benchmark dose（BMD） approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum.Results Significant decreases were found in the 144.0 mg/kg BW group in the growth index,including body weight,organ weights,and food consumption.This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day.Importantly,the 95% lower confidence value of the benchmark dose（BMDL） was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males.Conclusion The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements（REEs）.
基金supported by the National Key R&D Program of China[2019YFC1605203]China Food Safety Talent Competency Development Initiative:CFSA 523 Program
文摘Objective The present study was undertaken to evaluate the subchronic oral toxicity of sodium dehydroacetate(DHA-Na)and to determine the point of departure(POD),which is a critical factor in the establishment of an acceptable dietary intake.Methods DHA-Na was administered once daily by gavage to Sprague–Dawley rats at dose levels of 0.0,31.0,62.0,and 124.0 mg/kg BW per day for 90 days,followed by a recovery period of 4 weeks in the control and 124.0 mg/kg BW per day groups.The outcome parameters were mortality,clinical observations,body weights,food consumption,hematology and clinical biochemistry,endocrine hormone levels,and ophthalmic,urinary,and histopathologic indicators.The benchmark dose(BMD)approach was applied to estimate the POD.Results Significant decreases were found in the 62.0 and 124.0 mg/kg BW groups in terms of the body weight and food utilization rate,whereas a significant increase was found in the thyroid stimulating hormone levels of the 124.0 mg/kg BW group.Importantly,the 95%lower confidence limit on the BMD of 51.7 mg/kg BW was modeled for a reduction in body weight.Conclusion The repeated-dose study indicated the slight systemic toxicity of DHA-Na at certain levels(62.0 and 124.0 mg/kg BW)after a 90-day oral exposure.
