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Hans-joachim Lehmler - One of the best experts on this subject based on the ideXlab platform.
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Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes: Involvement of Arene Oxide Intermediates
bioRxiv, 2018Co-Authors: Eric Uwimana, Coby Yeung, Eric V. Patterson, Xueshu Li, Hans-joachim LehmlerAbstract:ABSTRACT Polychlorinated biphenyls (PCBs) have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB neurotoxicity. Only limited information is available regarding the atropselective metabolism of these congeners in humans and their atropselective effects on neurotoxic outcomes. Here we investigate the hypothesis that the oxidation of 2,2’,3,3’,4,6’-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) and their effects on dopaminergic cells in culture are atropselective. Racemic PCB 132 was incubated with pooled or single donor HLMs, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite was either 2,2’,3,4,4’,6’-hexachlorobiphenyl-3’-ol (3’-140), a 1,2-shift product, or 2,2’,3,3’,4,6’-hexachlorobiphenyl-5’-ol (5’-132). The PCB 132 metabolite profiles displayed inter-individual differences and depended on the PCB 132 Atropisomer. Computational studies demonstrated that 3’-140 is formed via a 3,4-arene oxide intermediate. The second eluting Atropisomer of PCB 132, first eluting Atropisomer of 3’-140, and second eluting Atropisomer of 5’-132 were enriched in all HLM incubations. Enantiomeric fractions of the PCB 132 metabolites differed only slightly between the single donor HLM preparations investigated. Reactive oxygen species and levels of dopamine and its metabolites were not significantly altered after a 24 h exposure of dopaminergic cells to pure PCB 132 Atropisomers. These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to its metabolites in humans; however, the resulting Atropisomeric enrichment of PCB 132 is unlikely to affect neurotoxic outcomes associated with the endpoints investigated in the study.
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atropselective oxidation of 2 2 3 3 4 6 hexachlorobiphenyl pcb 132 to hydroxylated metabolites by human liver microsomes involvement of arene oxide intermediates
bioRxiv, 2018Co-Authors: Eric Uwimana, Coby Yeung, Eric V. Patterson, Xueshu Li, Hans-joachim LehmlerAbstract:ABSTRACT Polychlorinated biphenyls (PCBs) have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB neurotoxicity. Only limited information is available regarding the atropselective metabolism of these congeners in humans and their atropselective effects on neurotoxic outcomes. Here we investigate the hypothesis that the oxidation of 2,2’,3,3’,4,6’-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) and their effects on dopaminergic cells in culture are atropselective. Racemic PCB 132 was incubated with pooled or single donor HLMs, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite was either 2,2’,3,4,4’,6’-hexachlorobiphenyl-3’-ol (3’-140), a 1,2-shift product, or 2,2’,3,3’,4,6’-hexachlorobiphenyl-5’-ol (5’-132). The PCB 132 metabolite profiles displayed inter-individual differences and depended on the PCB 132 Atropisomer. Computational studies demonstrated that 3’-140 is formed via a 3,4-arene oxide intermediate. The second eluting Atropisomer of PCB 132, first eluting Atropisomer of 3’-140, and second eluting Atropisomer of 5’-132 were enriched in all HLM incubations. Enantiomeric fractions of the PCB 132 metabolites differed only slightly between the single donor HLM preparations investigated. Reactive oxygen species and levels of dopamine and its metabolites were not significantly altered after a 24 h exposure of dopaminergic cells to pure PCB 132 Atropisomers. These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to its metabolites in humans; however, the resulting Atropisomeric enrichment of PCB 132 is unlikely to affect neurotoxic outcomes associated with the endpoints investigated in the study.
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Absolute configuration of 2,2′,3,3′,6-pentachlorinatedbiphenyl (PCB 84) Atropisomers
Environmental Science and Pollution Research, 2018Co-Authors: Sean R. Parkin, Hans-joachim LehmlerAbstract:Nineteen polychlorinated biphenyl (PCB) congeners, such as 2,2′,3,3′,6-pentachlorobiphenyl (PCB 84), display axial chirality because they form stable rotational isomers, or Atropisomers, that are non-superimposable mirror images of each other. Although chiral PCBs undergo atropselective biotransformation and atropselectively alter biological processes, the absolute structure of only a few PCB Atropisomers has been determined experimentally. To help close this knowledge gap, pure PCB 84 Atropisomers were obtained by semi-preparative liquid chromatography with two serially connected Nucleodex β-PM columns. The absolute configuration of both Atropisomers was determined by X-ray single-crystal diffraction. The PCB 84 Atropisomer eluting first and second on the Nucleodex β-PM column correspond to (a R )-(−)-PCB 84 and (a S )-(+)-PCB 84, respectively. Enantioselective gas chromatographic analysis with the β-cyclodextrin-based CP-Chirasil-Dex CB gas chromatography column showed the same elution order as the Nucleodex β-PM column. Based on earlier reports, the Atropisomers eluting first and second on the BGB-172 gas chromatography column are (a R )-(−)-PCB 84 and (a S )-(+)-PCB 84, respectively. An inversion of the elution order is observed on the Cyclosil-B gas chromatography and Cellulose-3 liquid chromatography columns. These results advance the interpretation of environmental and human biomonitoring as well as toxicological studies.
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Atropisomers of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro
Environmental Science and Pollution Research, 2018Co-Authors: Kateřina Pěnčíková, Hans-joachim Lehmler, Petra Brenerová, Lucie Svržková, Eva Hrubá, Lenka Pálková, Jan Vondráček, Miroslav MachalaAbstract:PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (Atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 Atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (−)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 Atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (−)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB Atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho -substituted PCB congeners.
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Human Liver Microsomes Atropselectively Metabolize 2,2′,3,4′,6-Pentachlorobiphenyl (PCB 91) to a 1,2-Shift Product as the Major Metabolite
2018Co-Authors: Eric Uwimana, Hans-joachim LehmlerAbstract:Polychlorinated biphenlys (PCBs) and their hydroxylated metabolites (OH-PCBs) have been implicated in neurodevelopmental disorders. Several neurotoxic PCBs, such as PCB 91, are chiral because they form stable rotational isomers, or Atropisomers, that are nonsuperimposable mirror images of each other. Because only limited information about the metabolism of these PCBs by human cytochrome P450 (P450) enzymes is available, we investigated the biotransformation of PCB 91 to OH-PCBs by human liver microsomes (HLMs). Racemic PCB 91 was incubated with pooled or individual donor HLMs at 37 °C, and levels and chiral signatures of PCB 91 and its metabolites were determined. Several OH-PCBs were formed in the order 2,2′,4,4′,6-pentachlorobiphenyl-3-ol (3–100; 1,2 shift product) > 2,2′,3,4′,6-pentachlorobiphenyl-5-ol (5–91) ≫ 2,2′,3,4′,6-pentachlorobiphenyl-4-ol (4–91) ≫ 4,5-dihydroxy-2,2′,3,4′,6-pentachlorobiphenyl (4,5–91). Metabolite formation rates displayed interindividual variability. The first eluting Atropisomers of PCB 91, 3–100 and 4–91, and the second eluting Atropisomer of 5–91 were enriched in most metabolism studies. The unexpected, preferential formation of a 1,2-shift product and the variability of the OH-PCBs profiles in experiments with individual donor HLMs underline the need for further systematic studies of the atropselective metabolism of PCBs in humans
Jason B. Benedict - One of the best experts on this subject based on the ideXlab platform.
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on the design of Atropisomer separable photochromic diarylethene based metal organic framework linkers
Journal of Materials Chemistry C, 2016Co-Authors: Jordan M. Cox, Ian M. Walton, Jason B. BenedictAbstract:The relative stability and accessibility of Atropisomers plays a prominent role in the efficacy of diarylethene-based photochromic materials. Herein, DFT methods, using the ωB97XD functional and a 6-31G(d) basis, are employed to determine the local energetic minima and maxima which describe the rotation of a thiophene group in derivatives of 9,10-bis(2-methyl-5-pheylthiophen-3-yl)phenanthrene-2,7-dicarboxylic acid, a photochromic linker molecule which exhibits Atropisomer-formation-related fatigue when incorporated into a metal–organic framework. Results of these potential energy surface mapping calculations as well as their applications to Atropisomer separability are discussed.
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On the design of Atropisomer-separable photochromic diarylethene-based metal–organic framework linkers
Journal of Materials Chemistry C, 2016Co-Authors: Jordan M. Cox, Ian M. Walton, Jason B. BenedictAbstract:The relative stability and accessibility of Atropisomers plays a prominent role in the efficacy of diarylethene-based photochromic materials. Herein, DFT methods, using the ωB97XD functional and a 6-31G(d) basis, are employed to determine the local energetic minima and maxima which describe the rotation of a thiophene group in derivatives of 9,10-bis(2-methyl-5-pheylthiophen-3-yl)phenanthrene-2,7-dicarboxylic acid, a photochromic linker molecule which exhibits Atropisomer-formation-related fatigue when incorporated into a metal–organic framework. Results of these potential energy surface mapping calculations as well as their applications to Atropisomer separability are discussed.
Jordan M. Cox - One of the best experts on this subject based on the ideXlab platform.
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on the design of Atropisomer separable photochromic diarylethene based metal organic framework linkers
Journal of Materials Chemistry C, 2016Co-Authors: Jordan M. Cox, Ian M. Walton, Jason B. BenedictAbstract:The relative stability and accessibility of Atropisomers plays a prominent role in the efficacy of diarylethene-based photochromic materials. Herein, DFT methods, using the ωB97XD functional and a 6-31G(d) basis, are employed to determine the local energetic minima and maxima which describe the rotation of a thiophene group in derivatives of 9,10-bis(2-methyl-5-pheylthiophen-3-yl)phenanthrene-2,7-dicarboxylic acid, a photochromic linker molecule which exhibits Atropisomer-formation-related fatigue when incorporated into a metal–organic framework. Results of these potential energy surface mapping calculations as well as their applications to Atropisomer separability are discussed.
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On the design of Atropisomer-separable photochromic diarylethene-based metal–organic framework linkers
Journal of Materials Chemistry C, 2016Co-Authors: Jordan M. Cox, Ian M. Walton, Jason B. BenedictAbstract:The relative stability and accessibility of Atropisomers plays a prominent role in the efficacy of diarylethene-based photochromic materials. Herein, DFT methods, using the ωB97XD functional and a 6-31G(d) basis, are employed to determine the local energetic minima and maxima which describe the rotation of a thiophene group in derivatives of 9,10-bis(2-methyl-5-pheylthiophen-3-yl)phenanthrene-2,7-dicarboxylic acid, a photochromic linker molecule which exhibits Atropisomer-formation-related fatigue when incorporated into a metal–organic framework. Results of these potential energy surface mapping calculations as well as their applications to Atropisomer separability are discussed.
Jerald L Schnoor - One of the best experts on this subject based on the ideXlab platform.
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Identification of a novel hydroxylated metabolite of 2,2′,3,5′,6-pentachlorobiphenyl formed in whole poplar plants
Environmental Science and Pollution Research, 2016Co-Authors: Guangshu Zhai, Hans-joachim Lehmler, Izabela Kania-korwel, Jerald L SchnoorAbstract:Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants consisting of 209 congeners. Oxidation of several PCB congeners to hydroxylated PCBs (OH-PCBs) in whole poplar plants has been reported before. Moreover, 2,2′,3,5′,6-pentachlorobiphenyl (PCB95), as a chiral congener, has been previously shown to be atropselectively taken up and transformed in whole poplar plants. The objective of this study was to determine if PCB95 is atropselectively metabolized to OH-PCBs in whole poplar plants. Two hydroxylated PCB95s were detected by high-performance liquid chromatography-mass spectrometry in the roots of whole poplar plants exposed to racemic PCB95 for 30 days. The major metabolite was confirmed to be 4′-hydroxy-2,2′,3,5′,6-pentachlorobiphenyl (4′-OH-PCB95) by gas chromatography-mass spectrometry (GC-MS) using an authentic reference standard. Enantioselective analysis showed that 4′-OH-PCB95 was formed atropselectively, with the Atropisomer eluting second on the Nucleodex β-PM column (E2-4′-OH-PCB95) being slightly more abundant in the roots of whole poplar plants. Therefore, PCB95 can at least be metabolized into 4′-OH-PCB95 and another unknown hydroxylated PCB95 (as a minor metabolite) in whole poplar plants. Both Atropisomers of 4′-OH-PCB95 are formed, but E2-4′-OH-PCB95 has greater Atropisomeric enrichment in the roots of whole poplar plants. A comparison with mammalian biotransformation studies indicates a distinctively different metabolite profile of OH-PCB95 metabolites in whole poplar plants. Our observations suggest that biotransformation of chiral PCBs to OH-PCBs by plants may represent an important source of enantiomerically enriched OH-PCBs in the environment.
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Atropisomeric determination of chiral hydroxylated metabolites of polychlorinated biphenyls using HPLC-MS
Chemistry Central Journal, 2013Co-Authors: Guangshu Zhai, Hans-joachim Lehmler, Jerald L SchnoorAbstract:Background Polychlorinated biphenyls (PCBs) are a group of environmental persistent organic pollutants, which can be metabolized into a series of metabolites, including hydroxylated metabolites (OH-PCBs) in biota. Nineteen of 209 PCB congeners can form chiral stable isomers. However, Atropisomeric determination of the hydroxylated metabolites of these chiral PCBs has never been reported by LC methods. In this work, a novel HPLC-MS method was developed to detect five chiral OH-PCBs (4OH-PCB91, 5OH-PCB91, 4OH-PCB95, 5OH-PCB95 and 5OH-PCB149) using HPLC-MS without a derivatization step. Results The influences of column-type, column temperature, flow rate and ratio of the mobile phase on the Atropisomeric separation were investigated in detail. In the final method, calibration curves, based on peak areas against concentration, were linear in a range of 1–100 ng mL^-1 of five chiral OH-PCBs with correlation coefficients ranging from 0.9996 to 0.9999 for all Atropisomers of OH-PCBs. The relative standard deviations measured at the 10.0 ng mL^-1 level for Atropisomers of five chiral OH-PCBs were in the range of 0.60-7.55% (n = 5). Calculated detection limits (S/N = 3) of five chiral OH-PCBs were between 0.31 and 0.60 ng mL^-1 for all OH-PCB Atropisomers. Conclusion This HPLC-MS method was developed to detect chiral OH-PCBs and further successfully applied to measure OH-PCB Atropisomer levels and enantiomeric fractions (EFs) in rat liver microsomal samples. The results from LC-MS method were highly consistent with those from GC-ECD method. It is the first time to report these OH-PCB Atropisomers detected in microsomes by HPLC-MS. The proposed method might be applied also to detect chiral OH-PCBs in environmental samples and for metabolites of PCBs in vivo .
Izabela Kania-korwel - One of the best experts on this subject based on the ideXlab platform.
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Identification of a novel hydroxylated metabolite of 2,2′,3,5′,6-pentachlorobiphenyl formed in whole poplar plants
Environmental Science and Pollution Research, 2016Co-Authors: Guangshu Zhai, Hans-joachim Lehmler, Izabela Kania-korwel, Jerald L SchnoorAbstract:Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants consisting of 209 congeners. Oxidation of several PCB congeners to hydroxylated PCBs (OH-PCBs) in whole poplar plants has been reported before. Moreover, 2,2′,3,5′,6-pentachlorobiphenyl (PCB95), as a chiral congener, has been previously shown to be atropselectively taken up and transformed in whole poplar plants. The objective of this study was to determine if PCB95 is atropselectively metabolized to OH-PCBs in whole poplar plants. Two hydroxylated PCB95s were detected by high-performance liquid chromatography-mass spectrometry in the roots of whole poplar plants exposed to racemic PCB95 for 30 days. The major metabolite was confirmed to be 4′-hydroxy-2,2′,3,5′,6-pentachlorobiphenyl (4′-OH-PCB95) by gas chromatography-mass spectrometry (GC-MS) using an authentic reference standard. Enantioselective analysis showed that 4′-OH-PCB95 was formed atropselectively, with the Atropisomer eluting second on the Nucleodex β-PM column (E2-4′-OH-PCB95) being slightly more abundant in the roots of whole poplar plants. Therefore, PCB95 can at least be metabolized into 4′-OH-PCB95 and another unknown hydroxylated PCB95 (as a minor metabolite) in whole poplar plants. Both Atropisomers of 4′-OH-PCB95 are formed, but E2-4′-OH-PCB95 has greater Atropisomeric enrichment in the roots of whole poplar plants. A comparison with mammalian biotransformation studies indicates a distinctively different metabolite profile of OH-PCB95 metabolites in whole poplar plants. Our observations suggest that biotransformation of chiral PCBs to OH-PCBs by plants may represent an important source of enantiomerically enriched OH-PCBs in the environment.
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Stereoselective Formation of Mono- and Dihydroxylated Polychlorinated Biphenyls by Rat Cytochrome P450 2B1
2013Co-Authors: Izabela Kania-korwel, Hans-joachim Lehmler, Charles S. WongAbstract:Changes in Atropisomer composition of chiral polychlorinated biphenyls (PCBs) and their mono- and dihydroxylated metabolites (OH- and diOH-PCBs) via rat cytochrome P450 2B1 (CYP2B1) mediated biotransformation were investigated in vitro. Rat CYP2B1 could stereoselectively biotransform chiral PCBs to generate meta-OH-PCBs as the major metabolites after 60 min incubations. Nonracemic enantiomer fractions (EFs: concentration ratios of the (+)-Atropisomer or the first-eluting Atropisomer over the total concentrations of two Atropisomers) of 5-OH-PCBs, were 0.17, 0.20, 0.85, 0.77, and 0.41 for incubations with PCBs 91, 95, 132, 136, and 149, respectively. CYP-mediated stereoselective formation of diOH-PCBs from OH-PCBs was observed for the first time. After 60 min stereoselective biotransformation, the EFs of both 4-OH-PCB 95 and 5-OH-PCB 95 changed from racemic (i.e., 0.50) to 0.62 and 0.46, respectively. These transformations generated statistically nonracemic 4,5-diOH-PCB 95, with EFs of 0.53 and 0.58 for 4-OH-PCB 95 and 5-OH-PCB 95 incubations, respectively. Biotransformation of PCBs 91 and 136 also generated 4,5-diOH-PCB 91 and 4,5-diOH-PCB 136, respectively. These in vitro results were consistent with that observed for stereoselective PCB biotransformation by rat liver microsomes and in vivo. Biotransformation interference between two Atropisomers of PCB 136 was investigated for the first time in this study. The biotransformation process of (-)-PCB 136 was significantly disrupted by the presence of (+)-PCB 136 but not the other way around. Thus, stereoselective metabolism of chiral PCBs and OH-PCBs by CYPs is a major mechanism for Atropisomer composition change of PCBs and their metabolites in the environment, with the degree of composition change dependent, at least in part, on stereoselective interference of Atropisomers with each other at the enzyme level
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Assigning Atropisomer elution orders using Atropisomerically enriched polychlorinated biphenyl fractions generated by microsomal metabolism.
Journal of chromatography. A, 2012Co-Authors: Izabela Kania-korwel, Hans-joachim LehmlerAbstract:Changes in the enantiomeric fraction of chiral polychlorinated biphenyls (PCBs) are a powerful tool to investigate the movement of PCBs in the environment, for example as part of source apportionment and ecological studies. Environmental studies typically employ a series of cyclodextrin-based gas chromatography columns to separate all environmentally relevant PCB congeners. The elution order of most PCB Atropisomers has not been established on different enantioselective columns due to the unavailability of analytical standards. To overcome this limitation, the current study generated Atropisomerically enriched fractions of chiral PCBs with rat liver microsomes. Subsequently, the enrichment profile of the enriched PCB fractions was used to determine the elution order of PCB Atropisomers on selected enantioselective gas chromatography columns. While the elution order of PCB 95, 131, 132, 136, 149 and 176 Atropisomers was identical on all enantioselective columns investigated, an inversion of the elution order was observed for PCB 45, 84, 91 and 174 Atropisomers on a few columns. These results demonstrate that Atropisomerically enriched fractions obtained from microsomal metabolism can be used to unambiguously establish the relative elution order of the Atropisomers of PCBs and potentially other environmental pollutant, especially if pure enantiomers are not available.
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Clearance of polychlorinated biphenyl Atropisomers is enantioselective in female C57Bl/6 mice.
Environmental science & technology, 2010Co-Authors: Izabela Kania-korwel, Mohammed H. Elkomy, Peter Veng-pedersen, Hans-joachim LehmlerAbstract:Changes in the enantiomeric composition of polychlorinated biphenyls (PCBs) can not only be used to investigate environmental and biological transport processes, but also have human health implications because of enantiospecific adverse health effects. To further understand differences in the disposition of PCB Atropisomers in vivo, the present study investigates the toxicokinetics of PCB Atropisomers in female C57Bl/6 mice after oral administration of a mixture of several PCBs, including racemic PCBs 91, 95, 132, 136, 149, 174, and 176. On the Chirasil-Dex column, an enrichment of the second eluting Atropisomers was generally observed, whereas only the first eluting Atropisomers E1-PCB 95, (−)-PCB 132, and (−)-PCB 149 had half-lives that were distinctively longer compared to the second eluting Atropisomers. The bioavailability normalized clearance of first eluting Atropisomers in blood was faster compared to that of second eluting Atropisomers. The opposite trend was observed for the accumulation factors...