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Ivonne M.c.m. Rietjens - One of the best experts on this subject based on the ideXlab platform.
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Molecular Dynamics and In Vitro Quantification of Safrole DNA Adducts Reveal DNA Adduct Persistence Due to Limited DNA Distortion Resulting in Inefficient Repair.
Chemical research in toxicology, 2020Co-Authors: Shuo Yang, Sebastiaan Wesseling, Jacques Vervoort, Jakob D. H. Liu, Matthias Diem, Chris Oostenbrink, Ivonne M.c.m. RietjensAbstract:The formation and repair of N2-(trans-isosafrol-3'-yl)-2'-deoxyguanosine (S-3'-N2-dG) DNA adduct derived from the spice and herbal alkenylbenzene constituent Safrole were investigated. DNA adduct formation and repair were studied in vitro and using molecular dynamics (MD) simulations. DNA adduct formation was quantified using liquid chromatography-mass spectrometry (LCMS) in wild type and NER (nucleotide excision repair) deficient CHO cells and also in HepaRG cells and primary rat hepatocytes after different periods of repair following exposure to Safrole or 1'-hydroxySafrole (1'-OH Safrole). The slower repair of the DNA adducts found in NER deficient cells compared to that in CHO wild type cells indicates a role for NER in repair of S-3'-N2-dG DNA adducts. However, DNA repair in liver cell models appeared to be limited, with over 90% of the adducts remaining even after 24 or 48 h recovery. In our further studies, MD simulations indicated that S-3'-N2-dG adduct formation causes only subtle changes in the DNA structure, potentially explaining inefficient activation of NER. Inefficiency of NER mediated repair of S-3'-N2-dG adducts points at persistence and potential bioaccumulation of Safrole DNA adducts upon daily dietary exposure.
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level of alkenylbenzenes in parsley and dill based teas and associated risk assessment using the margin of exposure approach
Journal of Agricultural and Food Chemistry, 2016Co-Authors: Abdalmajeed M. Alajlouni, Sebastiaan Wesseling, Jacques Vervoort, Farida Nur Isnaeni, Amer J Almalahmeh, Ivonne M.c.m. RietjensAbstract:Risk assessment of parsley and dill based teas that contain alkenylbenzenes was performed. To this end the estimated daily intake (EDI) of alkenylbenzenes resulting from use of the teas was quantified. Since most teas appeared to contain more than one alkenylbenzene, a combined risk assessment was performed based on equal potency of all alkenylbenzenes or using a so-called toxic equivalency (TEQ) approach through defining toxic equivalency factors (TEFs) for the different alkenylbenzenes. The EDI values resulting from consuming one cup of tea a day were 0.2–10.1 μg/kg bw for the individual alkenylbenzenes, 0.6–13.1 μg/kg bw for the sum of the alkenylbenzenes, and 0.3–10.7 μg Safrole equiv/kg bw for the sum of alkenylbenzenes when expressed in Safrole equivalents. The margin of exposure (MOE) values obtained were generally <10000, indicating a concern if the teas would be consumed on a daily basis over longer periods of time.
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Mode of action based risk assessment of the botanical food-borne alkenylbenzene apiol from parsley using physiologically based kinetic (PBK) modelling and read-across from Safrole
Food and Chemical Toxicology, 2016Co-Authors: Abdalmajeed M. Alajlouni, Amer J. Al-malahmeh, Ala A.a. Al-subeihi, Reiko Kiwamoto, Ans E.m.f. Soffers, Sebastiaan Wesseling, Jacques Vervoort, Ivonne M.c.m. RietjensAbstract:The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene apiol in order to facilitate risk assessment based on read-across from the related alkenylbenzene Safrole. Model predictions indicate that in rat liver the formation of the 1'-sulfoxy metabolite is about 3 times lower for apiol than for Safrole. These data support that the lower confidence limit of the benchmark dose resulting in a 10% extra cancer incidence (BMDL10) that would be obtained in a rodent carcinogenicity study with apiol may be 3-fold higher for apiol than for Safrole. These results enable a preliminary risk assessment for apiol, for which tumor data are not available, using a BMDL10value of 3 times the BMDL10for Safrole. Based on an estimated BMDL10for apiol of 5.7-15.3 mg/kg body wt per day and an estimated daily intake of 4 × 10-5mg/kg body wt per day, the margin of exposure (MOE) would amount to 140,000-385,000. This indicates a low priority for risk management. The present study shows how PBK modelling can contribute to the development of alternatives for animal testing, facilitating read-across from compounds for which in vivo toxicity studies on tumor formation are available to compounds for which these data are unavailable.
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Physiologically based biokinetic (PBBK) model for Safrole bioactivation and detoxification in rats.
Chemical research in toxicology, 2011Co-Authors: Erryana Martati, Jacques Vervoort, Marelle G Boersma, A. Spenkelink, Dambar B. Khadka, Ans Punt, P.j. Van Bladeren, Ivonne M.c.m. RietjensAbstract:A physiologically based biokinetic (PBBK) model for alkenylbenzene Safrole in rats was developed using in vitro metabolic parameters determined using relevant tissue fractions. The performance of the model was evaluated by comparison of the predicted levels of 1,2-dihydroxy-4-allylbenzene and 1'-hydroxySafrole glucuronide to levels of these metabolites reported in the literature to be excreted in the urine of rats exposed to Safrole and by comparison of the predicted amount of total urinary Safrole metabolites to the reported levels of Safrole metabolites in the urine of Safrole exposed rats. These comparisons revealed that the predictions adequately match observed experimental values. Next, the model was used to predict the relative extent of bioactivation and detoxification of Safrole at different oral doses. At low as well as high doses, P450 mediated oxidation of Safrole mainly occurs in the liver in which 1,2-dihydroxy-4-allylbenzene was predicted to be the major P450 metabolite of Safrole. A dose dependent shift in P450 mediated oxidation leading to a relative increase in bioactivation at high doses was not observed. Comparison of the results obtained for Safrole with the results previously obtained with PBBK models for the related alkenylbenzenes estragole and methyleugenol revealed that the overall differences in bioactivation of the three alkenylbenzenes to their ultimate carcinogenic 1'-sulfooxy metabolites are limited. This is in line with the generally less than 4-fold difference in their level of DNA binding in in vitro and in vivo studies and their almost similar BMDL(10) values (lower confidence limit of the benchmark dose that gives 10% increase in tumor incidence over background level) obtained in in vivo carcinogenicity studies. It is concluded that in spite of differences in the rates of specific metabolic conversions, overall the levels of bioactivation of the three alkenylbenzenes are comparable which is in line with their comparable carcinogenic potential.
Andrew M. Mcdonagh - One of the best experts on this subject based on the ideXlab platform.
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Organic Impurity Profiling of 3,4-Methylenedioxymethamphetamine (MDMA) Synthesised from Catechol and Eugenol via 4-Allylcatechol
Forensic Science International, 2020Co-Authors: Erin Heather, Ronald Shimmon, Andrew M. McdonaghAbstract:Abstract This work examines organic impurity profiles of 3,4-methylenedioxymethamphetamine (MDMA) that has been synthesised from the “pre-precursors” catechol (1,2-dihydroxybenzene) and eugenol, via a Safrole intermediate. MDMA was synthesised from the catechol- and eugenol-derived Safrole intermediate via two routes, which resulted in the synthesis of MDMA from catechol via two routes (Route 1A and 1B) and from eugenol via two routes (Route 2A and 2B). Twelve organic impurities were identified in MDMA synthesised via Routes 1A and 1B, and eleven organic impurities were identified in MDMA synthesised via Routes 2A and 2B. Route specific organic impurities were identified in MDMA that indicated the “pre-precursors” catechol and eugenol were used in the respective synthetic routes. Route specific organic impurities were also identified in MDMA that indicated the route used to synthesise Safrole from the “pre-precursor” and the route used to synthesise MDMA from Safrole. Thus, the use of the “pre-precursors” catechol and eugenol and the synthetic route utilised could be ascertained by the organic impurity profiling of MDMA under the conditions used here.
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Organic impurity profiling of 3,4-methylenedioxymethamphetamine (MDMA) synthesised from catechol
Forensic Science International, 2015Co-Authors: Erin Heather, Ronald Shimmon, Andrew M. McdonaghAbstract:Abstract This work examines the organic impurity profile of 3,4-methylenedioxymethamphetamine (MDMA) that has been synthesised from catechol (1,2-dihydroxybenzene), a common chemical reagent available in industrial quantities. The synthesis of MDMA from catechol proceeded via the common MDMA precursor Safrole. Methylenation of catechol yielded 1,3-benzodioxole, which was brominated and then reacted with magnesium allyl bromide to form Safrole. Eight organic impurities were identified in the synthetic Safrole. Safrole was then converted to 3,4-methylenedioxyphenyl-2-propanone (MDP2P) using two synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P. Thirteen organic impurities were identified in MDMA synthesised via Route 1 and eleven organic impurities were identified in MDMA synthesised via Route 2. Overall, organic impurities in MDMA prepared from catechol indicated that synthetic Safrole was used in the synthesis. The impurities also indicated which of the two synthetic routes was utilised.
Erin Heather - One of the best experts on this subject based on the ideXlab platform.
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Organic Impurity Profiling of 3,4-Methylenedioxymethamphetamine (MDMA) Synthesised from Catechol and Eugenol via 4-Allylcatechol
Forensic Science International, 2020Co-Authors: Erin Heather, Ronald Shimmon, Andrew M. McdonaghAbstract:Abstract This work examines organic impurity profiles of 3,4-methylenedioxymethamphetamine (MDMA) that has been synthesised from the “pre-precursors” catechol (1,2-dihydroxybenzene) and eugenol, via a Safrole intermediate. MDMA was synthesised from the catechol- and eugenol-derived Safrole intermediate via two routes, which resulted in the synthesis of MDMA from catechol via two routes (Route 1A and 1B) and from eugenol via two routes (Route 2A and 2B). Twelve organic impurities were identified in MDMA synthesised via Routes 1A and 1B, and eleven organic impurities were identified in MDMA synthesised via Routes 2A and 2B. Route specific organic impurities were identified in MDMA that indicated the “pre-precursors” catechol and eugenol were used in the respective synthetic routes. Route specific organic impurities were also identified in MDMA that indicated the route used to synthesise Safrole from the “pre-precursor” and the route used to synthesise MDMA from Safrole. Thus, the use of the “pre-precursors” catechol and eugenol and the synthetic route utilised could be ascertained by the organic impurity profiling of MDMA under the conditions used here.
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Organic impurity profiling of 3,4-methylenedioxymethamphetamine (MDMA) synthesised from catechol
Forensic Science International, 2015Co-Authors: Erin Heather, Ronald Shimmon, Andrew M. McdonaghAbstract:Abstract This work examines the organic impurity profile of 3,4-methylenedioxymethamphetamine (MDMA) that has been synthesised from catechol (1,2-dihydroxybenzene), a common chemical reagent available in industrial quantities. The synthesis of MDMA from catechol proceeded via the common MDMA precursor Safrole. Methylenation of catechol yielded 1,3-benzodioxole, which was brominated and then reacted with magnesium allyl bromide to form Safrole. Eight organic impurities were identified in the synthetic Safrole. Safrole was then converted to 3,4-methylenedioxyphenyl-2-propanone (MDP2P) using two synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P. Thirteen organic impurities were identified in MDMA synthesised via Route 1 and eleven organic impurities were identified in MDMA synthesised via Route 2. Overall, organic impurities in MDMA prepared from catechol indicated that synthetic Safrole was used in the synthesis. The impurities also indicated which of the two synthetic routes was utilised.
Marelle G Boersma - One of the best experts on this subject based on the ideXlab platform.
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Physiologically based biokinetic (PBBK) model for Safrole bioactivation and detoxification in rats.
Chemical research in toxicology, 2011Co-Authors: Erryana Martati, Jacques Vervoort, Marelle G Boersma, A. Spenkelink, Dambar B. Khadka, Ans Punt, P.j. Van Bladeren, Ivonne M.c.m. RietjensAbstract:A physiologically based biokinetic (PBBK) model for alkenylbenzene Safrole in rats was developed using in vitro metabolic parameters determined using relevant tissue fractions. The performance of the model was evaluated by comparison of the predicted levels of 1,2-dihydroxy-4-allylbenzene and 1'-hydroxySafrole glucuronide to levels of these metabolites reported in the literature to be excreted in the urine of rats exposed to Safrole and by comparison of the predicted amount of total urinary Safrole metabolites to the reported levels of Safrole metabolites in the urine of Safrole exposed rats. These comparisons revealed that the predictions adequately match observed experimental values. Next, the model was used to predict the relative extent of bioactivation and detoxification of Safrole at different oral doses. At low as well as high doses, P450 mediated oxidation of Safrole mainly occurs in the liver in which 1,2-dihydroxy-4-allylbenzene was predicted to be the major P450 metabolite of Safrole. A dose dependent shift in P450 mediated oxidation leading to a relative increase in bioactivation at high doses was not observed. Comparison of the results obtained for Safrole with the results previously obtained with PBBK models for the related alkenylbenzenes estragole and methyleugenol revealed that the overall differences in bioactivation of the three alkenylbenzenes to their ultimate carcinogenic 1'-sulfooxy metabolites are limited. This is in line with the generally less than 4-fold difference in their level of DNA binding in in vitro and in vivo studies and their almost similar BMDL(10) values (lower confidence limit of the benchmark dose that gives 10% increase in tumor incidence over background level) obtained in in vivo carcinogenicity studies. It is concluded that in spite of differences in the rates of specific metabolic conversions, overall the levels of bioactivation of the three alkenylbenzenes are comparable which is in line with their comparable carcinogenic potential.
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human cytochrome p450 enzyme specificity for bioactivation of Safrole to the proximate carcinogen 1 hydroxySafrole
Chemical Research in Toxicology, 2004Co-Authors: Suzanne M F Jeurissen, J J P Bogaards, Hanem M Awad, Marelle G Boersma, Walter Brand, Yiannis C Fiamegos, T A Van Beek, Gerrit M Alink, Ernst J R Sudholter, Nicole H P CnubbenAbstract:In the present study, the cytochrome P450 mediated bioactivation of Safrole to its proximate carcinogenic metabolite, 1'-hydroxySafrole, has been investigated for the purpose of identifying the human P450 enzymes involved. The 1'-hydroxylation of Safrole was characterized in a variety of in vitro test systems, including Supersomes, expressing individual human P450 enzymes to a high level, and microsomes derived from cell lines expressing individual human P450 enzymes to a lower, average human liver level. Additionally, a correlation study was performed, in which Safrole was incubated with a series of 15 human liver microsomes, and the 1'-hydroxylation rates obtained were correlated with the activities of these microsomes toward specific substrates for nine different isoenzymes. To complete the study, a final experiment was performed in which pooled human liver microsomes were incubated with Safrole in the presence and absence of coumarin, a selective P450 2A6 substrate. On the basis of the results of these experiments, important roles for P450 2C9*1, P450 2A6, P450 2D6*1, and P450 2E1 were elucidated. The possible consequences of these results for the effects of genetic polymorphisms and life style factors on the bioactivation of Safrole are discussed. Polymorphisms in P450 2C9, P450 2A6, and P450 2D6, leading to poor metabolizer phenotypes, may reduce the relative risk on the harmful effects of Safrole, whereas life style factors, such as the use of alcohol, an inducer of P450 2E1, and barbiturates, inducers of P450 2C9, and polymorphisms in P450 2D6 and P450 2A6, leading to ultraextensive metabolizer phenotypes, may increase the relative risk.
Jacques Vervoort - One of the best experts on this subject based on the ideXlab platform.
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Molecular Dynamics and In Vitro Quantification of Safrole DNA Adducts Reveal DNA Adduct Persistence Due to Limited DNA Distortion Resulting in Inefficient Repair.
Chemical research in toxicology, 2020Co-Authors: Shuo Yang, Sebastiaan Wesseling, Jacques Vervoort, Jakob D. H. Liu, Matthias Diem, Chris Oostenbrink, Ivonne M.c.m. RietjensAbstract:The formation and repair of N2-(trans-isosafrol-3'-yl)-2'-deoxyguanosine (S-3'-N2-dG) DNA adduct derived from the spice and herbal alkenylbenzene constituent Safrole were investigated. DNA adduct formation and repair were studied in vitro and using molecular dynamics (MD) simulations. DNA adduct formation was quantified using liquid chromatography-mass spectrometry (LCMS) in wild type and NER (nucleotide excision repair) deficient CHO cells and also in HepaRG cells and primary rat hepatocytes after different periods of repair following exposure to Safrole or 1'-hydroxySafrole (1'-OH Safrole). The slower repair of the DNA adducts found in NER deficient cells compared to that in CHO wild type cells indicates a role for NER in repair of S-3'-N2-dG DNA adducts. However, DNA repair in liver cell models appeared to be limited, with over 90% of the adducts remaining even after 24 or 48 h recovery. In our further studies, MD simulations indicated that S-3'-N2-dG adduct formation causes only subtle changes in the DNA structure, potentially explaining inefficient activation of NER. Inefficiency of NER mediated repair of S-3'-N2-dG adducts points at persistence and potential bioaccumulation of Safrole DNA adducts upon daily dietary exposure.
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level of alkenylbenzenes in parsley and dill based teas and associated risk assessment using the margin of exposure approach
Journal of Agricultural and Food Chemistry, 2016Co-Authors: Abdalmajeed M. Alajlouni, Sebastiaan Wesseling, Jacques Vervoort, Farida Nur Isnaeni, Amer J Almalahmeh, Ivonne M.c.m. RietjensAbstract:Risk assessment of parsley and dill based teas that contain alkenylbenzenes was performed. To this end the estimated daily intake (EDI) of alkenylbenzenes resulting from use of the teas was quantified. Since most teas appeared to contain more than one alkenylbenzene, a combined risk assessment was performed based on equal potency of all alkenylbenzenes or using a so-called toxic equivalency (TEQ) approach through defining toxic equivalency factors (TEFs) for the different alkenylbenzenes. The EDI values resulting from consuming one cup of tea a day were 0.2–10.1 μg/kg bw for the individual alkenylbenzenes, 0.6–13.1 μg/kg bw for the sum of the alkenylbenzenes, and 0.3–10.7 μg Safrole equiv/kg bw for the sum of alkenylbenzenes when expressed in Safrole equivalents. The margin of exposure (MOE) values obtained were generally <10000, indicating a concern if the teas would be consumed on a daily basis over longer periods of time.
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Mode of action based risk assessment of the botanical food-borne alkenylbenzene apiol from parsley using physiologically based kinetic (PBK) modelling and read-across from Safrole
Food and Chemical Toxicology, 2016Co-Authors: Abdalmajeed M. Alajlouni, Amer J. Al-malahmeh, Ala A.a. Al-subeihi, Reiko Kiwamoto, Ans E.m.f. Soffers, Sebastiaan Wesseling, Jacques Vervoort, Ivonne M.c.m. RietjensAbstract:The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene apiol in order to facilitate risk assessment based on read-across from the related alkenylbenzene Safrole. Model predictions indicate that in rat liver the formation of the 1'-sulfoxy metabolite is about 3 times lower for apiol than for Safrole. These data support that the lower confidence limit of the benchmark dose resulting in a 10% extra cancer incidence (BMDL10) that would be obtained in a rodent carcinogenicity study with apiol may be 3-fold higher for apiol than for Safrole. These results enable a preliminary risk assessment for apiol, for which tumor data are not available, using a BMDL10value of 3 times the BMDL10for Safrole. Based on an estimated BMDL10for apiol of 5.7-15.3 mg/kg body wt per day and an estimated daily intake of 4 × 10-5mg/kg body wt per day, the margin of exposure (MOE) would amount to 140,000-385,000. This indicates a low priority for risk management. The present study shows how PBK modelling can contribute to the development of alternatives for animal testing, facilitating read-across from compounds for which in vivo toxicity studies on tumor formation are available to compounds for which these data are unavailable.
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Level of Alkenylbenzenes in Parsley and Dill Based Teas and Associated Risk Assessment Using the Margin of Exposure Approach
2016Co-Authors: Abdalmajeed M. Alajlouni, Amer J. Al-malahmeh, Sebastiaan Wesseling, Jacques Vervoort, Farida Nur Isnaeni, Ivonne M. C. M. RietjensAbstract:Risk assessment of parsley and dill based teas that contain alkenylbenzenes was performed. To this end the estimated daily intake (EDI) of alkenylbenzenes resulting from use of the teas was quantified. Since most teas appeared to contain more than one alkenylbenzene, a combined risk assessment was performed based on equal potency of all alkenylbenzenes or using a so-called toxic equivalency (TEQ) approach through defining toxic equivalency factors (TEFs) for the different alkenylbenzenes. The EDI values resulting from consuming one cup of tea a day were 0.2–10.1 μg/kg bw for the individual alkenylbenzenes, 0.6–13.1 μg/kg bw for the sum of the alkenylbenzenes, and 0.3–10.7 μg Safrole equiv/kg bw for the sum of alkenylbenzenes when expressed in Safrole equivalents. The margin of exposure (MOE) values obtained were generally
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Physiologically based biokinetic (PBBK) model for Safrole bioactivation and detoxification in rats.
Chemical research in toxicology, 2011Co-Authors: Erryana Martati, Jacques Vervoort, Marelle G Boersma, A. Spenkelink, Dambar B. Khadka, Ans Punt, P.j. Van Bladeren, Ivonne M.c.m. RietjensAbstract:A physiologically based biokinetic (PBBK) model for alkenylbenzene Safrole in rats was developed using in vitro metabolic parameters determined using relevant tissue fractions. The performance of the model was evaluated by comparison of the predicted levels of 1,2-dihydroxy-4-allylbenzene and 1'-hydroxySafrole glucuronide to levels of these metabolites reported in the literature to be excreted in the urine of rats exposed to Safrole and by comparison of the predicted amount of total urinary Safrole metabolites to the reported levels of Safrole metabolites in the urine of Safrole exposed rats. These comparisons revealed that the predictions adequately match observed experimental values. Next, the model was used to predict the relative extent of bioactivation and detoxification of Safrole at different oral doses. At low as well as high doses, P450 mediated oxidation of Safrole mainly occurs in the liver in which 1,2-dihydroxy-4-allylbenzene was predicted to be the major P450 metabolite of Safrole. A dose dependent shift in P450 mediated oxidation leading to a relative increase in bioactivation at high doses was not observed. Comparison of the results obtained for Safrole with the results previously obtained with PBBK models for the related alkenylbenzenes estragole and methyleugenol revealed that the overall differences in bioactivation of the three alkenylbenzenes to their ultimate carcinogenic 1'-sulfooxy metabolites are limited. This is in line with the generally less than 4-fold difference in their level of DNA binding in in vitro and in vivo studies and their almost similar BMDL(10) values (lower confidence limit of the benchmark dose that gives 10% increase in tumor incidence over background level) obtained in in vivo carcinogenicity studies. It is concluded that in spite of differences in the rates of specific metabolic conversions, overall the levels of bioactivation of the three alkenylbenzenes are comparable which is in line with their comparable carcinogenic potential.
