Ans Soffers | Wageningen University (original) (raw)
Papers by Ans Soffers
Xenobiotica; the fate of foreign compounds in biological systems, 1994
1. The influence of a change in the type of halogen substituent on phase II metabolism of 2-fluor... more 1. The influence of a change in the type of halogen substituent on phase II metabolism of 2-fluoro-4-halophenol metabolites formed from 3-halo-fluorobenzenes was studied in vivo and in vitro using 19F nmr and spectroscopic assays. 2. The ratio of sulphation to glucuronidation of 2-fluoro-4-halophenol metabolites formed from 3-halofluorobenzenes decreased from 48 to 13 to 6 when the halogen substituent varied from fluorine to chlorine to bromine. 3. When the 2-fluoro-4-halophenols themselves were administered to the rats, the ratio of sulphation to glucuronidation was not affected by the type of halogen substituent at C4 and at a constant value of 0.6, i.e. significantly lower. 4. Kinetic data for P450 catalysed hydroxylation of the 3-halo-fluorobenzenes and for sulphation and glucuronidation of their 2-fluoro-4-halophenol metabolites were obtained from in vitro microsomal and cytosolic incubations. These data demonstrate that the effects of varying the halogen substituent on phase I...
Free Radical Biology and Medicine, 1999
The influence of pH, intrinsic electron donating capacity, and intrinsic hydrogen atom donating c... more The influence of pH, intrinsic electron donating capacity, and intrinsic hydrogen atom donating capacity on the antioxidant potential of series of hydroxy and fluorine substituted 4-hydroxybenzoates was investigated experimentally and also on the basis of computer calculations. The pH-dependent behavior of the compounds in the TEAC assay revealed different antioxidant behavior of the nondissociated monoanionic form and the deprotonated dianionic form of the 4-hydroxybenzoates. Upon deprotonation the radical scavenging ability of the 4-hydroxybenzoates increases significantly. For mechanistic comparison a series of fluorobenzoates was synthesized and included in the studies. The fluorine substituents were shown to affect the proton and electron donating abilities of 4-hydroxybenzoate in the same way as hydroxyl substituents. In contrast, the fluorine substituents influenced the TEAC value and the hydrogen atom donating capacity of 4-hydroxybenzoate in a way different from the hydroxyl moieties. Comparison of these experimental data to computer-calculated characteristics indicates that the antioxidant behavior of the monoanionic forms of the 4-hydroxybenzoates is not determined by the tendency of the molecule to donate an electron, but by its ability to donate a hydrogen atom. Altogether, the results explain qualitatively and quantitatively how the number and position of OH moieties affect the antioxidant behavior of 4-hydroxybenzoates.
Frontiers in Medicine, 2016
Food and Chemical Toxicology, 2016
The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene api... more 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 BMDL10 value of 3 times the BMDL10 for safrole. Based on an estimated BMDL10 for apiol of 5.7-15.3 mg/kg body wt per day and an estimated daily intake of 4 × 10(-5) mg/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.
Toxicol. Res., 2015
Absorption, distribution, metabolism and excretion (ADME) of food-borne toxic compounds may be in... more Absorption, distribution, metabolism and excretion (ADME) of food-borne toxic compounds may be influenced by other compounds or constituents present in the food.
FEBS letters, Jan 30, 1999
The steady state single electron reduction of polynitroaromatics by ferredoxin-NADP+ oxidoreducta... more The steady state single electron reduction of polynitroaromatics by ferredoxin-NADP+ oxidoreductase (EC 1.18.1.2) from cyanobacterium Anabaena PCC 7119 has been studied and quantitative structure activity relationships are described. The solubility of the polynitroaromatics as well as their reactivity towards ferredoxin-NADP+ oxidoreductase are markedly higher than those for previously studied mononitroaromatics and this enabled the independent measurement of the kinetic parameters-k(cat) and Km. Interestingly, the natural logarithm of the bimolecular rate constant, k(cat)/Km, and also the natural logarithm of k(cat) correlate with the calculated energy of the lowest unoccupied molecular orbital of the polynitroaromatic substrates. The minimal kinetic model in line with these quantitative structure activity relationships is a ping-pong mechanism which includes substrate binding equilibria in the second half reaction.
Environmental Toxicology and Chemistry, 2006
Fifteen experimental literature data sets on the acute toxicity of substituted nitrobenzenes to a... more Fifteen experimental literature data sets on the acute toxicity of substituted nitrobenzenes to algae (Scenedesmus obliquus, Chlorella pyrenoidosa, C. vulgaris), daphnids (Daphnia magna, D. carinata), fish (Cyprinus carpio, Poecilia reticulata), protozoa (Tetrahymena pyriformis), bacteria (Phosphobacterium phosphoreum), and yeast (Saccharomyces cerevisiae) were used to establish quantum chemistry based quantitative structure¿activity relationships (QSARs). The logarithm of the octanol/water partition coefficient, log Kow,
Chemical Contaminants and Residues in Food, 2012
Chemosphere, 2009
Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (Q... more Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (QSAR) models are expected to help reduce the number of animals used for experimental testing. The objective of this study was to develop QSAR models to describe the acute toxicity of organothiophosphate pesticides to aquatic organisms. Literature data sets for acute toxicity data of organothiophosphates to fish and one
Toxicology and Applied Pharmacology, 2012
This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human ba... more This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the current model were compared with those of a previously developed PBK model for methyleugenol (ME) in male rat. The results obtained reveal that formation of 1'-hydroxymethyleugenol glucuronide (1'HMEG), a major metabolic pathway in male rat liver, appears to represent a minor metabolic pathway in human liver whereas in human liver a significantly higher formation of 1'-oxomethyleugenol (1'OME) compared with male rat liver is observed. Furthermore, formation of 1'-sulfooxymethyleugenol (1'HMES), which readily undergoes desulfonation to a reactive carbonium ion (CA) that can form DNA or protein adducts (DA), is predicted to be the same in the liver of both human and male rat at oral doses of 0.0034 and 300 mg/kg bw. Altogether despite a significant difference in especially the metabolic pathways of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol (1'HME) between human and male rat, the influence of species differences on the ultimate overall bioactivation of methyleugenol (ME) to 1'-sulfooxymethyleugenol (1'HMES) appears to be negligible. Moreover, the PBK model predicted the formation of 1'-sulfooxymethyleugenol (1'HMES) in the liver of human and rat to be linear from doses as high as the benchmark dose (BMD10) down to as low as the virtual safe dose (VSD). This study shows that kinetic data do not provide a reason to argue against linear extrapolation from the rat tumor data to the human situation.
Toxicology and Applied Pharmacology, 1996
nemic capacity must rather result from differences in the inherent Influence of the Halogen-Subst... more nemic capacity must rather result from differences in the inherent Influence of the Halogen-Substituent Pattern of Fluoronitrobendirect methemoglobinemic capacity and/or reactivity of the varizenes on Their Biotransformation and Capacity to Induce Metheous toxic metabolites and/or from the fact that the halogen substitmoglobinemia. CNUBBEN, N. H. P., SOFFERS, A. E. M. F., PETERS, uent pattern influences the electrophilic reactivity, thereby chang-M. A. W., VERVOORT, J., AND RIETJENS, I. M. C. M. (1996). ing the possibilities for reactions of the nitrobenzenes with glutathi-Toxicol. Appl. Pharmacol. 139, 71-83. one and, especially, other cellular nucleophiles. When the number of fluorine substituents increases, the electrophilicity of the fluor-In the present study both the biotransformation patterns and onitrobenzenes can become so high that glutathione conjugation the capacity to induce methemoglobinemia of a series of fluoroniis no longer able to compete efficiently with covalent binding of trobenzenes were investigated. This was done to investigate to the fluoronitrobenzenes to cellular macromolecules. As a consewhat extent variation in the number and position of the halogen quence, it can be suggested that with an increasing number of substituents influence the metabolic fate of the fluoronitrobenfluorine substituents at electrophilic carbon centers in a nitrobenzenes, thereby influencing their capacity to induce methemoglobinzene derivative, a toxic end point of the nitrobenzene other than emia. The results obtained were compared to the effect of the formation of methemoglobinemia can be foreseen. ᭧ 1996 Academic fluorine substituent patterns on the calculated electronic charac-Press, Inc. teristics and, thus, on the chemical reactivity of the fluoronitrobenzenes. Analysis of the in vivo metabolic profiles demonstrates a dependence of the extent of nitroreduction, of glutathione conju-Halogenated nitrobenzenes are frequently used as indusgation, and of aromatic hydroxylation with the pattern of halogen substitution. With an increasing number of fluorine substituents trial intermediate reagents in the production of dyes, rubbers, at electrophilic carbon centers, 24-hr urine recovery values deand pharmaceuticals or are used as agrochemicals, for increased and fluoride anion elimination increased, due to increased stance the soil pesticide pentachloronitrobenzene (Rickert, reactivity of the fluoronitrobenzenes with cellular nucleophiles. 1987). Nitrobenzene derivatives are mutagenic in several In vitro studies even demonstrated a clear correlation between bacterial strains (Shimizu et al., 1983; Debnath et al., 1992), calculated parameters for the electrophilicity of the fluoronitrocause DNA damage in vivo (Cesarone et al., 1983), and benzenes and the natural logarithm of their rate of reaction with are hepatotoxic (Beauchamp et al., 1982) and nephrotoxic glutathione or with bovine serum albumin, taken as a model for (Yoshida et al., 1989). However, the most frequently recellular nucleophiles (r Å 0.97 and r Å 0.98, respectively). Inported consequence of exposure to nitrobenzenes is methecreased possibilities for the conjugation of the fluoronitrobenzenes moglobinemia and it is generally accepted that the intermedito cellular nucleophiles were accompanied by decreased contribuate oxidation states formed in the process of nitroreduction tions of nitroreduction and aromatic hydroxylation to the overall in vivo metabolite patterns, as well as by a decreased capacity of by the intestinal microflora (nitrosobenzene, N-hydroxyarylthe fluoronitrobenzenes to induce methemoglobinemia. In vitro amine, or the radical intermediates, all formed in the sixstudies on the rates of nitroreduction of the various fluoronitroelectron reduction pathway leading to aniline formation) are benzenes by cecal microflora and rat liver microsomes revealed responsible for inducing methemoglobinemia (for review, that the changes in the capacity of the fluoronitrobenzenes to see Kiese, 1974). Thus, some of the toxic effects require induce methemoglobinemia were not due to differences in their reactive intermediates formed upon the biotransformation of intrinsic reactivity in the pathway of nitroreduction, leading to nitrobenzenes. From several studies it became evident that methemoglobinemia-inducing metabolites. Thus, the results of the both the toxicity and the metabolism of nitrobenzenes can present study clearly demonstrate that the number and position be dependent on their substituent pattern (O'Brien et al., of fluorine substituents in the fluoronitrobenzenes influence the
Journal of Biological Inorganic Chemistry, 1996
Page 1. JBIC (1996) 1:460467 Q SBIC 1996 ORIGINAL ARTICLE Marjon JH van Haandel 7 Ivonne MCM Rie... more Page 1. JBIC (1996) 1:460467 Q SBIC 1996 ORIGINAL ARTICLE Marjon JH van Haandel 7 Ivonne MCM Rietjens Ans EMF Soffers 7 Cees Veeger 7 Jacques Vervoort Sandeep Modi 7 Madhu S. Mondal Prasanta K. Patel 7 Digambar V. Behere ...
Free Radical Research, 1999
Quantitative structure activity relationships (QSARs) are described for the antioxidant activity ... more Quantitative structure activity relationships (QSARs) are described for the antioxidant activity of series of all-trans carotenoids. The antioxidant activity of the carotenoids is characterised by literature data for (i) their relative ability to scavenge the ABTS*+ radical cation, reflected by the so-called trolox equivalent antioxidant capacity (TEAC) value, (ii) their relative rate of oxidation by a range of free radicals, or (iii) their capacity to inhibit lipid peroxidation in multilamellar liposomes, leading to a decrease in formation of thiobarbituric acid reactive substances (TBARS). All these antioxidant values for radical scavenging action correlate quantitatively with computer-calculated ionisation potentials of the carotenoids. These correlations are observed both when the ionisation potential is calculated as the negative of the energy of the highest occupied molecular orbital (-E(HOMO)) of the molecule, or as the relative change in heat of formation (deltadeltaHF) upon the one-electron oxidation of the carotenoids. The calculations provide a theoretical assay able to characterise the intrinsic electron donating capacity of an antioxidant, in hydrophilic, hydrophobic or artificial membrane environment.
Food and Chemical Toxicology, 2013
This study presents a consumer and farmer safety evaluation on the use of four botanical pesticid... more This study presents a consumer and farmer safety evaluation on the use of four botanical pesticides in pepper berry crop protection. The pesticides evaluated include preparations from clove, tuba root, sweet flag and pyrethrum. Their safety evaluation was based on their active ingredients being eugenol, rotenone, β-asarone and pyrethrins, respectively. Botanical pesticides from Acorus calamus are of possible concern because of the genotoxic and carcinogenic ingredient β-asarone although estimated margins of exposure (MOE) for consumers indicate a low priority for risk management. For the other three botanical pesticides the margin of safety (MOS) between established acute reference doses and/or acceptable daily intake values and intake estimates for the consumer, resulting from their use as a botanical pesticide are not of safety concern, with the exception for levels of rotenone upon use of tuba root extracts on stored berries. Used levels of clove and pyrethrum as botanical pesticides in pepper berry crop production is not of safety concern for consumers or farmers, whereas for use of tuba root and sweet flag some risk factors were defined requiring further evaluation and/or risk management. It seems prudent to look for alternatives for use of sweet flag extracts containing β-asarone.
Chemico-Biological Interactions, 2007
Xenobiotica; the fate of foreign compounds in biological systems, 1994
1. The influence of a change in the type of halogen substituent on phase II metabolism of 2-fluor... more 1. The influence of a change in the type of halogen substituent on phase II metabolism of 2-fluoro-4-halophenol metabolites formed from 3-halo-fluorobenzenes was studied in vivo and in vitro using 19F nmr and spectroscopic assays. 2. The ratio of sulphation to glucuronidation of 2-fluoro-4-halophenol metabolites formed from 3-halofluorobenzenes decreased from 48 to 13 to 6 when the halogen substituent varied from fluorine to chlorine to bromine. 3. When the 2-fluoro-4-halophenols themselves were administered to the rats, the ratio of sulphation to glucuronidation was not affected by the type of halogen substituent at C4 and at a constant value of 0.6, i.e. significantly lower. 4. Kinetic data for P450 catalysed hydroxylation of the 3-halo-fluorobenzenes and for sulphation and glucuronidation of their 2-fluoro-4-halophenol metabolites were obtained from in vitro microsomal and cytosolic incubations. These data demonstrate that the effects of varying the halogen substituent on phase I...
Free Radical Biology and Medicine, 1999
The influence of pH, intrinsic electron donating capacity, and intrinsic hydrogen atom donating c... more The influence of pH, intrinsic electron donating capacity, and intrinsic hydrogen atom donating capacity on the antioxidant potential of series of hydroxy and fluorine substituted 4-hydroxybenzoates was investigated experimentally and also on the basis of computer calculations. The pH-dependent behavior of the compounds in the TEAC assay revealed different antioxidant behavior of the nondissociated monoanionic form and the deprotonated dianionic form of the 4-hydroxybenzoates. Upon deprotonation the radical scavenging ability of the 4-hydroxybenzoates increases significantly. For mechanistic comparison a series of fluorobenzoates was synthesized and included in the studies. The fluorine substituents were shown to affect the proton and electron donating abilities of 4-hydroxybenzoate in the same way as hydroxyl substituents. In contrast, the fluorine substituents influenced the TEAC value and the hydrogen atom donating capacity of 4-hydroxybenzoate in a way different from the hydroxyl moieties. Comparison of these experimental data to computer-calculated characteristics indicates that the antioxidant behavior of the monoanionic forms of the 4-hydroxybenzoates is not determined by the tendency of the molecule to donate an electron, but by its ability to donate a hydrogen atom. Altogether, the results explain qualitatively and quantitatively how the number and position of OH moieties affect the antioxidant behavior of 4-hydroxybenzoates.
Frontiers in Medicine, 2016
Food and Chemical Toxicology, 2016
The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene api... more 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 BMDL10 value of 3 times the BMDL10 for safrole. Based on an estimated BMDL10 for apiol of 5.7-15.3 mg/kg body wt per day and an estimated daily intake of 4 × 10(-5) mg/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.
Toxicol. Res., 2015
Absorption, distribution, metabolism and excretion (ADME) of food-borne toxic compounds may be in... more Absorption, distribution, metabolism and excretion (ADME) of food-borne toxic compounds may be influenced by other compounds or constituents present in the food.
FEBS letters, Jan 30, 1999
The steady state single electron reduction of polynitroaromatics by ferredoxin-NADP+ oxidoreducta... more The steady state single electron reduction of polynitroaromatics by ferredoxin-NADP+ oxidoreductase (EC 1.18.1.2) from cyanobacterium Anabaena PCC 7119 has been studied and quantitative structure activity relationships are described. The solubility of the polynitroaromatics as well as their reactivity towards ferredoxin-NADP+ oxidoreductase are markedly higher than those for previously studied mononitroaromatics and this enabled the independent measurement of the kinetic parameters-k(cat) and Km. Interestingly, the natural logarithm of the bimolecular rate constant, k(cat)/Km, and also the natural logarithm of k(cat) correlate with the calculated energy of the lowest unoccupied molecular orbital of the polynitroaromatic substrates. The minimal kinetic model in line with these quantitative structure activity relationships is a ping-pong mechanism which includes substrate binding equilibria in the second half reaction.
Environmental Toxicology and Chemistry, 2006
Fifteen experimental literature data sets on the acute toxicity of substituted nitrobenzenes to a... more Fifteen experimental literature data sets on the acute toxicity of substituted nitrobenzenes to algae (Scenedesmus obliquus, Chlorella pyrenoidosa, C. vulgaris), daphnids (Daphnia magna, D. carinata), fish (Cyprinus carpio, Poecilia reticulata), protozoa (Tetrahymena pyriformis), bacteria (Phosphobacterium phosphoreum), and yeast (Saccharomyces cerevisiae) were used to establish quantum chemistry based quantitative structure¿activity relationships (QSARs). The logarithm of the octanol/water partition coefficient, log Kow,
Chemical Contaminants and Residues in Food, 2012
Chemosphere, 2009
Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (Q... more Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (QSAR) models are expected to help reduce the number of animals used for experimental testing. The objective of this study was to develop QSAR models to describe the acute toxicity of organothiophosphate pesticides to aquatic organisms. Literature data sets for acute toxicity data of organothiophosphates to fish and one
Toxicology and Applied Pharmacology, 2012
This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human ba... more This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the current model were compared with those of a previously developed PBK model for methyleugenol (ME) in male rat. The results obtained reveal that formation of 1'-hydroxymethyleugenol glucuronide (1'HMEG), a major metabolic pathway in male rat liver, appears to represent a minor metabolic pathway in human liver whereas in human liver a significantly higher formation of 1'-oxomethyleugenol (1'OME) compared with male rat liver is observed. Furthermore, formation of 1'-sulfooxymethyleugenol (1'HMES), which readily undergoes desulfonation to a reactive carbonium ion (CA) that can form DNA or protein adducts (DA), is predicted to be the same in the liver of both human and male rat at oral doses of 0.0034 and 300 mg/kg bw. Altogether despite a significant difference in especially the metabolic pathways of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol (1'HME) between human and male rat, the influence of species differences on the ultimate overall bioactivation of methyleugenol (ME) to 1'-sulfooxymethyleugenol (1'HMES) appears to be negligible. Moreover, the PBK model predicted the formation of 1'-sulfooxymethyleugenol (1'HMES) in the liver of human and rat to be linear from doses as high as the benchmark dose (BMD10) down to as low as the virtual safe dose (VSD). This study shows that kinetic data do not provide a reason to argue against linear extrapolation from the rat tumor data to the human situation.
Toxicology and Applied Pharmacology, 1996
nemic capacity must rather result from differences in the inherent Influence of the Halogen-Subst... more nemic capacity must rather result from differences in the inherent Influence of the Halogen-Substituent Pattern of Fluoronitrobendirect methemoglobinemic capacity and/or reactivity of the varizenes on Their Biotransformation and Capacity to Induce Metheous toxic metabolites and/or from the fact that the halogen substitmoglobinemia. CNUBBEN, N. H. P., SOFFERS, A. E. M. F., PETERS, uent pattern influences the electrophilic reactivity, thereby chang-M. A. W., VERVOORT, J., AND RIETJENS, I. M. C. M. (1996). ing the possibilities for reactions of the nitrobenzenes with glutathi-Toxicol. Appl. Pharmacol. 139, 71-83. one and, especially, other cellular nucleophiles. When the number of fluorine substituents increases, the electrophilicity of the fluor-In the present study both the biotransformation patterns and onitrobenzenes can become so high that glutathione conjugation the capacity to induce methemoglobinemia of a series of fluoroniis no longer able to compete efficiently with covalent binding of trobenzenes were investigated. This was done to investigate to the fluoronitrobenzenes to cellular macromolecules. As a consewhat extent variation in the number and position of the halogen quence, it can be suggested that with an increasing number of substituents influence the metabolic fate of the fluoronitrobenfluorine substituents at electrophilic carbon centers in a nitrobenzenes, thereby influencing their capacity to induce methemoglobinzene derivative, a toxic end point of the nitrobenzene other than emia. The results obtained were compared to the effect of the formation of methemoglobinemia can be foreseen. ᭧ 1996 Academic fluorine substituent patterns on the calculated electronic charac-Press, Inc. teristics and, thus, on the chemical reactivity of the fluoronitrobenzenes. Analysis of the in vivo metabolic profiles demonstrates a dependence of the extent of nitroreduction, of glutathione conju-Halogenated nitrobenzenes are frequently used as indusgation, and of aromatic hydroxylation with the pattern of halogen substitution. With an increasing number of fluorine substituents trial intermediate reagents in the production of dyes, rubbers, at electrophilic carbon centers, 24-hr urine recovery values deand pharmaceuticals or are used as agrochemicals, for increased and fluoride anion elimination increased, due to increased stance the soil pesticide pentachloronitrobenzene (Rickert, reactivity of the fluoronitrobenzenes with cellular nucleophiles. 1987). Nitrobenzene derivatives are mutagenic in several In vitro studies even demonstrated a clear correlation between bacterial strains (Shimizu et al., 1983; Debnath et al., 1992), calculated parameters for the electrophilicity of the fluoronitrocause DNA damage in vivo (Cesarone et al., 1983), and benzenes and the natural logarithm of their rate of reaction with are hepatotoxic (Beauchamp et al., 1982) and nephrotoxic glutathione or with bovine serum albumin, taken as a model for (Yoshida et al., 1989). However, the most frequently recellular nucleophiles (r Å 0.97 and r Å 0.98, respectively). Inported consequence of exposure to nitrobenzenes is methecreased possibilities for the conjugation of the fluoronitrobenzenes moglobinemia and it is generally accepted that the intermedito cellular nucleophiles were accompanied by decreased contribuate oxidation states formed in the process of nitroreduction tions of nitroreduction and aromatic hydroxylation to the overall in vivo metabolite patterns, as well as by a decreased capacity of by the intestinal microflora (nitrosobenzene, N-hydroxyarylthe fluoronitrobenzenes to induce methemoglobinemia. In vitro amine, or the radical intermediates, all formed in the sixstudies on the rates of nitroreduction of the various fluoronitroelectron reduction pathway leading to aniline formation) are benzenes by cecal microflora and rat liver microsomes revealed responsible for inducing methemoglobinemia (for review, that the changes in the capacity of the fluoronitrobenzenes to see Kiese, 1974). Thus, some of the toxic effects require induce methemoglobinemia were not due to differences in their reactive intermediates formed upon the biotransformation of intrinsic reactivity in the pathway of nitroreduction, leading to nitrobenzenes. From several studies it became evident that methemoglobinemia-inducing metabolites. Thus, the results of the both the toxicity and the metabolism of nitrobenzenes can present study clearly demonstrate that the number and position be dependent on their substituent pattern (O'Brien et al., of fluorine substituents in the fluoronitrobenzenes influence the
Journal of Biological Inorganic Chemistry, 1996
Page 1. JBIC (1996) 1:460467 Q SBIC 1996 ORIGINAL ARTICLE Marjon JH van Haandel 7 Ivonne MCM Rie... more Page 1. JBIC (1996) 1:460467 Q SBIC 1996 ORIGINAL ARTICLE Marjon JH van Haandel 7 Ivonne MCM Rietjens Ans EMF Soffers 7 Cees Veeger 7 Jacques Vervoort Sandeep Modi 7 Madhu S. Mondal Prasanta K. Patel 7 Digambar V. Behere ...
Free Radical Research, 1999
Quantitative structure activity relationships (QSARs) are described for the antioxidant activity ... more Quantitative structure activity relationships (QSARs) are described for the antioxidant activity of series of all-trans carotenoids. The antioxidant activity of the carotenoids is characterised by literature data for (i) their relative ability to scavenge the ABTS*+ radical cation, reflected by the so-called trolox equivalent antioxidant capacity (TEAC) value, (ii) their relative rate of oxidation by a range of free radicals, or (iii) their capacity to inhibit lipid peroxidation in multilamellar liposomes, leading to a decrease in formation of thiobarbituric acid reactive substances (TBARS). All these antioxidant values for radical scavenging action correlate quantitatively with computer-calculated ionisation potentials of the carotenoids. These correlations are observed both when the ionisation potential is calculated as the negative of the energy of the highest occupied molecular orbital (-E(HOMO)) of the molecule, or as the relative change in heat of formation (deltadeltaHF) upon the one-electron oxidation of the carotenoids. The calculations provide a theoretical assay able to characterise the intrinsic electron donating capacity of an antioxidant, in hydrophilic, hydrophobic or artificial membrane environment.
Food and Chemical Toxicology, 2013
This study presents a consumer and farmer safety evaluation on the use of four botanical pesticid... more This study presents a consumer and farmer safety evaluation on the use of four botanical pesticides in pepper berry crop protection. The pesticides evaluated include preparations from clove, tuba root, sweet flag and pyrethrum. Their safety evaluation was based on their active ingredients being eugenol, rotenone, β-asarone and pyrethrins, respectively. Botanical pesticides from Acorus calamus are of possible concern because of the genotoxic and carcinogenic ingredient β-asarone although estimated margins of exposure (MOE) for consumers indicate a low priority for risk management. For the other three botanical pesticides the margin of safety (MOS) between established acute reference doses and/or acceptable daily intake values and intake estimates for the consumer, resulting from their use as a botanical pesticide are not of safety concern, with the exception for levels of rotenone upon use of tuba root extracts on stored berries. Used levels of clove and pyrethrum as botanical pesticides in pepper berry crop production is not of safety concern for consumers or farmers, whereas for use of tuba root and sweet flag some risk factors were defined requiring further evaluation and/or risk management. It seems prudent to look for alternatives for use of sweet flag extracts containing β-asarone.
Chemico-Biological Interactions, 2007