S. McKarns, C. Hansch, W. Caldwell, Walter T. Morgan, Sarah K. Moore, D. Doolittle
The quantitative relationship between chemical structure and biological activity has received considerable attention in the fields of pharmacology and drug development. More recently, quantitative structure-activity relationships (QSARs) have been used for predicting chemical toxicity. It has been proposed that alcohols may elicit their toxic effects through hydrophobic interactions with the cellular membrane. The objective of this study was to evaluate the role of hydrophobicity in the loss of membrane integrity following acute exposure to short-chain aliphatic alcohols in rat liver epithelial cells in vitro. The series of alcohols studied included methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol. The lactate dehydrogenase (LDH) assay was used to quantify membrane integrity. The logarithm of the octanol/water partition coefficient (log P) was used to quantify hydrophobicity. LDH50 values, representing alcohol concentrations yielding a 50% increase in LDH release relative to untreated controls (i.e., mild disruption of membrane integrity), and EC50 values, representing alcohol concentrations yielding 50% of the maximal release of LDH (i.e., moderate disruption of LDH release), were experimentally determined for each alcohol. The LDH50 and EC50 values were then used to derive the QSAR relationship. The aqueous alcohol concentrations yielding LDH50 or EC50 values ranged from 8.9 x 10(-4) m (LDH50 for octanol) to 3.5 m (EC50 for methanol), and the log P of the alcohols ranged from -0.77 (methanol) to 3.00 (octanol). From these data, we have derived two QSAR equations describing the role of hydrophobicity in the release of LDH from rat liver epithelial cells following a 1-hr alcohol exposure. The QSAR equation for LDH50 values, log (1/LDH50) = 0.896 log P + 0.117 (n = 11, SD = 0.131), was nearly identical to the QSAR equation for EC50 values, log (1/EC50) = 0.893 log P + 0.101 (n = 11, SD = 0.133], suggesting that similar structure-activity relationships exist at both mild and moderate levels of membrane disruption. Our data indicate that an increase in LDH release was positively and linearly correlated with the hydrophobicity (r = 0.993). These data may help predict the potential biological effects of other, as yet untested, aliphatic alcohols and aliphatic alcohol-like compounds (e.g., anesthetics) on the plasma membrane.
{"title":"Correlation between hydrophobicity of short-chain aliphatic alcohols and their ability to alter plasma membrane integrity.","authors":"S. McKarns, C. Hansch, W. Caldwell, Walter T. Morgan, Sarah K. Moore, D. Doolittle","doi":"10.1093/TOXSCI/36.1.62","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.1.62","url":null,"abstract":"The quantitative relationship between chemical structure and biological activity has received considerable attention in the fields of pharmacology and drug development. More recently, quantitative structure-activity relationships (QSARs) have been used for predicting chemical toxicity. It has been proposed that alcohols may elicit their toxic effects through hydrophobic interactions with the cellular membrane. The objective of this study was to evaluate the role of hydrophobicity in the loss of membrane integrity following acute exposure to short-chain aliphatic alcohols in rat liver epithelial cells in vitro. The series of alcohols studied included methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol. The lactate dehydrogenase (LDH) assay was used to quantify membrane integrity. The logarithm of the octanol/water partition coefficient (log P) was used to quantify hydrophobicity. LDH50 values, representing alcohol concentrations yielding a 50% increase in LDH release relative to untreated controls (i.e., mild disruption of membrane integrity), and EC50 values, representing alcohol concentrations yielding 50% of the maximal release of LDH (i.e., moderate disruption of LDH release), were experimentally determined for each alcohol. The LDH50 and EC50 values were then used to derive the QSAR relationship. The aqueous alcohol concentrations yielding LDH50 or EC50 values ranged from 8.9 x 10(-4) m (LDH50 for octanol) to 3.5 m (EC50 for methanol), and the log P of the alcohols ranged from -0.77 (methanol) to 3.00 (octanol). From these data, we have derived two QSAR equations describing the role of hydrophobicity in the release of LDH from rat liver epithelial cells following a 1-hr alcohol exposure. The QSAR equation for LDH50 values, log (1/LDH50) = 0.896 log P + 0.117 (n = 11, SD = 0.131), was nearly identical to the QSAR equation for EC50 values, log (1/EC50) = 0.893 log P + 0.101 (n = 11, SD = 0.133], suggesting that similar structure-activity relationships exist at both mild and moderate levels of membrane disruption. Our data indicate that an increase in LDH release was positively and linearly correlated with the hydrophobicity (r = 0.993). These data may help predict the potential biological effects of other, as yet untested, aliphatic alcohols and aliphatic alcohol-like compounds (e.g., anesthetics) on the plasma membrane.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"201 1","pages":"62-70"},"PeriodicalIF":0.0,"publicationDate":"1997-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75872476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Nikulin, K. Reuula, B. Jarvis, P. Veijalainen, E. Hintikka
The effects of highly toxic and nontoxic spores of Stachybotrys atra were investigated in mice after six intranasal administrations of 1 x 10(5) and 1 x 10(3) spores in phosphate-buffered saline during a 3-week period. Toxic spores contained the trichothecene mycotoxins, satratoxins G and H, as well as the immunosuppressant stachybotrylactones and -lactams. No trichothecenes were detected in the nontoxic spores, and they contained only minor amounts of stachybotrylactones and -lactams. In mice injected with toxic and nontoxic spores, the platelet count was decreased and leucocyte and erythrocyte counts, hemoglobin concentration, and hematocrit were increased. No IgG antibodies to S. atra were detected in sera of mice exposed intranasally to spores. No histological changes were detected in spleen, thymus, or intestines of mice. The mice receiving 1 x 10(5) toxic spores intranasally developed severe inflammatory changes within both bronchioles and alveoli. Hemorrhage was detected in alveoli. The mice receiving 1 x 10(5) nontoxic spores also developed inflammatory changes in the lungs, but these changes were significantly milder than those in mice receiving toxic spores. The mice receiving 1 x 10(3) toxic spores developed inflammatory changes in the lungs that were less severe than those in the mice receiving 1 x 10(5) toxic spores. No inflammatory changes were detected in the mice receiving 1 x 10(3) of nontoxic spores. The present findings indicate that exposure to S. atra spores containing toxins (satratoxins) can be a significant health risk.
{"title":"Effects of intranasal exposure to spores of Stachybotrys atra in mice.","authors":"M. Nikulin, K. Reuula, B. Jarvis, P. Veijalainen, E. Hintikka","doi":"10.1093/TOXSCI/35.2.182","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.2.182","url":null,"abstract":"The effects of highly toxic and nontoxic spores of Stachybotrys atra were investigated in mice after six intranasal administrations of 1 x 10(5) and 1 x 10(3) spores in phosphate-buffered saline during a 3-week period. Toxic spores contained the trichothecene mycotoxins, satratoxins G and H, as well as the immunosuppressant stachybotrylactones and -lactams. No trichothecenes were detected in the nontoxic spores, and they contained only minor amounts of stachybotrylactones and -lactams. In mice injected with toxic and nontoxic spores, the platelet count was decreased and leucocyte and erythrocyte counts, hemoglobin concentration, and hematocrit were increased. No IgG antibodies to S. atra were detected in sera of mice exposed intranasally to spores. No histological changes were detected in spleen, thymus, or intestines of mice. The mice receiving 1 x 10(5) toxic spores intranasally developed severe inflammatory changes within both bronchioles and alveoli. Hemorrhage was detected in alveoli. The mice receiving 1 x 10(5) nontoxic spores also developed inflammatory changes in the lungs, but these changes were significantly milder than those in mice receiving toxic spores. The mice receiving 1 x 10(3) toxic spores developed inflammatory changes in the lungs that were less severe than those in the mice receiving 1 x 10(5) toxic spores. No inflammatory changes were detected in the mice receiving 1 x 10(3) of nontoxic spores. The present findings indicate that exposure to S. atra spores containing toxins (satratoxins) can be a significant health risk.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"37 1","pages":"182-8"},"PeriodicalIF":0.0,"publicationDate":"1997-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79819202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D. Parrish, M. Schlosser, J. C. Kapeghian, V. Traina
Many marketed pharmaceuticals are known to cause idiosyncratic agranulocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinical trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its parahydroxy metabolite, CGS 12094. To investigate mechanisms for this human specific toxicity, experiments were conducted to study the metabolism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophils and leukocyte progenitor cells. Although prinomide was not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90%; 2 min); this reaction was dependent on H2O2 and MPO and was inhibited by azide. During the MPO-catalyzed metabolism of CGS 12094, reactive intermediates that irreversibly bound to protein and cysteine were generated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a compound implicated in the myelotoxicity associated with benzene. Thus during conditions which lead to elevated levels of H2O2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced agranulocytosis.
{"title":"Activation of CGS 12094 (prinomide metabolite) to 1,4-benzoquinone by myeloperoxidase: implications for human idiosyncratic agranulocytosis.","authors":"D. Parrish, M. Schlosser, J. C. Kapeghian, V. Traina","doi":"10.1093/TOXSCI/35.2.197","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.2.197","url":null,"abstract":"Many marketed pharmaceuticals are known to cause idiosyncratic agranulocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinical trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its parahydroxy metabolite, CGS 12094. To investigate mechanisms for this human specific toxicity, experiments were conducted to study the metabolism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophils and leukocyte progenitor cells. Although prinomide was not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90%; 2 min); this reaction was dependent on H2O2 and MPO and was inhibited by azide. During the MPO-catalyzed metabolism of CGS 12094, reactive intermediates that irreversibly bound to protein and cysteine were generated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a compound implicated in the myelotoxicity associated with benzene. Thus during conditions which lead to elevated levels of H2O2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced agranulocytosis.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"70 1","pages":"197-204"},"PeriodicalIF":0.0,"publicationDate":"1997-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73670034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Virginia C. Moser, G. Becking, R. Macphail, B. Kulig
The International Programme on Chemical Safety sponsored a collaborative study to evaluate the utility of neurobehavioral test methods for identifying neurotoxic chemicals. The protocol consisted of a functional observational battery and automated assessment of motor activity. The study involved four laboratories in the United States and four in Europe, each of which evaluated the dose- and time-related effects of seven prototypic chemicals following both single and 4-week repeated exposures. The protocol was designed to assess the general utility and reliability of neurobehavioral screening procedures in a diversity of testing situations. The results of chemical testing indicated that all participating laboratories generally could detect and characterize the effects of known neurotoxicants, despite some differences on specific endpoints. These data provide important information regarding the reliability and sensitivity of neurobehavioral screening methods over a range of laboratory conditions. The purpose of this workshop was to describe the background and study design of the collaborative effort, present the data (including comparison of results across laboratories), and discuss issues regarding the conduct and interpretation of these behavioral tests, as well as future directions for neurotoxicity screening.
{"title":"The IPCS collaborative study on neurobehavioral screening methods.","authors":"Virginia C. Moser, G. Becking, R. Macphail, B. Kulig","doi":"10.1093/TOXSCI/35.2.143","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.2.143","url":null,"abstract":"The International Programme on Chemical Safety sponsored a collaborative study to evaluate the utility of neurobehavioral test methods for identifying neurotoxic chemicals. The protocol consisted of a functional observational battery and automated assessment of motor activity. The study involved four laboratories in the United States and four in Europe, each of which evaluated the dose- and time-related effects of seven prototypic chemicals following both single and 4-week repeated exposures. The protocol was designed to assess the general utility and reliability of neurobehavioral screening procedures in a diversity of testing situations. The results of chemical testing indicated that all participating laboratories generally could detect and characterize the effects of known neurotoxicants, despite some differences on specific endpoints. These data provide important information regarding the reliability and sensitivity of neurobehavioral screening methods over a range of laboratory conditions. The purpose of this workshop was to describe the background and study design of the collaborative effort, present the data (including comparison of results across laboratories), and discuss issues regarding the conduct and interpretation of these behavioral tests, as well as future directions for neurotoxicity screening.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"33 1","pages":"143-51"},"PeriodicalIF":0.0,"publicationDate":"1997-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79820390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G. Cruzan, JANETTE R. Cushman, LARRY S. Andrews, GEOFFREY C. Granville, ROLAND R. Miller, COLIN J. Hardy, D. W. Coombs, Pamela A. Mullins
Groups of 10 male and 10 female Charles River (CRL) CD (Sprague-Dawley-derived) rats were exposed to styrene vapor at 0, 200, 500, 1000, or 1500 ppm 6 hr per day 5 days per week for 13 weeks. Styrene had no effect on survival, hematology, or clinical chemistry. Males at 1500 ppm weighed 10% less after 13 weeks and males and females at 1000 and 1500 ppm consumed more water than controls. Histopathologic changes were confined to the olfactory epithelium of the nasal mucosa. Groups of 20 male and 20 female CRL CD-1 and B6C3F1 mice were exposed to styrene vapor at 0, 15, 60, 250, or 500 ppm 6 hr per day 5 days per week for 2 weeks. Mortality was observed in both CD-1 and B6C3F1 mice exposed to 250 or 500 ppm; more female mice, but not males, died from exposure to 250 ppm than from 500 ppm. Groups of 10 male and 10 female CRL CD-1 mice were exposed to styrene vapors at 0, 50, 100, 150, or 200 ppm 6 hr per day 5 days per week for 13 weeks. Two females exposed to 200 ppm died during the first week. Liver toxicity was evident in the decedents and in some female survivors at 200 ppm. Changes were observed in the lungs of mice exposed to 100, 150, or 200 ppm and in the nasal passages of all treatment groups, those exposed to 50 ppm being less affected. Satellite groups of 15 male rats and 30 male mice were exposed as described above for 2, 5, or 13 weeks for measurement of cell proliferation (BrdU labeling). No increase in cell proliferation was found in liver of rats or mice or in cells of the bronchiolar or alveolar region of the lung of rats. No increase in labeling index of type II pneumocytes was seen in mouse lungs, while at 150 and 200 ppm, an increased labeling index of Clara cells was seen after 2 weeks and in occasional mice after 5 weeks. Large variations in the labeling index among animals emphasize the need for large group sizes. For nasal tract effects, a NOAEL was not found in CD-1 mice, but in CD rats, the NOAEL was 200 ppm. For other effects, the NOAEL was 500 ppm in rats and 50 ppm in mice.
{"title":"Subchronic inhalation studies of styrene in CD rats and CD-1 mice.","authors":"G. Cruzan, JANETTE R. Cushman, LARRY S. Andrews, GEOFFREY C. Granville, ROLAND R. Miller, COLIN J. Hardy, D. W. Coombs, Pamela A. Mullins","doi":"10.1093/TOXSCI/35.2.152","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.2.152","url":null,"abstract":"Groups of 10 male and 10 female Charles River (CRL) CD (Sprague-Dawley-derived) rats were exposed to styrene vapor at 0, 200, 500, 1000, or 1500 ppm 6 hr per day 5 days per week for 13 weeks. Styrene had no effect on survival, hematology, or clinical chemistry. Males at 1500 ppm weighed 10% less after 13 weeks and males and females at 1000 and 1500 ppm consumed more water than controls. Histopathologic changes were confined to the olfactory epithelium of the nasal mucosa. Groups of 20 male and 20 female CRL CD-1 and B6C3F1 mice were exposed to styrene vapor at 0, 15, 60, 250, or 500 ppm 6 hr per day 5 days per week for 2 weeks. Mortality was observed in both CD-1 and B6C3F1 mice exposed to 250 or 500 ppm; more female mice, but not males, died from exposure to 250 ppm than from 500 ppm. Groups of 10 male and 10 female CRL CD-1 mice were exposed to styrene vapors at 0, 50, 100, 150, or 200 ppm 6 hr per day 5 days per week for 13 weeks. Two females exposed to 200 ppm died during the first week. Liver toxicity was evident in the decedents and in some female survivors at 200 ppm. Changes were observed in the lungs of mice exposed to 100, 150, or 200 ppm and in the nasal passages of all treatment groups, those exposed to 50 ppm being less affected. Satellite groups of 15 male rats and 30 male mice were exposed as described above for 2, 5, or 13 weeks for measurement of cell proliferation (BrdU labeling). No increase in cell proliferation was found in liver of rats or mice or in cells of the bronchiolar or alveolar region of the lung of rats. No increase in labeling index of type II pneumocytes was seen in mouse lungs, while at 150 and 200 ppm, an increased labeling index of Clara cells was seen after 2 weeks and in occasional mice after 5 weeks. Large variations in the labeling index among animals emphasize the need for large group sizes. For nasal tract effects, a NOAEL was not found in CD-1 mice, but in CD rats, the NOAEL was 200 ppm. For other effects, the NOAEL was 500 ppm in rats and 50 ppm in mice.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"273 1","pages":"152-65"},"PeriodicalIF":0.0,"publicationDate":"1997-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73487730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Syntower bottoms (STB) was evaluated for subchronic and developmental toxicity. In the subchronic study, undiluted STB was applied on the shaved backs of male and female rats at dose levels of 0, 8, 30, 125, and 500 mg/kg for 13 weeks, 5 days per week. Exposure sites were not covered. In the developmental toxicity study, STB was similarly applied, but to pregnant rats at dose levels of 0, 8, 30, and 125 mg/kg on Gestation Days 0-19. In addition, 4 mg/kg was dosed as 8 mg/kg every other day, starting on Gestation Day 0, and 500 mg/kg was dosed on Gestation Days 10-12. Evidence of toxicity observed in the subchronic study included death, decreased body weights, aberrant serum chemistry and hematology values, altered organ weights, and histopathologic changes in a variety of organs. A no observed adverse effect level for systemic toxicity could not be established. Evidence of maternal toxicity was observed at all exposure levels in the development study. Regardless of the length of the exposure period, STB was toxic to the developing conceptus. Evidence of developmental toxicity observed included increased resorptions with a concomitant decrease in litter size and reduced fetal body weights. Cleft palate was observed in fetuses exposed in utero to STB during Gestation Days 10-12 at 500 mg/kg. No evidence of teratogenicity was observed when the exposure period was throughout gestation. Ossification delays were observed in fetuses exposed in utero to STB at doses in excess of 4 mg/kg. A no observed adverse effect level for maternal and developmental toxicity could not be established.
{"title":"Systemic and developmental toxicity of dermally applied syntower bottoms in rats.","authors":"M. Feuston, C. E. Hamilton, C. Mackerer","doi":"10.1093/TOXSCI/35.2.166","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.2.166","url":null,"abstract":"Syntower bottoms (STB) was evaluated for subchronic and developmental toxicity. In the subchronic study, undiluted STB was applied on the shaved backs of male and female rats at dose levels of 0, 8, 30, 125, and 500 mg/kg for 13 weeks, 5 days per week. Exposure sites were not covered. In the developmental toxicity study, STB was similarly applied, but to pregnant rats at dose levels of 0, 8, 30, and 125 mg/kg on Gestation Days 0-19. In addition, 4 mg/kg was dosed as 8 mg/kg every other day, starting on Gestation Day 0, and 500 mg/kg was dosed on Gestation Days 10-12. Evidence of toxicity observed in the subchronic study included death, decreased body weights, aberrant serum chemistry and hematology values, altered organ weights, and histopathologic changes in a variety of organs. A no observed adverse effect level for systemic toxicity could not be established. Evidence of maternal toxicity was observed at all exposure levels in the development study. Regardless of the length of the exposure period, STB was toxic to the developing conceptus. Evidence of developmental toxicity observed included increased resorptions with a concomitant decrease in litter size and reduced fetal body weights. Cleft palate was observed in fetuses exposed in utero to STB during Gestation Days 10-12 at 500 mg/kg. No evidence of teratogenicity was observed when the exposure period was throughout gestation. Ossification delays were observed in fetuses exposed in utero to STB at doses in excess of 4 mg/kg. A no observed adverse effect level for maternal and developmental toxicity could not be established.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"27 1","pages":"166-76"},"PeriodicalIF":0.0,"publicationDate":"1997-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80022332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Nikulin, K Reijula, B B Jarvis, P Veijalainen, E L Hintikka
The effects of highly toxic and nontoxic spores of Stachybotrys atra were investigated in mice after six intranasal administrations of 1 x 10(5) and 1 x 10(3) spores in phosphate-buffered saline during a 3-week period. Toxic spores contained the trichothecene mycotoxins, satratoxins G and H, as well as the immunosuppressant stachybotrylactones and -lactams. No trichothecenes were detected in the nontoxic spores, and they contained only minor amounts of stachybotrylactones and -lactams. In mice injected with toxic and nontoxic spores, the platelet count was decreased and leucocyte and erythrocyte counts, hemoglobin concentration, and hematocrit were increased. No IgG antibodies to S. atra were detected in sera of mice exposed intranasally to spores. No histological changes were detected in spleen, thymus, or intestines of mice. The mice receiving 1 x 10(5) toxic spores intranasally developed severe inflammatory changes within both bronchioles and alveoli. Hemorrhage was detected in alveoli. The mice receiving 1 x 10(5) nontoxic spores also developed inflammatory changes in the lungs, but these changes were significantly milder than those in mice receiving toxic spores. The mice receiving 1 x 10(3) toxic spores developed inflammatory changes in the lungs that were less severe than those in the mice receiving 1 x 10(5) toxic spores. No inflammatory changes were detected in the mice receiving 1 x 10(3) of nontoxic spores. The present findings indicate that exposure to S. atra spores containing toxins (satratoxins) can be a significant health risk.
{"title":"Effects of intranasal exposure to spores of Stachybotrys atra in mice.","authors":"M Nikulin, K Reijula, B B Jarvis, P Veijalainen, E L Hintikka","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The effects of highly toxic and nontoxic spores of Stachybotrys atra were investigated in mice after six intranasal administrations of 1 x 10(5) and 1 x 10(3) spores in phosphate-buffered saline during a 3-week period. Toxic spores contained the trichothecene mycotoxins, satratoxins G and H, as well as the immunosuppressant stachybotrylactones and -lactams. No trichothecenes were detected in the nontoxic spores, and they contained only minor amounts of stachybotrylactones and -lactams. In mice injected with toxic and nontoxic spores, the platelet count was decreased and leucocyte and erythrocyte counts, hemoglobin concentration, and hematocrit were increased. No IgG antibodies to S. atra were detected in sera of mice exposed intranasally to spores. No histological changes were detected in spleen, thymus, or intestines of mice. The mice receiving 1 x 10(5) toxic spores intranasally developed severe inflammatory changes within both bronchioles and alveoli. Hemorrhage was detected in alveoli. The mice receiving 1 x 10(5) nontoxic spores also developed inflammatory changes in the lungs, but these changes were significantly milder than those in mice receiving toxic spores. The mice receiving 1 x 10(3) toxic spores developed inflammatory changes in the lungs that were less severe than those in the mice receiving 1 x 10(5) toxic spores. No inflammatory changes were detected in the mice receiving 1 x 10(3) of nontoxic spores. The present findings indicate that exposure to S. atra spores containing toxins (satratoxins) can be a significant health risk.</p>","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"35 2","pages":"182-8"},"PeriodicalIF":0.0,"publicationDate":"1997-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19997195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Tischler, J. Powers, M. Shahsavari, J. Ziar, P. Tsokas, J. Downing, R. Mcclain
Spontaneous and drug-induced pheochromocytomas are common in rats and rare in mice. The antihypertensive drug reserpine has been shown to both induce pheochromocytomas and stimulate chromaffin cell proliferation in rats, leading to the hypothesis that reserpine causes pheochromocytomas indirectly by providing a proliferative setting in which DNA damage may occur. The present investigation was undertaken to obtain baseline information on the relationship across species between chromaffin cell proliferation and pheochromocytomas. Basal chromaffin cell proliferation was compared in age-matched young adult mice and rats. In addition, mice were studied for adrenal medullary responses to reserpine, and mouse chromaffin cells in vitro were studied for responses to agents that are mitogenic for cultured rat chromaffin cells. Concurrently maintained F-344 rats and several strains of mice showed no significant difference in basal BrdU incorporation over a 1-week period. Mice also showed an adrenal medullary proliferative response to reserpine that was comparable to the response previously reported for rats. However, there was a marked disparity between rat and mouse chromaffin cells in vitro, and cultured mouse chromaffin cells did not respond to any mitogens. The in vivo data indicate that interspecies differences in basal- or reserpine-stimulated chromaffin cell proliferation sufficient to account for different frequencies of pheochromocytomas are not detectable at a single time point in young adult animals. However, the possibility that such differences might emerge with aging has not been ruled out. These data further suggest either that stimulation of chromaffin cell proliferation might be necessary but not sufficient for development of pheochromocytomas or that stimulated proliferation in mice might not be sustained. The inability of cultured mouse chromaffin cells to respond to mitogens raises the speculation of whether mechanisms that prevent proliferation of normal chromaffin cells in vitro might also help to protect mice from developing pheochromocytomas.
{"title":"Comparative studies of chromaffin cell proliferation in the adrenal medulla of rats and mice.","authors":"A. Tischler, J. Powers, M. Shahsavari, J. Ziar, P. Tsokas, J. Downing, R. Mcclain","doi":"10.1093/TOXSCI/35.2.216","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.2.216","url":null,"abstract":"Spontaneous and drug-induced pheochromocytomas are common in rats and rare in mice. The antihypertensive drug reserpine has been shown to both induce pheochromocytomas and stimulate chromaffin cell proliferation in rats, leading to the hypothesis that reserpine causes pheochromocytomas indirectly by providing a proliferative setting in which DNA damage may occur. The present investigation was undertaken to obtain baseline information on the relationship across species between chromaffin cell proliferation and pheochromocytomas. Basal chromaffin cell proliferation was compared in age-matched young adult mice and rats. In addition, mice were studied for adrenal medullary responses to reserpine, and mouse chromaffin cells in vitro were studied for responses to agents that are mitogenic for cultured rat chromaffin cells. Concurrently maintained F-344 rats and several strains of mice showed no significant difference in basal BrdU incorporation over a 1-week period. Mice also showed an adrenal medullary proliferative response to reserpine that was comparable to the response previously reported for rats. However, there was a marked disparity between rat and mouse chromaffin cells in vitro, and cultured mouse chromaffin cells did not respond to any mitogens. The in vivo data indicate that interspecies differences in basal- or reserpine-stimulated chromaffin cell proliferation sufficient to account for different frequencies of pheochromocytomas are not detectable at a single time point in young adult animals. However, the possibility that such differences might emerge with aging has not been ruled out. These data further suggest either that stimulation of chromaffin cell proliferation might be necessary but not sufficient for development of pheochromocytomas or that stimulated proliferation in mice might not be sustained. The inability of cultured mouse chromaffin cells to respond to mitogens raises the speculation of whether mechanisms that prevent proliferation of normal chromaffin cells in vitro might also help to protect mice from developing pheochromocytomas.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"26 1","pages":"216-20"},"PeriodicalIF":0.0,"publicationDate":"1997-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89749797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
U. Lutz, S. Lugli, A. Bitsch, J. Schlatter, W. Lutz
Caffeic acid (CA, 3,4-dihydroxycinnamic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats and B6C3F1 mice. Based on its occurrence in coffee and numerous foods and using a linear interpolation for cancer incidence between dose 0 and 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could represent the main mechanism of carcinogenic action. The dose-response relationship for this effect was investigated in male F344 rats after 4-week feeding with CA at different dietary concentrations (0, 0.05, 0.14, 0.40, and 1.64%). Cells in S-phase of DNA replication were visualized by immunohistochemical analysis of incorporated 5-bromo-2'-deoxyuridine (BrdU), 2 hr after intraperitoneal injection. In the forestomach, both the total number of epithelial cells per millimeter section length and the unit length labeling index of BrdU-positive cells (ULLI) were increased, about 2.5-fold, at 0.40 and 1.64%. The lowest concentration (0.05%) had no effect. At 0.14%, both variables were decreased by about one-third. In the kidney, the labeling index in proximal tubular cells also indicated a J-shaped (or U-shaped) dose response with a 1. 8-fold increase at 1.64%. In the glandular stomach and in the liver, which are not target organs, no dose-related effect was seen. The data show a good correlation between the organ specificity for cancer induction and stimulation of cell division. With respect to the dose-response relationship and the corresponding extrapolation of the animal tumor data to a human cancer risk, a linear extrapolation appears not to be appropriate.
{"title":"Dose response for the stimulation of cell division by caffeic acid in forestomach and kidney of the male F344 rat.","authors":"U. Lutz, S. Lugli, A. Bitsch, J. Schlatter, W. Lutz","doi":"10.1093/toxsci/39.2.131","DOIUrl":"https://doi.org/10.1093/toxsci/39.2.131","url":null,"abstract":"Caffeic acid (CA, 3,4-dihydroxycinnamic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats and B6C3F1 mice. Based on its occurrence in coffee and numerous foods and using a linear interpolation for cancer incidence between dose 0 and 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could represent the main mechanism of carcinogenic action. The dose-response relationship for this effect was investigated in male F344 rats after 4-week feeding with CA at different dietary concentrations (0, 0.05, 0.14, 0.40, and 1.64%). Cells in S-phase of DNA replication were visualized by immunohistochemical analysis of incorporated 5-bromo-2'-deoxyuridine (BrdU), 2 hr after intraperitoneal injection. In the forestomach, both the total number of epithelial cells per millimeter section length and the unit length labeling index of BrdU-positive cells (ULLI) were increased, about 2.5-fold, at 0.40 and 1.64%. The lowest concentration (0.05%) had no effect. At 0.14%, both variables were decreased by about one-third. In the kidney, the labeling index in proximal tubular cells also indicated a J-shaped (or U-shaped) dose response with a 1. 8-fold increase at 1.64%. In the glandular stomach and in the liver, which are not target organs, no dose-related effect was seen. The data show a good correlation between the organ specificity for cancer induction and stimulation of cell division. With respect to the dose-response relationship and the corresponding extrapolation of the animal tumor data to a human cancer risk, a linear extrapolation appears not to be appropriate.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"1 1","pages":"131-7"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78434890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emulphor, a polyethoxylated vegetable oil, is now being used widely to incorporate volatile organic compounds (VOCs) and other lipophilic compounds into aqueous solutions for biochemical, pharmacokinetic, and toxicological studies. Previous work in this laboratory demonstrated that 0.25% Emulphor did not alter the kinetics or hepatotoxicity of low doses of CCl4 compared to when the halocarbon was given to rats orally in water. The present study was undertaken as there was concern that higher concentrations of Emulphor (necessary to maintain lipophilic VOCs in stable aqueous emulsions for extended periods) might alter the VOCs' absorption, disposition, and/or toxicity. Dosages of 10 and 180 mg CCl4/kg bw were given, as an aqueous emulsion using 1, 2.5, 5, or 10% Emulphor, by gavage to fasted male Sprague-Dawley rats. Serial microsamples of blood were collected from an indwelling cannula in unanesthetized, freely moving rats at intervals of 2-60 min for up to 12 hr. The samples' CCl4 content was measured by headspace gas chromatography. Thereby, it was possible to obtain blood CCl4 concentration-versus-time profiles. Animals were euthanized 24 hr postdosing and blood was collected for measurement of serum enzymes as indices of hepatotoxicity. No toxicologically significant differences in pharmacokinetic parameters as a function of Emulphor concentration were found. Similarly the hepatotoxic potency of 10 and 180 mg/kg CCl4, as reflected by elevation in serum enzyme activities, did not vary significantly with the concentration of Emulphor utilized. Hence, it can be concluded that Emulphor, in concentrations as high as 10% (equivalent to 260 mg Emulphor/kg bw) in aqueous emulsions, does not significantly affect the absorption, disposition, or acute hepatotoxicity of CCl4 in male Sprague-Dawley rats.
{"title":"Effect of Emulphor, an emulsifier, on the pharmacokinetics and hepatotoxicity of oral carbon tetrachloride in the rat.","authors":"U. Sanzgiri, J. Bruckner","doi":"10.1093/toxsci/36.1.54","DOIUrl":"https://doi.org/10.1093/toxsci/36.1.54","url":null,"abstract":"Emulphor, a polyethoxylated vegetable oil, is now being used widely to incorporate volatile organic compounds (VOCs) and other lipophilic compounds into aqueous solutions for biochemical, pharmacokinetic, and toxicological studies. Previous work in this laboratory demonstrated that 0.25% Emulphor did not alter the kinetics or hepatotoxicity of low doses of CCl4 compared to when the halocarbon was given to rats orally in water. The present study was undertaken as there was concern that higher concentrations of Emulphor (necessary to maintain lipophilic VOCs in stable aqueous emulsions for extended periods) might alter the VOCs' absorption, disposition, and/or toxicity. Dosages of 10 and 180 mg CCl4/kg bw were given, as an aqueous emulsion using 1, 2.5, 5, or 10% Emulphor, by gavage to fasted male Sprague-Dawley rats. Serial microsamples of blood were collected from an indwelling cannula in unanesthetized, freely moving rats at intervals of 2-60 min for up to 12 hr. The samples' CCl4 content was measured by headspace gas chromatography. Thereby, it was possible to obtain blood CCl4 concentration-versus-time profiles. Animals were euthanized 24 hr postdosing and blood was collected for measurement of serum enzymes as indices of hepatotoxicity. No toxicologically significant differences in pharmacokinetic parameters as a function of Emulphor concentration were found. Similarly the hepatotoxic potency of 10 and 180 mg/kg CCl4, as reflected by elevation in serum enzyme activities, did not vary significantly with the concentration of Emulphor utilized. Hence, it can be concluded that Emulphor, in concentrations as high as 10% (equivalent to 260 mg Emulphor/kg bw) in aqueous emulsions, does not significantly affect the absorption, disposition, or acute hepatotoxicity of CCl4 in male Sprague-Dawley rats.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"65 1","pages":"54-61"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77900012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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