D. Bombick, B. Bombick, P. Ayres, K. Putnam, J. Avalos, M. Borgerding, D. Doolittle, B. Reed, D. Doolittle
A novel carbon filter has been developed which primarily reduces the amount of certain vapor phase constituents of tobacco smoke with greater efficiency than the charcoal filters of cigarettes currently in the market. In vitro indicators of genotoxic and cytotoxic potential were used to compare the cigarette smoke condensate (particulate phase) or whole cigarette smoke (vapor phase and particulate phase) from cigarettes containing the novel carbon filter with smoke condensate or whole smoke from commercial or prototype cigarettes not containing the novel carbon filter. Ames bacterial mutagenicity, sister chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells, and neutral red cytotoxicity assays in CHO cells were utilized to assess the genotoxic and cytotoxic potential of the cigarette smoke condensates. SCE and neutral red cytotoxicity assays were utilized to assess the genotoxic and cytotoxic potential of the whole smoke. As expected, the novel carbon filter did not significantly affect the genotoxic or cytotoxic activity of the smoke condensate, although we did observe that the use of low-nitrogen tobacco reduced the mutagenicity of the condensate in Salmonella typhimurium strain TA98. However, the whole smoke from cigarettes containing the novel carbon filter demonstrated significant reductions in genotoxic and cytotoxic potential compared to cigarettes without the novel carbon filter. The toxicity of the smoke was correlated (r = 0.7662 for cytotoxicity and r = 0.7562 for SCE induction) to the aggregate mass of several vapor phase components (acetone, acetaldehyde, acrolein, acrylonitrile, 1,3-butadiene, ammonia, NOx, HCN, benzene, isoprene, and formaldehyde) in the smoke of the cigarettes utilized in this study. In conclusion, this novel carbon filter, which significantly reduced the amount of carbonyls and other volatiles in mainstream cigarette smoke, resulted in significant reductions in the genotoxic and cytotoxic activity of the smoke as measured by these assays.
{"title":"Evaluation of the genotoxic and cytotoxic potential of mainstream whole smoke and smoke condensate from a cigarette containing a novel carbon filter.","authors":"D. Bombick, B. Bombick, P. Ayres, K. Putnam, J. Avalos, M. Borgerding, D. Doolittle, B. Reed, D. Doolittle","doi":"10.1093/toxsci/39.1.11","DOIUrl":"https://doi.org/10.1093/toxsci/39.1.11","url":null,"abstract":"A novel carbon filter has been developed which primarily reduces the amount of certain vapor phase constituents of tobacco smoke with greater efficiency than the charcoal filters of cigarettes currently in the market. In vitro indicators of genotoxic and cytotoxic potential were used to compare the cigarette smoke condensate (particulate phase) or whole cigarette smoke (vapor phase and particulate phase) from cigarettes containing the novel carbon filter with smoke condensate or whole smoke from commercial or prototype cigarettes not containing the novel carbon filter. Ames bacterial mutagenicity, sister chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells, and neutral red cytotoxicity assays in CHO cells were utilized to assess the genotoxic and cytotoxic potential of the cigarette smoke condensates. SCE and neutral red cytotoxicity assays were utilized to assess the genotoxic and cytotoxic potential of the whole smoke. As expected, the novel carbon filter did not significantly affect the genotoxic or cytotoxic activity of the smoke condensate, although we did observe that the use of low-nitrogen tobacco reduced the mutagenicity of the condensate in Salmonella typhimurium strain TA98. However, the whole smoke from cigarettes containing the novel carbon filter demonstrated significant reductions in genotoxic and cytotoxic potential compared to cigarettes without the novel carbon filter. The toxicity of the smoke was correlated (r = 0.7662 for cytotoxicity and r = 0.7562 for SCE induction) to the aggregate mass of several vapor phase components (acetone, acetaldehyde, acrolein, acrylonitrile, 1,3-butadiene, ammonia, NOx, HCN, benzene, isoprene, and formaldehyde) in the smoke of the cigarettes utilized in this study. In conclusion, this novel carbon filter, which significantly reduced the amount of carbonyls and other volatiles in mainstream cigarette smoke, resulted in significant reductions in the genotoxic and cytotoxic activity of the smoke as measured by these assays.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"17 1","pages":"11-7"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87289826","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}
J. Crowell, J. Page, L. E. Rodman, J. E. Heath, E. Goldenthal, L. Hall, G. Kelloff
The synthetic compound Oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione, is related to the 1,2-dithiolthiones naturally found in cruciferous vegetables, the consumption of which has been epidemiologically associated with reduced frequency of colorectal cancers. Oltipraz has shown chemopreventive efficacy in numerous laboratory epithelial cancer models and is a potential chemopreventive, antimutagenic compound that specifically induces Phase II enzymes. Thirteen-week and 1-year toxicity studies in rats and dogs were performed to characterize the toxicities of the compound at high dosages and to support potential further development as a chemopreventive agent in clinical trials. Administration to rats by gavage for 13 weeks at dosages of 5 and 50 mg/kg/day and for 52 weeks at dosages of 10, 30, and 60 mg/kg/day produced effects on the liver and on clinical chemistry and hematology parameters. Absolute and relative liver weight increases correlated with diffuse hypertrophy in the mid- and high-dose males and centrilobular hypertrophy in the high-dose females. Granularity of hepatocyte cytoplasm was also observed. These anatomical findings were associated with dose-associated slight increases in albumin, total protein, and cholesterol in the males and a moderate increase in cholesterol only in the females. In addition, slight decreases in erythrocyte count, hemoglobin, and hematocrit and reticulocyte elevations occurred. The no effect dose was considered 10 mg/kg/day. Administration by capsule to dogs at dosages of 10 and 100 mg/kg/day for 13 weeks and of 5, 15, and 60 mg/kg/day for 52 weeks also produced effects on the same endpoints noted in the rodent studies. In the 13-week study, precipitate was observed in the bile canaliculi, and gonadal atrophy and increased pituitary weights occurred in the males. Cholesterol and alkaline phosphatase activity were slightly elevated in both studies. Decreased hematology parameters in the 13-week study also occurred. The no effect dose was considered to be 5 mg/kg/day. Oltipraz is being carefully evaluated in clinical trials as a potential antimutagenic compound.
{"title":"Chronic toxicity studies of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione, a potential chemopreventive agent.","authors":"J. Crowell, J. Page, L. E. Rodman, J. E. Heath, E. Goldenthal, L. Hall, G. Kelloff","doi":"10.1093/toxsci/35.1.9","DOIUrl":"https://doi.org/10.1093/toxsci/35.1.9","url":null,"abstract":"The synthetic compound Oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione, is related to the 1,2-dithiolthiones naturally found in cruciferous vegetables, the consumption of which has been epidemiologically associated with reduced frequency of colorectal cancers. Oltipraz has shown chemopreventive efficacy in numerous laboratory epithelial cancer models and is a potential chemopreventive, antimutagenic compound that specifically induces Phase II enzymes. Thirteen-week and 1-year toxicity studies in rats and dogs were performed to characterize the toxicities of the compound at high dosages and to support potential further development as a chemopreventive agent in clinical trials. Administration to rats by gavage for 13 weeks at dosages of 5 and 50 mg/kg/day and for 52 weeks at dosages of 10, 30, and 60 mg/kg/day produced effects on the liver and on clinical chemistry and hematology parameters. Absolute and relative liver weight increases correlated with diffuse hypertrophy in the mid- and high-dose males and centrilobular hypertrophy in the high-dose females. Granularity of hepatocyte cytoplasm was also observed. These anatomical findings were associated with dose-associated slight increases in albumin, total protein, and cholesterol in the males and a moderate increase in cholesterol only in the females. In addition, slight decreases in erythrocyte count, hemoglobin, and hematocrit and reticulocyte elevations occurred. The no effect dose was considered 10 mg/kg/day. Administration by capsule to dogs at dosages of 10 and 100 mg/kg/day for 13 weeks and of 5, 15, and 60 mg/kg/day for 52 weeks also produced effects on the same endpoints noted in the rodent studies. In the 13-week study, precipitate was observed in the bile canaliculi, and gonadal atrophy and increased pituitary weights occurred in the males. Cholesterol and alkaline phosphatase activity were slightly elevated in both studies. Decreased hematology parameters in the 13-week study also occurred. The no effect dose was considered to be 5 mg/kg/day. Oltipraz is being carefully evaluated in clinical trials as a potential antimutagenic compound.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"58 1","pages":"9-21"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85731345","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}
Ruth A. Roberts, D. W. Nebert, John A. Hickman, J. Richburg, Thomas L. Goldsworthy
Perturbations of the balance between cell gain via mitosis and cell loss by apoptosis play a pivotal role in mediating and modifying the action of carcinogens and other toxicants in tissues such as liver, brain, the immune system, the gastrointestinal tract, and the reproductive organs. Apoptosis describes a highly conserved morphology associated with the death of many different cell types from diverse tissues. This symposium focused on induced changes in this critical balance as a key mechanism of action of a variety of diverse toxicants. In the colon, the "toxicology" of 5 fluorouracil (5FU) is entirely dependent on p53, since p53 knockouts lose the pathology of 5FU damage. Presumably, this is because DNA damage is not detected and there is no cell cycle arrest. In the testes, testicular germ cell survival is mediated by adjacent Sertoli cells via the Fas ligand (FasL)-Fas receptor (Fas) system. This system appears to mediate germ cell apoptosis after exposure to testicular toxicants such as the phthalate, mono(2-ethylhexyl) phthalate (MEHP). Interestingly, MEHP is a member of the peroxisome proliferator (PP) class of nongenotoxic carcinogens. PPs perturb both hepatocyte apoptosis and mitosis. This suppression of apoptosis occurs via activation of the peroxisome proliferator-activated receptor alpha (PPARalpha), providing a paradigm for the regulation of liver growth via activation of nuclear receptors. Similarly, the toxicological effects of dioxins are mediated via the Ah receptor (AHR), another ligand-activated nuclear receptor. This receptor upregulates a variety of genes (the Ah gene battery) associated with the toxicology of dioxins. Taken together, the data presented in this symposium illustrate to the toxicologist the need to quantitate and interpret modulations in apoptosis alongside more conventional assessments of S-phase. Although the toxicant may initiate cell damage, genes like Bcl-2, p53, Fas, PPARalpha, and AHR are final arbiters of the choice between death, survival, and proliferation.
{"title":"Perturbation of the mitosis/apoptosis balance: a fundamental mechanism in toxicology.","authors":"Ruth A. Roberts, D. W. Nebert, John A. Hickman, J. Richburg, Thomas L. Goldsworthy","doi":"10.1093/toxsci/38.2.107","DOIUrl":"https://doi.org/10.1093/toxsci/38.2.107","url":null,"abstract":"Perturbations of the balance between cell gain via mitosis and cell loss by apoptosis play a pivotal role in mediating and modifying the action of carcinogens and other toxicants in tissues such as liver, brain, the immune system, the gastrointestinal tract, and the reproductive organs. Apoptosis describes a highly conserved morphology associated with the death of many different cell types from diverse tissues. This symposium focused on induced changes in this critical balance as a key mechanism of action of a variety of diverse toxicants. In the colon, the \"toxicology\" of 5 fluorouracil (5FU) is entirely dependent on p53, since p53 knockouts lose the pathology of 5FU damage. Presumably, this is because DNA damage is not detected and there is no cell cycle arrest. In the testes, testicular germ cell survival is mediated by adjacent Sertoli cells via the Fas ligand (FasL)-Fas receptor (Fas) system. This system appears to mediate germ cell apoptosis after exposure to testicular toxicants such as the phthalate, mono(2-ethylhexyl) phthalate (MEHP). Interestingly, MEHP is a member of the peroxisome proliferator (PP) class of nongenotoxic carcinogens. PPs perturb both hepatocyte apoptosis and mitosis. This suppression of apoptosis occurs via activation of the peroxisome proliferator-activated receptor alpha (PPARalpha), providing a paradigm for the regulation of liver growth via activation of nuclear receptors. Similarly, the toxicological effects of dioxins are mediated via the Ah receptor (AHR), another ligand-activated nuclear receptor. This receptor upregulates a variety of genes (the Ah gene battery) associated with the toxicology of dioxins. Taken together, the data presented in this symposium illustrate to the toxicologist the need to quantitate and interpret modulations in apoptosis alongside more conventional assessments of S-phase. Although the toxicant may initiate cell damage, genes like Bcl-2, p53, Fas, PPARalpha, and AHR are final arbiters of the choice between death, survival, and proliferation.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"15 1","pages":"107-15"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74627046","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}
Nobuyuki Nishida, Jackie D. Farmer, Prasad R. S. Kodavanti, Hugh A. Tilson, R. Macphail
While considerable research has focused on the neurotoxicity of developmental exposures to polychlorinated biphenyls, including Aroclor 1254, relatively little is known about exposures in adult animals. This study investigated the behavioral effects of acute and repeated Aroclor 1254 exposures to adult rats on motor activity and flavor aversion conditioning. Male Long-Evans rats (60 days old) were tested for motor activity in a photocell device after acute (0, 100, 300, or 1000 mg/kg, p.o.) or repeated (0, 1, 3, 10, 30 or 100 mg/kg/day, po, 5 days/week for 4 to 6 weeks exposure to Aroclor 1254. Motor activity was decreased dose-dependently at doses of 300 mg/kg or more after acute exposure. Severe body weight loss and deaths occurred at 1000 mg/kg. Recovery of activity occurred over 9 weeks but was incomplete. After repeated exposure, motor activity was decreased dose-dependently at doses of 30 mg/kg or more, and severe weight loss and deaths occurred at 100 mg/kg. In contrast to acute exposure, complete recovery of activity occurred 3 weeks after exposure. Additional rats were water deprived (30 min/day) and received acute po administration of Aroclor 1254 (0, 10, 15, 25, 30, 100, or 300 mg/kg) shortly after consuming a saccharin solution. Three days later they were given the choice between consuming saccharin or water, and saccharin preferences were recorded. Saccharin preference was decreased at doses of 25 mg/kg or more. Additional experiments determined the effect of repeated saccharin-Aroclor 1254 pairings (0, 3.75, 7.5, or 15 mg/kg/day, 14 days) followed by a choice test 1 day after the last dose. Repeated exposure to 15 mg/kg produced robust flavor aversion conditioning. Repeated exposure to 7.5 mg/kg produced flavor aversion conditioning in four of 12 rats. These results demonstrate that Aroclor 1254 causes hypoactivity and flavor aversions in adult rats; the no observable effect level (NOEL) for motor activity was 100 mg/kg for acute exposure and 10 mg/kg for repeated exposure for a period of up to 6 weeks. The acute NOEL for flavor aversion conditioning was 15 mg/kg while the repeated NOEL was 7.5 mg/kg.
{"title":"Effects of acute and repeated exposures to Aroclor 1254 in adult rats: motor activity and flavor aversion conditioning.","authors":"Nobuyuki Nishida, Jackie D. Farmer, Prasad R. S. Kodavanti, Hugh A. Tilson, R. Macphail","doi":"10.1093/toxsci/40.1.68","DOIUrl":"https://doi.org/10.1093/toxsci/40.1.68","url":null,"abstract":"While considerable research has focused on the neurotoxicity of developmental exposures to polychlorinated biphenyls, including Aroclor 1254, relatively little is known about exposures in adult animals. This study investigated the behavioral effects of acute and repeated Aroclor 1254 exposures to adult rats on motor activity and flavor aversion conditioning. Male Long-Evans rats (60 days old) were tested for motor activity in a photocell device after acute (0, 100, 300, or 1000 mg/kg, p.o.) or repeated (0, 1, 3, 10, 30 or 100 mg/kg/day, po, 5 days/week for 4 to 6 weeks exposure to Aroclor 1254. Motor activity was decreased dose-dependently at doses of 300 mg/kg or more after acute exposure. Severe body weight loss and deaths occurred at 1000 mg/kg. Recovery of activity occurred over 9 weeks but was incomplete. After repeated exposure, motor activity was decreased dose-dependently at doses of 30 mg/kg or more, and severe weight loss and deaths occurred at 100 mg/kg. In contrast to acute exposure, complete recovery of activity occurred 3 weeks after exposure. Additional rats were water deprived (30 min/day) and received acute po administration of Aroclor 1254 (0, 10, 15, 25, 30, 100, or 300 mg/kg) shortly after consuming a saccharin solution. Three days later they were given the choice between consuming saccharin or water, and saccharin preferences were recorded. Saccharin preference was decreased at doses of 25 mg/kg or more. Additional experiments determined the effect of repeated saccharin-Aroclor 1254 pairings (0, 3.75, 7.5, or 15 mg/kg/day, 14 days) followed by a choice test 1 day after the last dose. Repeated exposure to 15 mg/kg produced robust flavor aversion conditioning. Repeated exposure to 7.5 mg/kg produced flavor aversion conditioning in four of 12 rats. These results demonstrate that Aroclor 1254 causes hypoactivity and flavor aversions in adult rats; the no observable effect level (NOEL) for motor activity was 100 mg/kg for acute exposure and 10 mg/kg for repeated exposure for a period of up to 6 weeks. The acute NOEL for flavor aversion conditioning was 15 mg/kg while the repeated NOEL was 7.5 mg/kg.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"57 1","pages":"68-74"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84872023","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}
Several chronic inhalation bioassays of poorly soluble, nonfibrous particles have resulted in an increased incidence of lung tumors in rats, no increase in lung tumors in Syrian hamsters, and inconsistent results in mice. These results have raised concerns that rats may be more prone than other species to develop persistent pulmonary epithelial hyperplasia, metaplasia, and tumors in response to the accumulation of inhaled particles. In addition, particle deposition and the rate of particle clearance from the lung differ between rats and primates, as does the anatomy of the centriacinar region. For these reasons, the usefulness of pulmonary carcinogenicity data from rats exposed to high concentrations of particles for quantitatively predicting lung cancer risk in humans exposed to much lower environmental or occupational concentrations has been questioned. The purpose of this investigation was to directly compare the anatomical patterns of particle retention and the lung tissue responses of rats and monkeys exposed chronically to high occupational concentrations of poorly soluble particles. Lung sections from male cynomolgus monkeys and F344 rats exposed 7 hr/day, 5 days/week for 24 months to filtered ambient air, diesel exhaust (2 mg soot/m3), coal dust (2 mg respirable particulate material/m3), or diesel exhaust and coal dust combined (1 mg soot and 1 mg respirable coal dust/m3) were examined histopathologically. The relative volume density of particulate material and the volume percentage of the total particulate material in defined pulmonary compartments were determined morphometrically to assess the relative amount and the anatomic distribution of retained particulate material. In all groups, relatively more particulate material was retained in monkey than in rat lungs. After adjustment for differences between rat and monkey controls, the coal dust- and the combined diesel exhaust and coal dust-exposed monkeys retained more particulate material than the coal dust- and the combined diesel exhaust and coal dust-exposed rats, respectively. There was no significant difference in the relative amount of retained particulate material between diesel exhaust-exposed monkeys and rats. Within each species, the sites of particle retention and lung tissue responses were the same for diesel soot, coal dust, and the combined material. Rats retained a greater portion of the particulate material in lumens of alveolar ducts and alveoli than monkeys. Conversely, monkeys retained a greater portion of the particulate material in the interstitium than rats. Rats, but not monkeys, had significant alveolar epithelial hyperplastic, inflammatory, and septal fibrotic responses to the retained particles. These results suggest that intrapulmonary particle retention patterns and tissue reactions in rats may not be predictive of retention patterns and tissue responses in primates exposed to poorly soluble particles at concentrations representing high occupational exposures
{"title":"Lung tissue responses and sites of particle retention differ between rats and cynomolgus monkeys exposed chronically to diesel exhaust and coal dust.","authors":"K. Nikula, K. Ávila, W. Griffith, Joe, Mauderly","doi":"10.1093/toxsci/37.1.37","DOIUrl":"https://doi.org/10.1093/toxsci/37.1.37","url":null,"abstract":"Several chronic inhalation bioassays of poorly soluble, nonfibrous particles have resulted in an increased incidence of lung tumors in rats, no increase in lung tumors in Syrian hamsters, and inconsistent results in mice. These results have raised concerns that rats may be more prone than other species to develop persistent pulmonary epithelial hyperplasia, metaplasia, and tumors in response to the accumulation of inhaled particles. In addition, particle deposition and the rate of particle clearance from the lung differ between rats and primates, as does the anatomy of the centriacinar region. For these reasons, the usefulness of pulmonary carcinogenicity data from rats exposed to high concentrations of particles for quantitatively predicting lung cancer risk in humans exposed to much lower environmental or occupational concentrations has been questioned. The purpose of this investigation was to directly compare the anatomical patterns of particle retention and the lung tissue responses of rats and monkeys exposed chronically to high occupational concentrations of poorly soluble particles. Lung sections from male cynomolgus monkeys and F344 rats exposed 7 hr/day, 5 days/week for 24 months to filtered ambient air, diesel exhaust (2 mg soot/m3), coal dust (2 mg respirable particulate material/m3), or diesel exhaust and coal dust combined (1 mg soot and 1 mg respirable coal dust/m3) were examined histopathologically. The relative volume density of particulate material and the volume percentage of the total particulate material in defined pulmonary compartments were determined morphometrically to assess the relative amount and the anatomic distribution of retained particulate material. In all groups, relatively more particulate material was retained in monkey than in rat lungs. After adjustment for differences between rat and monkey controls, the coal dust- and the combined diesel exhaust and coal dust-exposed monkeys retained more particulate material than the coal dust- and the combined diesel exhaust and coal dust-exposed rats, respectively. There was no significant difference in the relative amount of retained particulate material between diesel exhaust-exposed monkeys and rats. Within each species, the sites of particle retention and lung tissue responses were the same for diesel soot, coal dust, and the combined material. Rats retained a greater portion of the particulate material in lumens of alveolar ducts and alveoli than monkeys. Conversely, monkeys retained a greater portion of the particulate material in the interstitium than rats. Rats, but not monkeys, had significant alveolar epithelial hyperplastic, inflammatory, and septal fibrotic responses to the retained particles. These results suggest that intrapulmonary particle retention patterns and tissue reactions in rats may not be predictive of retention patterns and tissue responses in primates exposed to poorly soluble particles at concentrations representing high occupational exposures","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"6 1","pages":"37-53"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80171223","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}
Jack B. Bishop, Richard W. Morris, John C. Seely, L. Hughes, K. Cain, W. Generoso
Chemicals, by virtue of their varied interactions with biological molecules, are expected to differ in the way they may alter female reproduction. Reproductive toxicity may reflect effects either on the female germ cells or on various maternal processes such as ovulation, implantation, pregnancy, and parturition. In either case, the ultimate manifestation of chemical toxicity on female reproduction is a decrease in the number of normal young born. Very little information is available on the effects of chemicals that are nonhormonal in nature on the long-term ability of treated females to produce offspring. This report presents the results of long-term female total reproductive capacity (TRC) tests on 29 chemicals, including pharmaceuticals, pesticides, and alkylating and industrial agents. For each chemical, the minimum test involved an evaluation of the maximum tolerated dose administered as a single intraperitoneal injection. Females were single-pair mated with an untreated male for most of the female's reproductive life span (a minimum of 347 days posttreatment) and scored for the number of live births produced during this period. Confirmatory dominant lethal experiments or histological examinations for numbers of small follicles were carried out when mutagenic effects or cytotoxicity, respectively, were suspected as the basis for reduced fertility. Of the 29 chemicals studied, 17 had reproductive effects which may be grouped into one of three classes: (1) those that reduced the total number of young and litters per female, (2) those that reduced the total number of young but not of litters, and (3) those that had no significant effect on the total number of young produced but reduced the size of the first and/or second litters. The TRC provides a capacity for detecting a range of toxic insults upon female reproduction. Many of the chemicals were indeed shown to affect the reproductive performance of females through mutagenic and/or cytotoxic effects on follicles. In some cases, however, no causative mechanism could be identified for the observed reduction in reproductive performance. Nevertheless, with this report the number of chemicals tested by this TRC procedure has been quadrupled and the categories of chemicals tested have been substantially broadened.
{"title":"Alterations in the reproductive patterns of female mice exposed to xenobiotics.","authors":"Jack B. Bishop, Richard W. Morris, John C. Seely, L. Hughes, K. Cain, W. Generoso","doi":"10.1093/toxsci/40.2.191","DOIUrl":"https://doi.org/10.1093/toxsci/40.2.191","url":null,"abstract":"Chemicals, by virtue of their varied interactions with biological molecules, are expected to differ in the way they may alter female reproduction. Reproductive toxicity may reflect effects either on the female germ cells or on various maternal processes such as ovulation, implantation, pregnancy, and parturition. In either case, the ultimate manifestation of chemical toxicity on female reproduction is a decrease in the number of normal young born. Very little information is available on the effects of chemicals that are nonhormonal in nature on the long-term ability of treated females to produce offspring. This report presents the results of long-term female total reproductive capacity (TRC) tests on 29 chemicals, including pharmaceuticals, pesticides, and alkylating and industrial agents. For each chemical, the minimum test involved an evaluation of the maximum tolerated dose administered as a single intraperitoneal injection. Females were single-pair mated with an untreated male for most of the female's reproductive life span (a minimum of 347 days posttreatment) and scored for the number of live births produced during this period. Confirmatory dominant lethal experiments or histological examinations for numbers of small follicles were carried out when mutagenic effects or cytotoxicity, respectively, were suspected as the basis for reduced fertility. Of the 29 chemicals studied, 17 had reproductive effects which may be grouped into one of three classes: (1) those that reduced the total number of young and litters per female, (2) those that reduced the total number of young but not of litters, and (3) those that had no significant effect on the total number of young produced but reduced the size of the first and/or second litters. The TRC provides a capacity for detecting a range of toxic insults upon female reproduction. Many of the chemicals were indeed shown to affect the reproductive performance of females through mutagenic and/or cytotoxic effects on follicles. In some cases, however, no causative mechanism could be identified for the observed reduction in reproductive performance. Nevertheless, with this report the number of chemicals tested by this TRC procedure has been quadrupled and the categories of chemicals tested have been substantially broadened.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"22 1","pages":"191-204"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86542273","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}
R. Corley, D. Markham, C. Banks, P. Delorme, A. Masterman, J. Houle
It has generally been assumed that the skin contributes only minor amounts to the total uptake of solvent vapors, relative to the respiratory tract. Contrary to this assumption, the widely used glycol ether solvent, 2-butoxyethanol (BE), has been reported to be more effectively absorbed through the skin (75% of the total uptake) than through the lungs of humans (Johanson and Boman, 1991, Br. J. Ind. Med. 48, 788). The possibility that the finger prick blood sampling technique used in the Johanson and Boman study was confounded by locally high concentrations of BE at the site of absorption was suggested using a previously developed PBPK model (Corley et al., 1994, Toxicol. Appl. Pharmacol. 129, 61). The current study was conducted to verify the PBPK analysis and to determine whether or not the skin was the major site for absorption of BE vapor by exposing one arm from each of six human volunteers to 50 ppm 13C2-BE vapor for 2 hr. To evaluate the potential consequences of blood sampling techniques, samples were taken from both the unexposed arm (catheter; during and after exposure) and the exposed arm (finger prick; end of the exposure only) for analysis of both BE and its major metabolite, butoxyacetic acid (BAA). Butoxyacetic acid is responsible for the hemolysis observed in toxicity studies with laboratory animals. Humans, however, are significantly less sensitive to this effect. The concentration of BE in the finger prick blood samples averaged 1500 times higher than the corresponding concentration in venous blood sampled from a catheter installed in the unexposed arm at the end of the exposure. Blood BAA levels were generally within a factor of 4 of each other for the two techniques and, therefore, was considered a better indicator of systemic absorption. Urine was collected for 24 hr and analyzed for the following metabolites found in rat metabolism studies: free and conjugated BE, BAA, ethylene glycol (EG), and glycolic acid (GA), with only BAA detected in the human urine. More importantly, urinary BAA was found to be extensively conjugated ( approximately 67%) with glutamine, confirming recent reports. These results, coupled with PBPK modeling of worst-case exposure scenarios (no clothing, 100% of the body was exposed), demonstrated that no more than 15-27% (low-to-high relative temperatures and humidities), not 75%, of the total uptake of BE could be attributed to the skin of humans during simulated 8-hr exposures to the ACGIH TLV concentration of 25 ppm. Even less of the total uptake was attributed to the skin during simulations of exercise with whole-body exposures (5-9%) or by more realistic exposures of only the arms and head (1-8%). As a result, humans are unlikely to reach hemolytic concentrations of the metabolite BAA in blood following vapor exposures to BE.
一般认为，相对于呼吸道，皮肤对溶剂蒸气的总吸收率只有很小的贡献。与这一假设相反，据报道，广泛使用的乙二醇醚溶剂2-丁氧基乙醇(BE)通过皮肤吸收(占总吸取量的75%)比通过人体肺部吸收更有效(Johanson和Boman, 1991, Br。中华医学杂志，48,788)。使用先前开发的PBPK模型(Corley et al.， 1994, Toxicol)表明，Johanson和Boman研究中使用的手指刺血取样技术可能与吸收部位局部高浓度BE相混淆。达成。药学。129,61)。目前的研究是为了验证PBPK分析，并确定皮肤是否是吸收BE蒸气的主要部位，方法是将6名志愿者中的每名志愿者的一只手臂暴露在50 ppm的13C2-BE蒸气中2小时。为了评估血液采样技术的潜在后果，从未暴露的手臂(导管;暴露期间和之后)和暴露的手臂(手指刺痛;仅在暴露结束时)进行BE及其主要代谢物丁氧乙酸(BAA)的分析。在实验室动物毒性研究中发现，丁氧基乙酸是导致溶血的原因。然而，人类对这种影响明显不那么敏感。暴露结束时，手指刺血样本中BE的浓度平均比未暴露手臂上的导管中静脉血的浓度高1500倍。两种方法的血BAA水平一般相差在4倍以内，因此被认为是更好的全身吸收指标。收集尿液24小时，分析在大鼠代谢研究中发现的以下代谢物:游离和共轭BE, BAA，乙二醇(EG)和乙醇酸(GA)，仅在人尿中检测到BAA。更重要的是，尿BAA被发现与谷氨酰胺广泛结合(约67%)，证实了最近的报道。这些结果，加上PBPK模拟的最坏情况暴露情景(不穿衣服，100%的身体暴露)，表明在模拟的8小时暴露于25ppm的ACGIH TLV浓度下，人体皮肤吸收的BE总量不超过15-27%(低到高的相对温度和湿度)，而不是75%。在模拟全身暴露运动时，皮肤吸收的总剂量更少(5-9%)，而在更现实的情况下，只暴露在手臂和头部(1-8%)。因此，在蒸汽暴露于BE后，人类不太可能达到血液中代谢产物BAA的溶血浓度。
{"title":"Physiologically based pharmacokinetics and the dermal absorption of 2-butoxyethanol vapor by humans.","authors":"R. Corley, D. Markham, C. Banks, P. Delorme, A. Masterman, J. Houle","doi":"10.1093/toxsci/39.2.120","DOIUrl":"https://doi.org/10.1093/toxsci/39.2.120","url":null,"abstract":"It has generally been assumed that the skin contributes only minor amounts to the total uptake of solvent vapors, relative to the respiratory tract. Contrary to this assumption, the widely used glycol ether solvent, 2-butoxyethanol (BE), has been reported to be more effectively absorbed through the skin (75% of the total uptake) than through the lungs of humans (Johanson and Boman, 1991, Br. J. Ind. Med. 48, 788). The possibility that the finger prick blood sampling technique used in the Johanson and Boman study was confounded by locally high concentrations of BE at the site of absorption was suggested using a previously developed PBPK model (Corley et al., 1994, Toxicol. Appl. Pharmacol. 129, 61). The current study was conducted to verify the PBPK analysis and to determine whether or not the skin was the major site for absorption of BE vapor by exposing one arm from each of six human volunteers to 50 ppm 13C2-BE vapor for 2 hr. To evaluate the potential consequences of blood sampling techniques, samples were taken from both the unexposed arm (catheter; during and after exposure) and the exposed arm (finger prick; end of the exposure only) for analysis of both BE and its major metabolite, butoxyacetic acid (BAA). Butoxyacetic acid is responsible for the hemolysis observed in toxicity studies with laboratory animals. Humans, however, are significantly less sensitive to this effect. The concentration of BE in the finger prick blood samples averaged 1500 times higher than the corresponding concentration in venous blood sampled from a catheter installed in the unexposed arm at the end of the exposure. Blood BAA levels were generally within a factor of 4 of each other for the two techniques and, therefore, was considered a better indicator of systemic absorption. Urine was collected for 24 hr and analyzed for the following metabolites found in rat metabolism studies: free and conjugated BE, BAA, ethylene glycol (EG), and glycolic acid (GA), with only BAA detected in the human urine. More importantly, urinary BAA was found to be extensively conjugated ( approximately 67%) with glutamine, confirming recent reports. These results, coupled with PBPK modeling of worst-case exposure scenarios (no clothing, 100% of the body was exposed), demonstrated that no more than 15-27% (low-to-high relative temperatures and humidities), not 75%, of the total uptake of BE could be attributed to the skin of humans during simulated 8-hr exposures to the ACGIH TLV concentration of 25 ppm. Even less of the total uptake was attributed to the skin during simulations of exercise with whole-body exposures (5-9%) or by more realistic exposures of only the arms and head (1-8%). As a result, humans are unlikely to reach hemolytic concentrations of the metabolite BAA in blood following vapor exposures to BE.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"52 1","pages":"120-30"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85403014","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}
Concomitant treatment of rats with a nonhepatotoxic dose of dichloromethane (6 mmol/kg, i.p.) significantly potentiated the hepatotoxicity of carbon tetrachloride (2 mmol/kg, i.p.). Toxicity was determined by increases in serum sorbitol dehydrogenase and alanine aminotransferase activities measured 24 hr following the treatments. Dichloromethane did not affect the lipid peroxidation induced by carbon tetrachloride as determined by conjugated diene formation in hepatic microsomal lipids. The covalent binding of [14C]Cl4 metabolites to microsomal lipids was increased significantly by dichloromethane. The results suggest that dichloromethane potentiates carbon tetrachloride hepatotoxicity by increasing covalent binding of its metabolites to hepatic microsomal lipids.
{"title":"Dichloromethane potentiation of carbon tetrachloride hepatotoxicity in rats.","authors":"Young Chul Kim","doi":"10.1093/TOXSCI/35.1.138","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.1.138","url":null,"abstract":"Concomitant treatment of rats with a nonhepatotoxic dose of dichloromethane (6 mmol/kg, i.p.) significantly potentiated the hepatotoxicity of carbon tetrachloride (2 mmol/kg, i.p.). Toxicity was determined by increases in serum sorbitol dehydrogenase and alanine aminotransferase activities measured 24 hr following the treatments. Dichloromethane did not affect the lipid peroxidation induced by carbon tetrachloride as determined by conjugated diene formation in hepatic microsomal lipids. The covalent binding of [14C]Cl4 metabolites to microsomal lipids was increased significantly by dichloromethane. The results suggest that dichloromethane potentiates carbon tetrachloride hepatotoxicity by increasing covalent binding of its metabolites to hepatic microsomal lipids.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"20 1","pages":"138-41"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81735061","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. Daher, K. Lawson, P. H. Long, D. Tallmadge, A. Boothe, P. Vanderploeg, K. W. Miller
Female guinea pigs (12/group) were given a single dose of [14C]olestra by gavage after consuming either 3% poligeenan in tap water (Compromised group) or just tap water (Normal group) for 5 weeks. A Sentinel group (N = 2) was given 3% poligeenan for 5 weeks. Ten sentinel animals were killed 1 day before and 10 1 day after the other animals were dosed with [14C]olestra and their gastrointestinal tracts were examined by histology. The Compromised and Normal animals were endoscoped just before dosing with [14C]olestra. Urine and feces were collected continuously and CO2 was collected for 7 days after dosing. The samples were analyzed for 14C and urine was also analyzed for [14C]sucrose. Animals (3/group) were killed 1, 3, 7, and 21 days after dosing, and tissues were collected and assayed for 14C. Tissue lipids were extracted, fractionated by high-pressure liquid chromatography, and analyzed for [14C]olestra by liquid scintillation. Animals fed poligeenan showed mucosal edema, congestion, ulceration, and fibrin deposition within the distal colon and rectum. Histology revealed inflammation, epithelial degeneration, and multifocal ulceration of the cecum, distal colon, and rectum. The gastrointestinal mucosae of nonpoligeenan fed animals were normal. No [14C]olestra was detected in liver lipids and no [14C]sucrose was found in the urine for any animal in the Normal or Compromised groups, indicating that intact olestra was not absorbed. The amount, distribution, and elimination of absorbed 14C did not differ between guinea pigs with normal and compromised gastrointestinal tracts. The poligeenan-treated animals displayed mucosal damage similar to that seen in human inflammatory bowel diseases; therefore, these results suggest that patients with inflammatory bowel conditions will not absorb olestra to any greater extent than normal healthy people.
{"title":"Comparison of olestra absorption in guinea pigs with normal and compromised gastrointestinal tracts.","authors":"G. Daher, K. Lawson, P. H. Long, D. Tallmadge, A. Boothe, P. Vanderploeg, K. W. Miller","doi":"10.1093/toxsci/39.2.138","DOIUrl":"https://doi.org/10.1093/toxsci/39.2.138","url":null,"abstract":"Female guinea pigs (12/group) were given a single dose of [14C]olestra by gavage after consuming either 3% poligeenan in tap water (Compromised group) or just tap water (Normal group) for 5 weeks. A Sentinel group (N = 2) was given 3% poligeenan for 5 weeks. Ten sentinel animals were killed 1 day before and 10 1 day after the other animals were dosed with [14C]olestra and their gastrointestinal tracts were examined by histology. The Compromised and Normal animals were endoscoped just before dosing with [14C]olestra. Urine and feces were collected continuously and CO2 was collected for 7 days after dosing. The samples were analyzed for 14C and urine was also analyzed for [14C]sucrose. Animals (3/group) were killed 1, 3, 7, and 21 days after dosing, and tissues were collected and assayed for 14C. Tissue lipids were extracted, fractionated by high-pressure liquid chromatography, and analyzed for [14C]olestra by liquid scintillation. Animals fed poligeenan showed mucosal edema, congestion, ulceration, and fibrin deposition within the distal colon and rectum. Histology revealed inflammation, epithelial degeneration, and multifocal ulceration of the cecum, distal colon, and rectum. The gastrointestinal mucosae of nonpoligeenan fed animals were normal. No [14C]olestra was detected in liver lipids and no [14C]sucrose was found in the urine for any animal in the Normal or Compromised groups, indicating that intact olestra was not absorbed. The amount, distribution, and elimination of absorbed 14C did not differ between guinea pigs with normal and compromised gastrointestinal tracts. The poligeenan-treated animals displayed mucosal damage similar to that seen in human inflammatory bowel diseases; therefore, these results suggest that patients with inflammatory bowel conditions will not absorb olestra to any greater extent than normal healthy people.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"105 1","pages":"138-47"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87738966","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}
Hydroquinone (HQ), catechol, and phenol exist in microgram quantities in cigarette tar and represent the predominant form of human exposure to benzene. Exposure of human T lymphoblasts (HTL) in vitro to 50 microM HQ or 50 microM catechol decreased IL-2-dependent DNA synthesis and cell proliferation by >90% with no effect on cell viability. Phenol had no effect on HTL proliferation at concentrations up to 1 mm. The addition of HQ or catechol to proliferating HTL blocked 3H-TdR uptake by >90% within 2 hr without significantly affecting 3H-UR uptake, suggesting that both compounds inhibit a rate-limiting step in DNA synthesis. However, the effects of HQ and catechol appear to involve different mechanisms. Ferric chloride (FeCl3) reversed the inhibitory effect of catechol, but not HQ, corresponding with the known ability of catechol to chelate iron. HQ, but not catechol, caused a decrease in transferrin receptor (TfR, CD71) expression, comparable to the level observed in IL-2-starved cells. HQ also inhibited DNA synthesis in cultures of transformed Jurkat T lymphocytes, primary and transformed fibroblasts, and mink lung epithelial cells, indicating that its antiproliferative effect was not restricted to IL-2 mediated proliferation. However, DNA synthesis by primary lymphocytes was more sensitive to HQ (IC50 = 6 microM) than that of the transformed Jurkat T cell line (IC50 = 37 microM) or primary human fibroblasts (IC50 = 45 microM), suggesting that normal lymphocytes may be particularly sensitive to HQ. The effects of HQ and catechol on DNA synthesis could be partially reversed by a combination of adenosine deoxyribose and guanosine deoxyribose, suggesting that both compounds may inhibit ribonucleotide reductase.
{"title":"Differential inhibition of DNA synthesis in human T cells by the cigarette tar components hydroquinone and catechol.","authors":"Q. Li, M. Aubrey, T. Christian, B. Freed","doi":"10.1093/toxsci/38.2.158","DOIUrl":"https://doi.org/10.1093/toxsci/38.2.158","url":null,"abstract":"Hydroquinone (HQ), catechol, and phenol exist in microgram quantities in cigarette tar and represent the predominant form of human exposure to benzene. Exposure of human T lymphoblasts (HTL) in vitro to 50 microM HQ or 50 microM catechol decreased IL-2-dependent DNA synthesis and cell proliferation by >90% with no effect on cell viability. Phenol had no effect on HTL proliferation at concentrations up to 1 mm. The addition of HQ or catechol to proliferating HTL blocked 3H-TdR uptake by >90% within 2 hr without significantly affecting 3H-UR uptake, suggesting that both compounds inhibit a rate-limiting step in DNA synthesis. However, the effects of HQ and catechol appear to involve different mechanisms. Ferric chloride (FeCl3) reversed the inhibitory effect of catechol, but not HQ, corresponding with the known ability of catechol to chelate iron. HQ, but not catechol, caused a decrease in transferrin receptor (TfR, CD71) expression, comparable to the level observed in IL-2-starved cells. HQ also inhibited DNA synthesis in cultures of transformed Jurkat T lymphocytes, primary and transformed fibroblasts, and mink lung epithelial cells, indicating that its antiproliferative effect was not restricted to IL-2 mediated proliferation. However, DNA synthesis by primary lymphocytes was more sensitive to HQ (IC50 = 6 microM) than that of the transformed Jurkat T cell line (IC50 = 37 microM) or primary human fibroblasts (IC50 = 45 microM), suggesting that normal lymphocytes may be particularly sensitive to HQ. The effects of HQ and catechol on DNA synthesis could be partially reversed by a combination of adenosine deoxyribose and guanosine deoxyribose, suggesting that both compounds may inhibit ribonucleotide reductase.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"28 14 1","pages":"158-65"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90561761","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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