{"title":"Author Index for Volume 37","authors":"","doi":"10.1006/faat.1997.2333","DOIUrl":"https://doi.org/10.1006/faat.1997.2333","url":null,"abstract":"","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Page 190"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2333","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137367593","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}
Manganese chloride (50–800 μg) was injected unilaterally into the right nostril of rats and its accumulation in the central nervous system (CNS) was monitored. Brain manganese levels were elevated in a dose-dependent, time-dependent, and tissue-dependent manner. Elevated levels of manganese were detected in the right olfactory bulb and olfactory tubercle within 12 hr after instillation and remained elevated for at least 3 days. As little as 100 μg of manganese chloride was sufficient to increase brain manganese levels. No changes were detected on the left side of the brain. The manganese content of the striatum, the target site for manganese neurotoxicity, was unchanged following acute administration, but was elevated when two injections were made 1 week apart. These results suggest that air-borne manganese can be retrogradely transported along olfactory neurons to the CNS and can reach deeper brain structures under appropriate exposure conditions.
{"title":"Accumulation of Manganese in Rat Brain Following Intranasal Administration","authors":"Gerald Gianutsos, Gale R. Morrow, John B. Morris","doi":"10.1006/faat.1997.2306","DOIUrl":"10.1006/faat.1997.2306","url":null,"abstract":"<div><p>Manganese chloride (50–800 μg) was injected unilaterally into the right nostril of rats and its accumulation in the central nervous system (CNS) was monitored. Brain manganese levels were elevated in a dose-dependent, time-dependent, and tissue-dependent manner. Elevated levels of manganese were detected in the right olfactory bulb and olfactory tubercle within 12 hr after instillation and remained elevated for at least 3 days. As little as 100 μg of manganese chloride was sufficient to increase brain manganese levels. No changes were detected on the left side of the brain. The manganese content of the striatum, the target site for manganese neurotoxicity, was unchanged following acute administration, but was elevated when two injections were made 1 week apart. These results suggest that air-borne manganese can be retrogradely transported along olfactory neurons to the CNS and can reach deeper brain structures under appropriate exposure conditions.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 102-105"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20186437","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}
The effect that cotreatment with 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has on the antibody plaque-forming cell (PFC) response to sheep red blood cells (SRBCs) was determined in female B6C3F1 mice. Groups of eight mice per group were given a single oral dose of PCB153 alone (0, 3.58, 35.8, or 358 mg/kg), TCDD alone (0, 0.1, 1, or 10 μg/kg), and all possible combinations of these doses in corn oil 7 days prior to immunization with SRBCs. Separate groups of mice were given phenobarbital (PB) parenterally by intraperitoneal injection at a dosage of 160 mg/kg/day for 3 days. Four days after intravenous immunization, body, spleen, thymus, and liver weights and the PFC response to SRBCs were determined. Exposure to TCDD alone resulted in a dose-related suppression of the PFC response, with significant suppression at 1 and 10 μg/kg. In contrast, exposure to PCB153 alone resulted in the enhancement of the PFC response at 358 mg/kg. Combined exposure to 358 mg/kg PCB153 and TCDD resulted in no change (PCB153 + 0.1 μg/kg TCDD) or suppression (PCB153 + 1 or 10 μg/kg TCDD) of the PFC response relative to PCB153 alone; however, the PFC response was enhanced (PCB153 + 0.1 μg/kg TCDD), unaffected (PCB153 + 1 μg/kg TCDD), or suppressed (PCB153 + 10 μg/kg TCDD) relative to corn oil controls. PB did not affect the PFC response to SRBCs, despite a 13-fold induction of hepatic pentoxyresorufinO-dealkylase (PROD) activity. These results suggest that PCB153 enhancement of the PFC response is not related to PROD induction and that it acts as a functional antagonist rather than an aryl hydrocarbon receptor or dispositional antagonist. By enhancing the PFC response to SRBCs, PCB153 raises the “setpoint” response level. Consequently, cotreatment with an immunosuppressive dose of TCDD fails to suppress the PFC response relative to corn oil controls, while clearly suppressing it relative to the appropriate control, PCB153 alone.
{"title":"Opposite Effects of 2,2′,4,4′,5,5′-Hexachlorobiphenyl and 2,3,7,8-Tetrachlorodibenzo-p-dioxin on the Antibody Response to Sheep Erythrocytes in Mice","authors":"R.J. Smialowicz , M.J. Devito, M.M. Riddle, W.C. Williams, L.S. Birnbaum","doi":"10.1006/faat.1997.2323","DOIUrl":"10.1006/faat.1997.2323","url":null,"abstract":"<div><p>The effect that cotreatment with 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) and 2,3,7,8-tetrachlorodibenzo-<em>p</em>-dioxin (TCDD) has on the antibody plaque-forming cell (PFC) response to sheep red blood cells (SRBCs) was determined in female B6C3F1 mice. Groups of eight mice per group were given a single oral dose of PCB153 alone (0, 3.58, 35.8, or 358 mg/kg), TCDD alone (0, 0.1, 1, or 10 μg/kg), and all possible combinations of these doses in corn oil 7 days prior to immunization with SRBCs. Separate groups of mice were given phenobarbital (PB) parenterally by intraperitoneal injection at a dosage of 160 mg/kg/day for 3 days. Four days after intravenous immunization, body, spleen, thymus, and liver weights and the PFC response to SRBCs were determined. Exposure to TCDD alone resulted in a dose-related suppression of the PFC response, with significant suppression at 1 and 10 μg/kg. In contrast, exposure to PCB153 alone resulted in the enhancement of the PFC response at 358 mg/kg. Combined exposure to 358 mg/kg PCB153 and TCDD resulted in no change (PCB153 + 0.1 μg/kg TCDD) or suppression (PCB153 + 1 or 10 μg/kg TCDD) of the PFC response relative to PCB153 alone; however, the PFC response was enhanced (PCB153 + 0.1 μg/kg TCDD), unaffected (PCB153 + 1 μg/kg TCDD), or suppressed (PCB153 + 10 μg/kg TCDD) relative to corn oil controls. PB did not affect the PFC response to SRBCs, despite a 13-fold induction of hepatic pentoxyresorufin<em>O</em>-dealkylase (PROD) activity. These results suggest that PCB153 enhancement of the PFC response is not related to PROD induction and that it acts as a functional antagonist rather than an aryl hydrocarbon receptor or dispositional antagonist. By enhancing the PFC response to SRBCs, PCB153 raises the “setpoint” response level. Consequently, cotreatment with an immunosuppressive dose of TCDD fails to suppress the PFC response relative to corn oil controls, while clearly suppressing it relative to the appropriate control, PCB153 alone.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 141-149"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20187037","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}
Kristen J. Nikula, Kelly J. Avila, William C. Griffith, Joe L. Mauderly
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
{"title":"Lung Tissue Responses and Sites of Particle Retention Differ between Rats and Cynomolgus Monkeys Exposed Chronically to Diesel Exhaust and Coal Dust","authors":"Kristen J. Nikula, Kelly J. Avila, William C. Griffith, Joe L. Mauderly","doi":"10.1006/faat.1997.2297","DOIUrl":"10.1006/faat.1997.2297","url":null,"abstract":"<div><p>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/m<sup>3</sup>), coal dust (2 mg respirable particulate material/m<sup>3</sup>), or diesel exhaust and coal dust combined (1 mg soot and 1 mg respirable coal dust/m<sup>3</sup>) 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","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 37-53"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139226","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}
Previous studies have shown that acute, oral administration of malathion modulated the humoral immune response to T-cell-dependent antigen, mitogenic responses, macrophage function, and mast cell degranulation. While administration of malathion for 14 days did not affect the generation of an immune response to antigen, it was possible that macrophage and mast cell functions were affected. In this report, the effect of malathion administration for 14 days upon these parameters were assessed. This treatment regimen increased the respiratory burst capacity to a maximal level at a dose of 1 mg/kg/day or greater. The effect of oral administration of malathion for 14 days on the degranulation of mast cells in various organs (heart, skin, and small intestine) and peritoneal lavage fluid was also assessed. At doses of 1 mg/kg/day and above, the number of mast cells that was undegranulated decreased and the number that was severely degranulated increased. There was no change in mast cell integrity in biopsies from heart and skin, and in peritoneal fluid after 14-day administration of 0.1 mg/kg/day. However, the number of mast cells associated with the small intestine that had undergone degranulation was increased at this dose of malathion. These data indicate that repeated administration of malathion increased macrophage function at doses as low as 1 mg/kg/day and led to mast cell degranulation at doses as low as 0.1 mg/kg/day.
{"title":"Effect of Administration of Malathion for 14 Days on Macrophage Function and Mast Cell Degranulation","authors":"Kathleen Rodgers , Shiquan Xiong","doi":"10.1006/faat.1997.2302","DOIUrl":"10.1006/faat.1997.2302","url":null,"abstract":"<div><p>Previous studies have shown that acute, oral administration of malathion modulated the humoral immune response to T-cell-dependent antigen, mitogenic responses, macrophage function, and mast cell degranulation. While administration of malathion for 14 days did not affect the generation of an immune response to antigen, it was possible that macrophage and mast cell functions were affected. In this report, the effect of malathion administration for 14 days upon these parameters were assessed. This treatment regimen increased the respiratory burst capacity to a maximal level at a dose of 1 mg/kg/day or greater. The effect of oral administration of malathion for 14 days on the degranulation of mast cells in various organs (heart, skin, and small intestine) and peritoneal lavage fluid was also assessed. At doses of 1 mg/kg/day and above, the number of mast cells that was undegranulated decreased and the number that was severely degranulated increased. There was no change in mast cell integrity in biopsies from heart and skin, and in peritoneal fluid after 14-day administration of 0.1 mg/kg/day. However, the number of mast cells associated with the small intestine that had undergone degranulation was increased at this dose of malathion. These data indicate that repeated administration of malathion increased macrophage function at doses as low as 1 mg/kg/day and led to mast cell degranulation at doses as low as 0.1 mg/kg/day.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 95-99"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139831","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}
Urmila P. Kodavanti , Daniel L. Costa , Shri N. Giri , Barry Starcher , Gary E. Hatch
Phosgene, an acylating agent, is a very potent inducer of pulmonary edema. Subchronic effects of phosgene in laboratory animals are not well characterized. The purpose of the study was to elucidate potential long-term effects on collagen and elastin metabolism during pulmonary injury/recovery and obtain information about the concentration × time (C × T) behavior of low levels of phosgene. Male Fischer 344 rats (60 days old) were exposed either to clean air or phosgene, 6 hr/day: 0.1 ppm (5 days/week), 0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1 day/week), for 4 or 12 weeks. A group of rats was allowed clean air recovery for 4 weeks after 12 weeks of phosgene exposure. This exposure scenario was designed to provide equalC × Tproduct for all concentrations at one particular time point except for 0.1 ppm (50%C × T). Phosgene exposure for 4 or 12 weeks increased lung to body weight ratio and lung displacement volume in a concentration-dependent manner. The increase in lung displacement volume was significant even at 0.1 ppm phosgene at 4 weeks. Light microscopic level histopathology examination of lung was conducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4 and 12 and 16 weeks (recovery). Small but clearly apparent terminal bronchiolar thickening and inflammation were evident with 0.1 ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminal bronchiolar thickening and inflammation appeared to be more prominent when compared to the 0.1 ppm group and changes in alveolar parenchyma were minimal. At 1.0 ppm, extensive inflammation and thickening of terminal bronchioles as well as alveolar walls were evident. Concentration rather thanC × Tseems to drive pathology response. Trichrome staining for collagen at the terminal bronchiolar sites indicated a slight increase at 4 weeks and marked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5 ppm was not examined), 1.0 ppm being more intense. Whole-lung prolyl hydroxylase activity and hydroxyproline, taken as an index of collagen synthesis, were increased following 1.0 ppm phosgene exposure at 4 as well as 12 weeks, respectively. Desmosine levels, taken as an index of changes in elastin, were increased in the lung after 4 or 12 weeks in the 1.0 ppm phosgene group. Following 4 weeks of air recovery, lung hydroxyproline was further increased in 0.5 and 1.0 ppm phosgene groups. Lung weight also remained significantly higher than the controls; however, desmosine and lung displacement volume in phosgene-exposed animals were similar to controls. In summary, terminal bronchiolar and lung volume displacement changes occurred at very low phosgene concentrations (0.1 ppm). Phosgene concentration, rather thanC × Tproduct appeared to drive toxic responses. The changes induced by phosgene (except of collagen) following 4 weeks were not further amplified at 12 weeks despite continued exposure. Phosgene-induced alterations of matrix
{"title":"Pulmonary Structural and Extracellular Matrix Alterations in Fischer 344 Rats Following Subchronic Phosgene Exposure","authors":"Urmila P. Kodavanti , Daniel L. Costa , Shri N. Giri , Barry Starcher , Gary E. Hatch","doi":"10.1006/faat.1997.2298","DOIUrl":"10.1006/faat.1997.2298","url":null,"abstract":"<div><p>Phosgene, an acylating agent, is a very potent inducer of pulmonary edema. Subchronic effects of phosgene in laboratory animals are not well characterized. The purpose of the study was to elucidate potential long-term effects on collagen and elastin metabolism during pulmonary injury/recovery and obtain information about the concentration × time (<em>C × T</em>) behavior of low levels of phosgene. Male Fischer 344 rats (60 days old) were exposed either to clean air or phosgene, 6 hr/day: 0.1 ppm (5 days/week), 0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1 day/week), for 4 or 12 weeks. A group of rats was allowed clean air recovery for 4 weeks after 12 weeks of phosgene exposure. This exposure scenario was designed to provide equal<em>C × T</em>product for all concentrations at one particular time point except for 0.1 ppm (50%<em>C × T</em>). Phosgene exposure for 4 or 12 weeks increased lung to body weight ratio and lung displacement volume in a concentration-dependent manner. The increase in lung displacement volume was significant even at 0.1 ppm phosgene at 4 weeks. Light microscopic level histopathology examination of lung was conducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4 and 12 and 16 weeks (recovery). Small but clearly apparent terminal bronchiolar thickening and inflammation were evident with 0.1 ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminal bronchiolar thickening and inflammation appeared to be more prominent when compared to the 0.1 ppm group and changes in alveolar parenchyma were minimal. At 1.0 ppm, extensive inflammation and thickening of terminal bronchioles as well as alveolar walls were evident. Concentration rather than<em>C × T</em>seems to drive pathology response. Trichrome staining for collagen at the terminal bronchiolar sites indicated a slight increase at 4 weeks and marked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5 ppm was not examined), 1.0 ppm being more intense. Whole-lung prolyl hydroxylase activity and hydroxyproline, taken as an index of collagen synthesis, were increased following 1.0 ppm phosgene exposure at 4 as well as 12 weeks, respectively. Desmosine levels, taken as an index of changes in elastin, were increased in the lung after 4 or 12 weeks in the 1.0 ppm phosgene group. Following 4 weeks of air recovery, lung hydroxyproline was further increased in 0.5 and 1.0 ppm phosgene groups. Lung weight also remained significantly higher than the controls; however, desmosine and lung displacement volume in phosgene-exposed animals were similar to controls. In summary, terminal bronchiolar and lung volume displacement changes occurred at very low phosgene concentrations (0.1 ppm). Phosgene concentration, rather than<em>C × T</em>product appeared to drive toxic responses. The changes induced by phosgene (except of collagen) following 4 weeks were not further amplified at 12 weeks despite continued exposure. Phosgene-induced alterations of matrix ","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 54-63"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2298","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139826","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}
N.P. Page , D.V. Singh , W. Farland , J.I. Goodman , R.B. Conolly , M.E. Andersen , H.J. Clewell , C.B. Frederick , H. Yamasaki , G. Lucier
A workshop entitled “Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data” was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and trichloroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinearmargin of exposureanalyses were proposed for these chemicals instead of thelinearized multistage modelpreviously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.
{"title":"Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data","authors":"N.P. Page , D.V. Singh , W. Farland , J.I. Goodman , R.B. Conolly , M.E. Andersen , H.J. Clewell , C.B. Frederick , H. Yamasaki , G. Lucier","doi":"10.1006/faat.1997.2305","DOIUrl":"10.1006/faat.1997.2305","url":null,"abstract":"<div><p>A workshop entitled “Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data” was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and trichloroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinear<em>margin of exposure</em>analyses were proposed for these chemicals instead of the<em>linearized multistage model</em>previously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 16-36"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139225","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}
Phenylmethylsulfonyl fluoride (PMSF), a nonneuropathic inhibitor of neurotoxic esterase (NTE), is a known potentiator of organophosphorus-induced delayed neurotoxicity (OPIDN). The ability of PMSF posttreatment (90 mg/kg, sc, 4 hr after the last PSP injection) to modify development of delayed neurotoxicity was examined in 2-, 5-, and 8-week-old White Leghorn chickens treated either one, two, or three times (doses separated by 24 hr) with the neuropathic OP compound phenyl saligenin phosphate (PSP, 5 mg/kg, sc). NTE activity was measured in the cervical spinal cord 4 hr after the last PSP treatment. Development of delayed neurotoxicity was measured over a 16-day postexposure period. All PSP-treated groups exhibited >97% NTE inhibition regardless of age or number of OP treatments. Two-week-old birds did not develop clinical signs of neurotoxicity in response to either single or repeated OP treatment regimens nor following subsequent treatment with PMSF. Five-week-old birds were resistant to the clinical effects of a single PSP exposure and were minimally affected by repeated doses. PMSF posttreatment, however, significantly amplified the clinical effects of one, two, or three doses of PSP. A single exposure to PSP induced slight to moderate signs of delayed neurotoxicity in 8-week-old birds with more extensive neurotoxicity being noted following repeated dosing. As with 5-week-old birds, PMSF exacerbated the clinical signs of neurotoxicity when given after one, two, or three doses of PSP in 8-week-old birds. Axonal degeneration studies supported the clinical findings: PMSF posttreatment did not influence the degree of degeneration in 2-week-old chickens but resulted in more severe degeneration (relative to PSP only exposure) in cervical cords from both 5- and 8-week-old birds. The results indicate that PMSF does not alter the progression of delayed neurotoxicity in very young (2 weeks of age) chickens but potentiates PSP-induced delayed neurotoxicity in the presence of 0–3% residual NTE activity in older animals. We conclude that posttreatment with neuropathic or nonneuropathic NTE inhibitors, following virtually complete NTE inhibition by either single or repeated doses of a neuropathic agent in sensitive age groups, can modify both the clinical and morphological indices of delayed neurotoxicity. This study further supports the hypothesis that potentiation of OPIDN occurs through a mechanism unrelated to NTE.
{"title":"Potentiation of Organophosphorus-Induced Delayed Neurotoxicity Following Phenyl Saligenin Phosphate Exposures in 2-, 5-, and 8-Week-Old Chickens","authors":"Paul Harp , Duke Tanaka Jr. , Carey N. Pope","doi":"10.1006/faat.1997.2301","DOIUrl":"10.1006/faat.1997.2301","url":null,"abstract":"<div><p>Phenylmethylsulfonyl fluoride (PMSF), a nonneuropathic inhibitor of neurotoxic esterase (NTE), is a known potentiator of organophosphorus-induced delayed neurotoxicity (OPIDN). The ability of PMSF posttreatment (90 mg/kg, sc, 4 hr after the last PSP injection) to modify development of delayed neurotoxicity was examined in 2-, 5-, and 8-week-old White Leghorn chickens treated either one, two, or three times (doses separated by 24 hr) with the neuropathic OP compound phenyl saligenin phosphate (PSP, 5 mg/kg, sc). NTE activity was measured in the cervical spinal cord 4 hr after the last PSP treatment. Development of delayed neurotoxicity was measured over a 16-day postexposure period. All PSP-treated groups exhibited >97% NTE inhibition regardless of age or number of OP treatments. Two-week-old birds did not develop clinical signs of neurotoxicity in response to either single or repeated OP treatment regimens nor following subsequent treatment with PMSF. Five-week-old birds were resistant to the clinical effects of a single PSP exposure and were minimally affected by repeated doses. PMSF posttreatment, however, significantly amplified the clinical effects of one, two, or three doses of PSP. A single exposure to PSP induced slight to moderate signs of delayed neurotoxicity in 8-week-old birds with more extensive neurotoxicity being noted following repeated dosing. As with 5-week-old birds, PMSF exacerbated the clinical signs of neurotoxicity when given after one, two, or three doses of PSP in 8-week-old birds. Axonal degeneration studies supported the clinical findings: PMSF posttreatment did not influence the degree of degeneration in 2-week-old chickens but resulted in more severe degeneration (relative to PSP only exposure) in cervical cords from both 5- and 8-week-old birds. The results indicate that PMSF does not alter the progression of delayed neurotoxicity in very young (2 weeks of age) chickens but potentiates PSP-induced delayed neurotoxicity in the presence of 0–3% residual NTE activity in older animals. We conclude that posttreatment with neuropathic or nonneuropathic NTE inhibitors, following virtually complete NTE inhibition by either single or repeated doses of a neuropathic agent in sensitive age groups, can modify both the clinical and morphological indices of delayed neurotoxicity. This study further supports the hypothesis that potentiation of OPIDN occurs through a mechanism unrelated to NTE.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 64-70"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139827","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}
Chloroform administered by gavage in corn oil, but not when administrated in drinking water, has been shown to induce liver cancer in female B6C3F1mice and to enhance cell proliferation. Since humans are exposed to chloroform in their drinking water, we evaluated whether exposure by this route would interact with the activity of chloroform when administered by gavage in corn oil. Female B6C3F1mice were exposed to chloroform in drinking water for 33 days at 0, 300, or 1800 ppm (Experiment 1) or for 31 days at 0, 120, 240, or 480 ppm (Experiment 2) and for 3 days prior to termination also received a daily dose of 263 mg/kg chloroform administered by gavage in corn oil. Exposure to chloroform in drinking water reduced both the hepatotoxicity and the enhanced cell proliferation (bromodeoxyuridine-labeling index and mitotic index) elicited in response to chloroform administered by gavage in corn oil. Hence, chloroform administered in drinking water reduced the activity of chloroform administered by gavage in corn oil, suggesting that it would also reduce the hepatocarcinogenic activity of chloroform administered by gavage.
{"title":"Chloroform in Drinking Water Prevents Hepatic Cell Proliferation Induced by Chloroform Administered by Gavage in Corn Oil to Mice","authors":"Michael A. Pereira, Matthew Grothaus","doi":"10.1006/faat.1997.2308","DOIUrl":"10.1006/faat.1997.2308","url":null,"abstract":"<div><p>Chloroform administered by gavage in corn oil, but not when administrated in drinking water, has been shown to induce liver cancer in female B6C3F<sub>1</sub>mice and to enhance cell proliferation. Since humans are exposed to chloroform in their drinking water, we evaluated whether exposure by this route would interact with the activity of chloroform when administered by gavage in corn oil. Female B6C3F<sub>1</sub>mice were exposed to chloroform in drinking water for 33 days at 0, 300, or 1800 ppm (Experiment 1) or for 31 days at 0, 120, 240, or 480 ppm (Experiment 2) and for 3 days prior to termination also received a daily dose of 263 mg/kg chloroform administered by gavage in corn oil. Exposure to chloroform in drinking water reduced both the hepatotoxicity and the enhanced cell proliferation (bromodeoxyuridine-labeling index and mitotic index) elicited in response to chloroform administered by gavage in corn oil. Hence, chloroform administered in drinking water reduced the activity of chloroform administered by gavage in corn oil, suggesting that it would also reduce the hepatocarcinogenic activity of chloroform administered by gavage.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 82-87"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139829","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}
Robert W. Luebke , Peter V. Hodson , Mohamed Faisal , Peter S. Ross , Keith A. Grasman , Judith Zelikoff
The potential for chemicals to adversely affect human immunologic health has traditionally been evaluated in rodents, under laboratory conditions. These laboratory studies have generated valuable hazard identification and immunotoxicologic mechanism data; however, genetically diverse populations exposed in the wild may better reflect both human exposure conditions and may provide insight into potential immunotoxic effects in humans. In addition, comparative studies of species occupying reference and impacted sites provide important information on the effects of environmental pollution on the immunologic health of wildlife populations. In this symposium overview, Peter Hodson describes physiological changes in fish collected above or below the outflows of paper mills discharging effluent from the bleaching process (BKME). Effects attributable to BKME were identified, as were physiological changes attributable to other environmental factors. In this context, he discussed the problems of identifying true cause and effect relationships in field studies. Mohamed Faisal described changes in immune function of fish collected from areas with high levels of polyaromatic hydrocarbon contamination. His studies identified a contaminant-related decreases in the ability of anterior kidney leukocytes to bind to and kill tumor cell line targets, as well as changes in lymphocyte proliferation in response to mitogens. Altered proliferative responses of fish from the contaminated site were partially reversed by maintaining fish in water from the reference site. Peter Ross described studies in which harbor seals were fed herring obtained from relatively clean (Atlantic Ocean) and contaminated (Baltic Sea) waters. Decreased natural killer cell activity and lymphoproliferative responses to T and B cell mitogens, as well as depressed antibody and delayed hypersensitivity responses to injected antigens, were identified in seals fed contaminated herring. In laboratory studies, it was determined that rats fed freeze-dried Baltic Sea herring had higher virus titers after challenge with rat cytomegalovirus (RCMV) than rats fed Atlantic Ocean herring; perinatal exposure of rats to oil extracted from Baltic herring also reduced the response to challenge with RCMV. Keith Grassman reported an association between exposure to polyhalogenated aryl hydrocarbons and decreased T cell immunity in the offspring of fish-eating birds (herring gulls and Capsian terns) at highly contaminated sites in the Great Lakes. The greatest suppression of skin test responses to phytohemagglutinin injection (an indicator of T cell immunity) was consistently found at sites with the highest contaminant concentrations. Judith Zelikoff addressed the applicability of immunotoxicity studies developed in laboratory-reared fish for detecting altered immune function in wild populations. She presented data from studies done in her laboratory with environmentally relevant concentrations of metals as exam
{"title":"Aquatic Pollution-Induced Immunotoxicity in Wildlife Species","authors":"Robert W. Luebke , Peter V. Hodson , Mohamed Faisal , Peter S. Ross , Keith A. Grasman , Judith Zelikoff","doi":"10.1006/faat.1997.2310","DOIUrl":"10.1006/faat.1997.2310","url":null,"abstract":"<div><p>The potential for chemicals to adversely affect human immunologic health has traditionally been evaluated in rodents, under laboratory conditions. These laboratory studies have generated valuable hazard identification and immunotoxicologic mechanism data; however, genetically diverse populations exposed in the wild may better reflect both human exposure conditions and may provide insight into potential immunotoxic effects in humans. In addition, comparative studies of species occupying reference and impacted sites provide important information on the effects of environmental pollution on the immunologic health of wildlife populations. In this symposium overview, Peter Hodson describes physiological changes in fish collected above or below the outflows of paper mills discharging effluent from the bleaching process (BKME). Effects attributable to BKME were identified, as were physiological changes attributable to other environmental factors. In this context, he discussed the problems of identifying true cause and effect relationships in field studies. Mohamed Faisal described changes in immune function of fish collected from areas with high levels of polyaromatic hydrocarbon contamination. His studies identified a contaminant-related decreases in the ability of anterior kidney leukocytes to bind to and kill tumor cell line targets, as well as changes in lymphocyte proliferation in response to mitogens. Altered proliferative responses of fish from the contaminated site were partially reversed by maintaining fish in water from the reference site. Peter Ross described studies in which harbor seals were fed herring obtained from relatively clean (Atlantic Ocean) and contaminated (Baltic Sea) waters. Decreased natural killer cell activity and lymphoproliferative responses to T and B cell mitogens, as well as depressed antibody and delayed hypersensitivity responses to injected antigens, were identified in seals fed contaminated herring. In laboratory studies, it was determined that rats fed freeze-dried Baltic Sea herring had higher virus titers after challenge with rat cytomegalovirus (RCMV) than rats fed Atlantic Ocean herring; perinatal exposure of rats to oil extracted from Baltic herring also reduced the response to challenge with RCMV. Keith Grassman reported an association between exposure to polyhalogenated aryl hydrocarbons and decreased T cell immunity in the offspring of fish-eating birds (herring gulls and Capsian terns) at highly contaminated sites in the Great Lakes. The greatest suppression of skin test responses to phytohemagglutinin injection (an indicator of T cell immunity) was consistently found at sites with the highest contaminant concentrations. Judith Zelikoff addressed the applicability of immunotoxicity studies developed in laboratory-reared fish for detecting altered immune function in wild populations. She presented data from studies done in her laboratory with environmentally relevant concentrations of metals as exam","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 1-15"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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