W. L. Casley, W. L. Casley, J.Allan Menzies, Michel Girard, Lyse Larocque, N. Mousseau, Larry W. Whitehouse, Thomas W. Moon
The 3-demethylation of caffeine can be used as an index of cytochrome P450 CYP1A2 activity in vivo. We compared the plasma levels of caffeine and the 3-demethylated metabolite. 1,7-dimethylxanthine, in six common inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J, and SWR/J) and one inbred strain (APN) derived in our laboratory from outbred Swiss-Webster mice on the basis of its relative susceptibility to acetaminophen-induced hepatotoxicity. We found significant variations between a number of the common strains, all of which produced significantly higher caffeine 3-demethylation indices than our APN strain. In three of the six common strains, there was a significant difference between males and females, with the females having consistently lower 1,7-xanthine/caffeine ratios. Hepatic Cyp1a2 expression was compared between APN and C3H/HeJ males. Microsomal methoxyresorufin O-demethylation, acetanilide 4-hydroxylation, and CYP1A2 immunoreactive protein levels were significantly higher in C3H/HeJ relative to APN mice, as were hepatic CYP1A2 mRNA levels. These results indicate the importance of strain and gender to the outcome of pharmacological or toxicological studies involving CYP1A2-mediated metabolism, as well as the suitability of the plasma 1,7-dimethylxanthine/caffeine ratio as a marker of CYP1A2 activity in the mouse. The striking differences observed between the APN and C3H/HeJ mice suggest that these strains may be suitable for a genetic analysis of the regulation of the basal expression of CYP1A2, a key enzyme in procarcinogen activation.
{"title":"Differences in caffeine 3-demethylation activity among inbred mouse strains: a comparison of hepatic Cyp1a2 gene expression between two inbred strains.","authors":"W. L. Casley, W. L. Casley, J.Allan Menzies, Michel Girard, Lyse Larocque, N. Mousseau, Larry W. Whitehouse, Thomas W. Moon","doi":"10.1093/TOXSCI/40.2.228","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.2.228","url":null,"abstract":"The 3-demethylation of caffeine can be used as an index of cytochrome P450 CYP1A2 activity in vivo. We compared the plasma levels of caffeine and the 3-demethylated metabolite. 1,7-dimethylxanthine, in six common inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J, and SWR/J) and one inbred strain (APN) derived in our laboratory from outbred Swiss-Webster mice on the basis of its relative susceptibility to acetaminophen-induced hepatotoxicity. We found significant variations between a number of the common strains, all of which produced significantly higher caffeine 3-demethylation indices than our APN strain. In three of the six common strains, there was a significant difference between males and females, with the females having consistently lower 1,7-xanthine/caffeine ratios. Hepatic Cyp1a2 expression was compared between APN and C3H/HeJ males. Microsomal methoxyresorufin O-demethylation, acetanilide 4-hydroxylation, and CYP1A2 immunoreactive protein levels were significantly higher in C3H/HeJ relative to APN mice, as were hepatic CYP1A2 mRNA levels. These results indicate the importance of strain and gender to the outcome of pharmacological or toxicological studies involving CYP1A2-mediated metabolism, as well as the suitability of the plasma 1,7-dimethylxanthine/caffeine ratio as a marker of CYP1A2 activity in the mouse. The striking differences observed between the APN and C3H/HeJ mice suggest that these strains may be suitable for a genetic analysis of the regulation of the basal expression of CYP1A2, a key enzyme in procarcinogen activation.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"16 1","pages":"228-37"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84642470","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}
W. Boyes, M. Dourson, J. Patterson, H. Tilson, W. Sette, R. Macphail, A. Li, J. O’Donoghue
The proposed Neurotoxicity Risk Assessment Guidelines (U.S. EPA, 1995c Fed. Reg. 60(192), 52032-52056) of the U.S. Environmental Protection Agency (EPA) were the subject of a workshop at the 1997 Meeting of the Society of Toxicology. The workshop considered the role of guidelines in the risk assessment process, the primary features, scientific basis, and implications of the guidelines for EPA program offices, as well as for industrial neurotoxicologists from the perspectives of both pesticides and toxic substances regulation. The U.S. National Academy of Sciences (NAS, 1983, Risk Assessment in the Federal Government: Managing the Process) established a framework for distinguishing risk management from risk assessment, the latter being the result of integrating hazard identification, hazard characterization, and exposure assessment data. The guidelines are intended to establish operating principles that will be used when examining data in a risk assessment context. The proposed neurotoxicity risk assessment guidelines provide a conceptual framework for deciding whether or not a chemically induced effect can be considered to be evidence of neurotoxicity. Topics in the proposed guidelines include structural and functional effects, dose-response and -duration considerations, and relationships between effects. Among the issues that must be considered are the multiplicity of chemical effects, the levels of biological organization in the nervous system, and the tests, measurements, and protocols used. Judgment of the adversity of an effect depends heavily on the amount and types of data available. The attribution of a chemically induced effect to an action on the nervous system depends on several factors such as the quality of the study, the nature of the outcome, dose-response and time-response relationships, and the possible involvement of nonneural factors. The guidelines will also serve as a reference for those conducting neurotoxicity testing, as well as establish a consistent approach to neurotoxicity risk assessment by regulators. Extending this approach through international harmonization would be advantageous to the development of products for a worldwide market. Thus, both risk assessors and regulated industries have a large stake in the guidelines to provide a framework that will lead to accurate risk assessment decisions.
{"title":"EPA's neurotoxicity risk assessment guidelines.","authors":"W. Boyes, M. Dourson, J. Patterson, H. Tilson, W. Sette, R. Macphail, A. Li, J. O’Donoghue","doi":"10.1093/TOXSCI/40.2.175","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.2.175","url":null,"abstract":"The proposed Neurotoxicity Risk Assessment Guidelines (U.S. EPA, 1995c Fed. Reg. 60(192), 52032-52056) of the U.S. Environmental Protection Agency (EPA) were the subject of a workshop at the 1997 Meeting of the Society of Toxicology. The workshop considered the role of guidelines in the risk assessment process, the primary features, scientific basis, and implications of the guidelines for EPA program offices, as well as for industrial neurotoxicologists from the perspectives of both pesticides and toxic substances regulation. The U.S. National Academy of Sciences (NAS, 1983, Risk Assessment in the Federal Government: Managing the Process) established a framework for distinguishing risk management from risk assessment, the latter being the result of integrating hazard identification, hazard characterization, and exposure assessment data. The guidelines are intended to establish operating principles that will be used when examining data in a risk assessment context. The proposed neurotoxicity risk assessment guidelines provide a conceptual framework for deciding whether or not a chemically induced effect can be considered to be evidence of neurotoxicity. Topics in the proposed guidelines include structural and functional effects, dose-response and -duration considerations, and relationships between effects. Among the issues that must be considered are the multiplicity of chemical effects, the levels of biological organization in the nervous system, and the tests, measurements, and protocols used. Judgment of the adversity of an effect depends heavily on the amount and types of data available. The attribution of a chemically induced effect to an action on the nervous system depends on several factors such as the quality of the study, the nature of the outcome, dose-response and time-response relationships, and the possible involvement of nonneural factors. The guidelines will also serve as a reference for those conducting neurotoxicity testing, as well as establish a consistent approach to neurotoxicity risk assessment by regulators. Extending this approach through international harmonization would be advantageous to the development of products for a worldwide market. Thus, both risk assessors and regulated industries have a large stake in the guidelines to provide a framework that will lead to accurate risk assessment decisions.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"28 1","pages":"175-84"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86999201","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}
Nitroaromatic musks, including musk ketone (MK; 2,6-dimethyl-3,5-dinitro-4-t-butylacetophenone), are chemicals used as perfume ingredients in household products, cosmetics, and toiletries. Musk xylene (MX; 1,3,5-trinitro-2-t-butylxylene), another nitromusk, is not genotoxic but has been reported to produce mouse liver tumors in a chronic bioassay. In addition, MX has been shown to both induce and inhibit mouse liver cytochrome P450 2B (CYP2B) isozymes. The ability of MX to inhibit CYP2B enzyme activity is attributable to inactivation of the enzyme by a specific amine metabolite. MK is structurally similar to MX, but lacks the nitro substitution that is reduced to the inactivating amine metabolite. Therefore, we hypothesized that MK would induce, but not inhibit, CYP2B isozymes. To test this hypothesis, and to evaluate the effects of MK on mouse liver cytochrome P450 enzymes, two sets of experiments were performed. To evaluate the ability of MK to induce cytochromes P450, mice were dosed daily by oral gavage at dosages ranging from 5 to 500 mg/ kg MK for 7 days. This treatment resulted in a pleiotropic response in mouse liver, including increased liver weight, increased total microsomal protein, and centrilobular hepatocellular hypertrophy. At the highest dose tested, MK caused a 28-fold increase in CYP2B enzyme activity and a small (approximately 2-fold) increase in both cytochromes P450 1A and 3A (CYP1A and CYP3A) enzyme activities over control levels. Protein and mRNA analyses confirmed the relative levels of induction for CYP2B, CYP1A, and CYP3A. In addition, the no-observable-effect level (NOEL) for CYP2B induction by MK was 20 mg/kg. To evaluate the ability of MK to inhibit phenobarbital-induced CYP2B activity, mice were given 500 ppm phenobarbital (PB) in the drinking water for 5 days to induce CYP2B isozymes, followed by a single equimolar (0.67 mmol/kg) oral gavage dose of either MK (198 mg/kg) or MX (200 mg/kg), and microsomes were prepared 18 h later. While MX inhibited more than 90% of the PB-induced CYP2B activity in the microsomes, MK caused only a small (about 20%) reduction in PB-induced CYP2B enzyme activity. These results indicate that, like MX. MK is a PB-type inducer of mouse liver CYP2B isozymes, but unlike MX, MK does not effectively inhibit PB-induced CYP2B enzyme activity.
{"title":"Characterization of the effects of musk ketone on mouse hepatic cytochrome P450 enzymes.","authors":"S. Stuard, D. Caudill, L. Lehman-Mckeeman","doi":"10.1093/TOXSCI/40.2.264","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.2.264","url":null,"abstract":"Nitroaromatic musks, including musk ketone (MK; 2,6-dimethyl-3,5-dinitro-4-t-butylacetophenone), are chemicals used as perfume ingredients in household products, cosmetics, and toiletries. Musk xylene (MX; 1,3,5-trinitro-2-t-butylxylene), another nitromusk, is not genotoxic but has been reported to produce mouse liver tumors in a chronic bioassay. In addition, MX has been shown to both induce and inhibit mouse liver cytochrome P450 2B (CYP2B) isozymes. The ability of MX to inhibit CYP2B enzyme activity is attributable to inactivation of the enzyme by a specific amine metabolite. MK is structurally similar to MX, but lacks the nitro substitution that is reduced to the inactivating amine metabolite. Therefore, we hypothesized that MK would induce, but not inhibit, CYP2B isozymes. To test this hypothesis, and to evaluate the effects of MK on mouse liver cytochrome P450 enzymes, two sets of experiments were performed. To evaluate the ability of MK to induce cytochromes P450, mice were dosed daily by oral gavage at dosages ranging from 5 to 500 mg/ kg MK for 7 days. This treatment resulted in a pleiotropic response in mouse liver, including increased liver weight, increased total microsomal protein, and centrilobular hepatocellular hypertrophy. At the highest dose tested, MK caused a 28-fold increase in CYP2B enzyme activity and a small (approximately 2-fold) increase in both cytochromes P450 1A and 3A (CYP1A and CYP3A) enzyme activities over control levels. Protein and mRNA analyses confirmed the relative levels of induction for CYP2B, CYP1A, and CYP3A. In addition, the no-observable-effect level (NOEL) for CYP2B induction by MK was 20 mg/kg. To evaluate the ability of MK to inhibit phenobarbital-induced CYP2B activity, mice were given 500 ppm phenobarbital (PB) in the drinking water for 5 days to induce CYP2B isozymes, followed by a single equimolar (0.67 mmol/kg) oral gavage dose of either MK (198 mg/kg) or MX (200 mg/kg), and microsomes were prepared 18 h later. While MX inhibited more than 90% of the PB-induced CYP2B activity in the microsomes, MK caused only a small (about 20%) reduction in PB-induced CYP2B enzyme activity. These results indicate that, like MX. MK is a PB-type inducer of mouse liver CYP2B isozymes, but unlike MX, MK does not effectively inhibit PB-induced CYP2B enzyme activity.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"42 1","pages":"264-71"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81384154","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}
Ketoconazole (KCZ) is an imidazole antifungal agent that also affects P450 enzymes of the mammalian steroidogenic system. Several steps in the ovarian steroidogenesis pathway are known to be inhibited by KCZ, but previous work has failed to address the ramifications of such inhibition with respect to early pregnancy. In initial studies, Holtzman rats (8-10/group) were administered 10-100 mg/kg KCZ during days 1-8 of pregnancy. On day 9, evaluations revealed a reduction at both 75 and 100 mg KCZ/kg in the number of implantation sites and serum progesterone levels as well as an increase in ovarian weight. The decidual cell response (DCR) was blocked by KCZ in parallel with decreased serum progesterone and increased ovarian weight, indicating direct interference with uterine function. KCZ had no effect when given to long-term-ovariectomized rats that were hormone supplemented to permit the DCR, indicating that the ovary was at least one site of KCZ action on early pregnancy. Measurement of ovarian progesterone production in vitro from ovaries removed from rats treated in vivo with KCZ indicated a decline in progesterone production, suggesting a direct effect of KCZ on ovarian steroidogenesis. These data demonstrate that KCZ can compromise early pregnancy and appears to do so by inhibiting progesterone synthesis in the ovary.
{"title":"Ketoconazole impairs early pregnancy and the decidual cell response via alterations in ovarian function.","authors":"Andrey M. Cummings, Joan L. Hedge, John W. Laskey","doi":"10.1093/TOXSCI/40.2.238","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.2.238","url":null,"abstract":"Ketoconazole (KCZ) is an imidazole antifungal agent that also affects P450 enzymes of the mammalian steroidogenic system. Several steps in the ovarian steroidogenesis pathway are known to be inhibited by KCZ, but previous work has failed to address the ramifications of such inhibition with respect to early pregnancy. In initial studies, Holtzman rats (8-10/group) were administered 10-100 mg/kg KCZ during days 1-8 of pregnancy. On day 9, evaluations revealed a reduction at both 75 and 100 mg KCZ/kg in the number of implantation sites and serum progesterone levels as well as an increase in ovarian weight. The decidual cell response (DCR) was blocked by KCZ in parallel with decreased serum progesterone and increased ovarian weight, indicating direct interference with uterine function. KCZ had no effect when given to long-term-ovariectomized rats that were hormone supplemented to permit the DCR, indicating that the ovary was at least one site of KCZ action on early pregnancy. Measurement of ovarian progesterone production in vitro from ovaries removed from rats treated in vivo with KCZ indicated a decline in progesterone production, suggesting a direct effect of KCZ on ovarian steroidogenesis. These data demonstrate that KCZ can compromise early pregnancy and appears to do so by inhibiting progesterone synthesis in the ovary.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"42 1","pages":"238-46"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77287375","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. Laborde, K. Terry, P. Howard, James J. Chen, T. Collins, M. Shackelford, D. Hansen
Fumonisin B1 (FB1) is one of a number of mycotoxins produced by fungi, especially Fusarium sp. As a contaminant of many maize-derived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3-19 with purified FB1 at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive implantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB1 did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB1.
{"title":"Lack of embryotoxicity of fumonisin B1 in New Zealand white rabbits.","authors":"J. Laborde, K. Terry, P. Howard, James J. Chen, T. Collins, M. Shackelford, D. Hansen","doi":"10.1093/TOXSCI/40.1.120","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.1.120","url":null,"abstract":"Fumonisin B1 (FB1) is one of a number of mycotoxins produced by fungi, especially Fusarium sp. As a contaminant of many maize-derived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3-19 with purified FB1 at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive implantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB1 did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB1.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"216 1","pages":"120-8"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75804739","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}
Bromodichloromethane (BDCM) and chloroform (CHCl3) are by-products of drinking water chlorination and are the two most prevalent trihalomethanes (THMs) in finished drinking water. To date, no comprehensive comparison of the acute renal and hepatic effects of BDCM and CHCl3 following oral gavage in an aqueous dosing vehicle has been conducted. To characterize BDCM- and CHCl3-induced nephro- and hepatotoxicity following aqueous gavage and compare directly the responses between these THMs, 95-day-old male F-344 rats were given single oral doses of 0.0, 0.75, 1.0, 1.5, 2.0, or 3.0 mmol BDCM or CHCl3/kg body wt in an aqueous 10% Emulphor solution. Compound-related hepatic and renal damage was evaluated by quantitating clinical toxicity markers in the serum and urine, respectively. Both THMs appear to be equally hepatotoxic after 24 h, but BDCM caused significantly greater elevations in serum hepatotoxicity markers than CHCl3 at 48 h following exposure to 2.0 and 3.0 mmol/kg. In addition to causing more persistent liver toxicity than CHCl3, BDCM also appears to be slightly more toxic to the kidney at lower doses. Potency differences between the two THMs may be due to pharmacokinetic dissimilarities such as greater metabolism of BDCM to reactive metabolites or more extensive partitioning of BDCM into kidneys and fat depots, resulting in prolonged target tissue exposure.
{"title":"Trihalomethane comparative toxicity: acute renal and hepatic toxicity of chloroform and bromodichloromethane following aqueous gavage.","authors":"P. Lilly, T. M. Ross, R. Pegram","doi":"10.1093/TOXSCI/40.1.101","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.1.101","url":null,"abstract":"Bromodichloromethane (BDCM) and chloroform (CHCl3) are by-products of drinking water chlorination and are the two most prevalent trihalomethanes (THMs) in finished drinking water. To date, no comprehensive comparison of the acute renal and hepatic effects of BDCM and CHCl3 following oral gavage in an aqueous dosing vehicle has been conducted. To characterize BDCM- and CHCl3-induced nephro- and hepatotoxicity following aqueous gavage and compare directly the responses between these THMs, 95-day-old male F-344 rats were given single oral doses of 0.0, 0.75, 1.0, 1.5, 2.0, or 3.0 mmol BDCM or CHCl3/kg body wt in an aqueous 10% Emulphor solution. Compound-related hepatic and renal damage was evaluated by quantitating clinical toxicity markers in the serum and urine, respectively. Both THMs appear to be equally hepatotoxic after 24 h, but BDCM caused significantly greater elevations in serum hepatotoxicity markers than CHCl3 at 48 h following exposure to 2.0 and 3.0 mmol/kg. In addition to causing more persistent liver toxicity than CHCl3, BDCM also appears to be slightly more toxic to the kidney at lower doses. Potency differences between the two THMs may be due to pharmacokinetic dissimilarities such as greater metabolism of BDCM to reactive metabolites or more extensive partitioning of BDCM into kidneys and fat depots, resulting in prolonged target tissue exposure.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"64 1","pages":"101-10"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75884415","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}
Rats were administered hexamethylphosphoramide (HMPA) at dosages of 10, 100, 300, and 1000 ppm in drinking water or at 15, 40, or 120 mg/kg/day by gavage for approximately 90 days. Another group of rats was implanted subcutaneously with HMPA-filled osmotic minipumps, designed to deliver a dosage of 40 mg/kg/day to prevent the possibility of direct contact of HMPA with the nasal epithelium. After 90 days at 10 ppm in the drinking water, some rats had tracheas lined with regenerated epithelium, but no HMPA-related lesions were present in any other organs and tissues. At 100 ppm, nasal lesions (epithelial denudation, regeneration, and squamous metaplasia) were mostly in the maxilloturbinates, tips of nasoturbinates, and the adjacent septum in the anterior nasal cavity (level I), but the lesions were confined to the ventral region of the mid-anterior nasal cavity (level II) and to recesses of the posterior nasal cavity (levels III and IV). At 300 ppm, nasal turbinates in level I were partially adhered to the nasal septum by fibrous tissue. In level II the lesions were mainly confined to the ventral medial meatus, but were scattered diffusely in levels III and IV. Denuded turbinates showed minimal bone proliferation. At 1000 ppm, the anterior nasal cavity was partially occluded by extensive adhesion of the turbinates to the nasal septum by granulation tissue and proliferating turbinate bone. The general architecture of the posterior nasal cavity was obliterated by the marked proliferation of turbinate bone and fibrous tissue in the interturbinate spaces. Tracheas showed regenerated epithelium and bronchi had focal epithelial denudation at 100, 300, and 1000 ppm. Foamy alveolar macrophages (histiocytosis) were increased in the lungs at 300 and 1000 ppm. Testicular atrophy occurred at 1000 ppm. No other tissues were affected by HMPA treatment. Nasal lesions in rats given HMPA by gavage were identical in nature to, but sometimes slightly more severe than, the lesions in rats given HMPA in the drinking water. Rats given 40 mg/kg/day HMPA via an osmotic minipump had slightly less severe nasal lesions than did the rats given the same dosage of HMPA by gavage. Testicular atrophy was present in the rats given 120 mg/kg/day by gavage. The results of this study show that, with the exception of bone proliferation, systemic delivery of HMPA or its metabolites to the nasal tissue following oral administration causes tissue damage similar to that caused by direct exposure of the nasal tissue via inhalation. Oral administration of HMPA is a less potent route for producing nasal lesions than is inhalation.
{"title":"Subchronic nasal toxicity of hexamethylphosphoramide administered to rats orally for 90 days.","authors":"D. Keller, C. E. Marshall, K. P. Lee","doi":"10.1093/TOXSCI/40.1.15","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.1.15","url":null,"abstract":"Rats were administered hexamethylphosphoramide (HMPA) at dosages of 10, 100, 300, and 1000 ppm in drinking water or at 15, 40, or 120 mg/kg/day by gavage for approximately 90 days. Another group of rats was implanted subcutaneously with HMPA-filled osmotic minipumps, designed to deliver a dosage of 40 mg/kg/day to prevent the possibility of direct contact of HMPA with the nasal epithelium. After 90 days at 10 ppm in the drinking water, some rats had tracheas lined with regenerated epithelium, but no HMPA-related lesions were present in any other organs and tissues. At 100 ppm, nasal lesions (epithelial denudation, regeneration, and squamous metaplasia) were mostly in the maxilloturbinates, tips of nasoturbinates, and the adjacent septum in the anterior nasal cavity (level I), but the lesions were confined to the ventral region of the mid-anterior nasal cavity (level II) and to recesses of the posterior nasal cavity (levels III and IV). At 300 ppm, nasal turbinates in level I were partially adhered to the nasal septum by fibrous tissue. In level II the lesions were mainly confined to the ventral medial meatus, but were scattered diffusely in levels III and IV. Denuded turbinates showed minimal bone proliferation. At 1000 ppm, the anterior nasal cavity was partially occluded by extensive adhesion of the turbinates to the nasal septum by granulation tissue and proliferating turbinate bone. The general architecture of the posterior nasal cavity was obliterated by the marked proliferation of turbinate bone and fibrous tissue in the interturbinate spaces. Tracheas showed regenerated epithelium and bronchi had focal epithelial denudation at 100, 300, and 1000 ppm. Foamy alveolar macrophages (histiocytosis) were increased in the lungs at 300 and 1000 ppm. Testicular atrophy occurred at 1000 ppm. No other tissues were affected by HMPA treatment. Nasal lesions in rats given HMPA by gavage were identical in nature to, but sometimes slightly more severe than, the lesions in rats given HMPA in the drinking water. Rats given 40 mg/kg/day HMPA via an osmotic minipump had slightly less severe nasal lesions than did the rats given the same dosage of HMPA by gavage. Testicular atrophy was present in the rats given 120 mg/kg/day by gavage. The results of this study show that, with the exception of bone proliferation, systemic delivery of HMPA or its metabolites to the nasal tissue following oral administration causes tissue damage similar to that caused by direct exposure of the nasal tissue via inhalation. Oral administration of HMPA is a less potent route for producing nasal lesions than is inhalation.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"6 1","pages":"15-29"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73368034","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}
Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperitoneally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were compared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.
{"title":"Repeated independent exposures to domoic acid do not enhance symptomatic toxicity in outbred or seizure-sensitive inbred mice.","authors":"Y. Peng, E. Clayton, L. Means, J. Ramsdell","doi":"10.1093/TOXSCI/40.1.63","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.1.63","url":null,"abstract":"Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperitoneally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were compared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"29 1","pages":"63-7"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83767911","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. Mattsson, J. Charles, B. Yano, H. Cunny, R. D. Wilson, J. Bus
Forms of 2,4-dichlorophenoxyacetic acid (collectively known as 2,4-D) are herbicides used to control a wide variety of broadleaf and woody plants. Single-dose acute and 1-year chronic neurotoxicity screening studies in male and female Fischer 344 rats (10/sex/dose) were conducted on 2,4-D according to the U.S. EPA 1991 guidelines. The studies emphasized a Functional Observational Battery (which included grip performance and hindlimb splay tests), automated motor activity testing, and comprehensive neurohistopathology of perfused tissues. Dosages were up to 250 mg/kg by gavage for the single-dose study, and up to 150 mg/kg/day in the diet for 52 weeks in the repeated-dose study. In the acute study, gavage with 250 mg/kg test material caused slight transient gait and coordination changes and clearly decreased motor activity at the time of maximal effect on the day of treatment (day 1). Mild locomotor effects occurred in one mid-dose rat (75 mg/kg), on Day 1 only. No gait, coordination, or motor activity effects were noted by day 8. In the chronic study, the only finding of neurotoxicologic significance was retinal degeneration in females in the high-dose group (150 mg/kg/day). Body weights of both sexes were slightly less than controls in the mid-dose group, and 10% less than controls in the high-dose group. In summary, the findings of these studies indicated a mild, transient locomotor effect from high-level acute exposure, and retinal degeneration in female rats from high-level chronic exposure. Based on the results from these two studies, the no-observed-adverse-effect level for acute neurotoxicity was 15 mg/kg/day and for chronic neurotoxicity was 75 mg/kg/day.
{"title":"Single-dose and chronic dietary neurotoxicity screening studies on 2,4-dichlorophenoxyacetic acid in rats.","authors":"J. Mattsson, J. Charles, B. Yano, H. Cunny, R. D. Wilson, J. Bus","doi":"10.1093/TOXSCI/40.1.111","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.1.111","url":null,"abstract":"Forms of 2,4-dichlorophenoxyacetic acid (collectively known as 2,4-D) are herbicides used to control a wide variety of broadleaf and woody plants. Single-dose acute and 1-year chronic neurotoxicity screening studies in male and female Fischer 344 rats (10/sex/dose) were conducted on 2,4-D according to the U.S. EPA 1991 guidelines. The studies emphasized a Functional Observational Battery (which included grip performance and hindlimb splay tests), automated motor activity testing, and comprehensive neurohistopathology of perfused tissues. Dosages were up to 250 mg/kg by gavage for the single-dose study, and up to 150 mg/kg/day in the diet for 52 weeks in the repeated-dose study. In the acute study, gavage with 250 mg/kg test material caused slight transient gait and coordination changes and clearly decreased motor activity at the time of maximal effect on the day of treatment (day 1). Mild locomotor effects occurred in one mid-dose rat (75 mg/kg), on Day 1 only. No gait, coordination, or motor activity effects were noted by day 8. In the chronic study, the only finding of neurotoxicologic significance was retinal degeneration in females in the high-dose group (150 mg/kg/day). Body weights of both sexes were slightly less than controls in the mid-dose group, and 10% less than controls in the high-dose group. In summary, the findings of these studies indicated a mild, transient locomotor effect from high-level acute exposure, and retinal degeneration in female rats from high-level chronic exposure. Based on the results from these two studies, the no-observed-adverse-effect level for acute neurotoxicity was 15 mg/kg/day and for chronic neurotoxicity was 75 mg/kg/day.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"1 1","pages":"111-9"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81890067","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. Petruska, J. G. Beattie, B. O. Stuart, S. Pai, K. Walters, C. Banks, G. Lulham, E. Mirro
Albuterol is a quickly acting beta-2 adrenergic agonist bronchodilator widely used by asthmatics. Because recent case-control studies have suggested a relationship between the increase in mortality of asthmatics over the past decade and the use of beta 2-adrenergic agonists in the control of asthma, concern has developed regarding the potential cardiotoxicity of beta 2-specific adrenergic agonists, including albuterol. The aim of this investigation was to assess the potential for cardiotoxicity of inhaled albuterol dry powder in rats, monkeys, and dogs. All species were exposed to an aerosol of albuterol 1 h per day, 7 days per week, for at least 2 weeks. Control groups were exposed to filtered conditioned air and handled in the same manner as the albuterol-exposed animals. Plasma concentrations of albuterol confirmed systemic exposure. The daily inhaled dose received by the animals was calculated based on measured respiratory minute volumes, published respiratory tract deposition data, as well as HPLC-determined particle size distribution data and aerosolized albuterol concentrations. Multiples of the maximum daily clinical dose (presentation of 15 micrograms/kg in a 70-kg human) were approximately 0.25- to 2500-fold in the rat, 9- to 100-fold in the monkey, and 0.5- to 90-fold in the dog. No findings attributed to albuterol were observed in the monkey. Tachycardia and transient hypokalemia occurred in rats at multiples of 1.5 times or greater of the maximum clinical dose. Absolute and relative heart weights increased in rats receiving multiples of 47 times or greater of the maximum human dose. In the absence of histopathologic findings, the increases in rat heart weights were considered a physiologic hypertrophic response to tachycardia. In dogs tachycardia and transient hypokalemia occurred at all doses tested. Slight to mild fibrosis in the papillary muscles of the left ventricle of the heart occurred in dogs at multiples > or = 19 times the clinical dose. The cardiovascular effects observed were consistent with the known pharmacologic action of beta 2-adrenergic agonists. Due to the lack of toxicologically relevant findings in rats and monkeys and the wide safety margin in dogs, the findings in this study do not suggest a cardiotoxicity risk in the human population after repeated exposures to clinical doses of albuterol currently used in the treatment of asthma.
{"title":"Cardiovascular effects after inhalation of large doses of albuterol dry powder in rats, monkeys, and dogs: a species comparison.","authors":"J. Petruska, J. G. Beattie, B. O. Stuart, S. Pai, K. Walters, C. Banks, G. Lulham, E. Mirro","doi":"10.1093/TOXSCI/40.1.52","DOIUrl":"https://doi.org/10.1093/TOXSCI/40.1.52","url":null,"abstract":"Albuterol is a quickly acting beta-2 adrenergic agonist bronchodilator widely used by asthmatics. Because recent case-control studies have suggested a relationship between the increase in mortality of asthmatics over the past decade and the use of beta 2-adrenergic agonists in the control of asthma, concern has developed regarding the potential cardiotoxicity of beta 2-specific adrenergic agonists, including albuterol. The aim of this investigation was to assess the potential for cardiotoxicity of inhaled albuterol dry powder in rats, monkeys, and dogs. All species were exposed to an aerosol of albuterol 1 h per day, 7 days per week, for at least 2 weeks. Control groups were exposed to filtered conditioned air and handled in the same manner as the albuterol-exposed animals. Plasma concentrations of albuterol confirmed systemic exposure. The daily inhaled dose received by the animals was calculated based on measured respiratory minute volumes, published respiratory tract deposition data, as well as HPLC-determined particle size distribution data and aerosolized albuterol concentrations. Multiples of the maximum daily clinical dose (presentation of 15 micrograms/kg in a 70-kg human) were approximately 0.25- to 2500-fold in the rat, 9- to 100-fold in the monkey, and 0.5- to 90-fold in the dog. No findings attributed to albuterol were observed in the monkey. Tachycardia and transient hypokalemia occurred in rats at multiples of 1.5 times or greater of the maximum clinical dose. Absolute and relative heart weights increased in rats receiving multiples of 47 times or greater of the maximum human dose. In the absence of histopathologic findings, the increases in rat heart weights were considered a physiologic hypertrophic response to tachycardia. In dogs tachycardia and transient hypokalemia occurred at all doses tested. Slight to mild fibrosis in the papillary muscles of the left ventricle of the heart occurred in dogs at multiples > or = 19 times the clinical dose. The cardiovascular effects observed were consistent with the known pharmacologic action of beta 2-adrenergic agonists. Due to the lack of toxicologically relevant findings in rats and monkeys and the wide safety margin in dogs, the findings in this study do not suggest a cardiotoxicity risk in the human population after repeated exposures to clinical doses of albuterol currently used in the treatment of asthma.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"27 1","pages":"52-62"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91282605","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：