Fundamental and applied toxicology : official journal of the Society of Toxicology最新文献

{"title":"Dichloromethane metabolism to formaldehyde and reaction of formaldehyde with nucleic acids in hepatocytes of rodents and humans with and without glutathione S-transferase T1 and M1 genes.","authors":"M. Casanova, Douglas A. Bell, H. Heck","doi":"10.1093/TOXSCI/37.2.168","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.2.168","url":null,"abstract":"Metabolism of dichloromethane (DCM) to formaldehyde (HCHO) via a glutathione S-transferase (GST) pathway is thought to be required for its carcinogenic effects in B6C3F1 mice. In humans, this reaction is catalyzed primarily by the protein product of the gene GSTT1, a member of the Theta class of GST, and perhaps to a small extent by the protein product of the gene GSTM1. Humans are polymorphic with respect to both genes. Since HCHO may bind to both DNA and RNA forming DNA-protein crosslinks (DPX) and RNA-formaldehyde adducts (RFA), respectively, these products were determined in isolated hepatocytes from B6C3F1 mice, F344 rats, Syrian golden hamsters, and humans to compare species with respect to the production of HCHO from DCM and its reaction with nucleic acids. Only mouse hepatocytes formed detectable amounts of DPX, the quantities of which corresponded well with quantities of DPX formed in the livers of mice exposed to DCM in vivo [Casanova, M., Conolly, R.B., and Heck, H. d'A. (1996). Fundam. Appl. Toxicol. 31, 103-116]. Hepatocytes from all rodent species and from humans with functional GSTT1 and GSTM1 genes formed RFA. No RFA were detected in human cells lacking these genes. Yields of RFA in hepatocytes of mice were 4-fold higher than in those of rats, 7-fold higher than in those of humans, and 14-fold higher than in those of hamsters. The RFA:DPX ratio in mouse hepatocytes incubated with DCM was approximately 9.0 +/- 1.4, but it was 1.1 +/- 0.3 when HCHO was added directly to the medium, indicating that HCHO generated internally from DCM is not equivalent to that added externally to cells and that it may occupy separate pools. DPX were not detected in human hepatocytes even at concentrations equivalent to an in vivo exposure of 10,000 ppm; however, the possibility that very small amounts of DPX were produced from DCM cannot be excluded, since HCHO was formed in human cells. Maximal amounts of DPXliver that might be formed in humans were predicted from the amounts in mice and the relative amounts of RFA in hepatocytes of both species. With predicted DPXliver as the dosimeter, the unit risk, the upper 95% confidence limit on the cancer risk, and the margin of exposure were calculated at several concentrations using the linearized multistage and benchmark dose methods. Since the actual delivered dose is smaller than that predicted, the results suggest that DCM poses at most a very low risk of liver cancer to humans.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"49 1","pages":"168-80"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73537175","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}

{"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. Smialowicz, M. DeVito, M. Riddle, W. Williams, L. Birnbaum","doi":"10.1093/TOXSCI/37.2.141","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.2.141","url":null,"abstract":"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 micrograms/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 micrograms/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 microgram/ kg TCDD) or suppression (PCB153 + 1 or 10 micrograms/kg TCDD) of the PFC response relative to PCB153 alone; however, the PFC response was enhanced (PCB153 + 0.1 microgram/kg TCDD), unaffected (PCB153 + 1 microgram/kg TCDD), or suppressed (PCB153 + 10 micrograms/kg TCDD) relative to corn oil controls. PB did not affect the PFC response to SRBCs, despite a 13-fold induction of hepatic pentoxyresorufin O-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.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"22 1","pages":"141-9"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83331390","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}

{"title":"Trichloroethylene-induced mouse lung tumors: studies of the mode of action and comparisons between species.","authors":"Trevor Green, G. Mainwaring, J. Foster","doi":"10.1093/TOXSCI/37.2.125","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.2.125","url":null,"abstract":"CD-1 mice exposed to 450 ppm trichloroethylene, 6 hr/day, 5 days/week, for 2 weeks showed a marked vacuolation of lung Clara cells after the first exposure of each week and a marked increase in cell division after the last exposure of each week. The damage seen in mouse lung Clara cells is caused by an accumulation of chloral resulting from high rates of metabolism of trichloroethylene but poor clearance of chloral to trichloroethanol and its glucuronide. The activity and distribution of the key metabolizing enzymes in this pathway have been compared in mouse, rat, and human lung. While mouse lung microsomal fractions were able to metabolize trichloroethylene to chloral at significant rates, the rate in rat lung was 23-fold lower and a rate could not be detected in human lung microsomes at all. Immunolocalization of cytochrome P450IIE1 in lung sections revealed high concentrations in mouse lung Clara cells with lesser amounts in type II cells. Lower levels of enzyme could be detected in Clara cells of rat lung, but not at all in human lung sections. Western blots of lung tissues from the three species and of mouse lung Clara cells were entirely consistent with these observations. Consequently, it is highly unlikely that humans exposed to trichloroethylene are at risk from the lung damage/cell proliferation mechanism that is believed to lead to the development of tumors in the mouse lung.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"56 1","pages":"125-30"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90271382","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}

{"title":"Accumulation of manganese in rat brain following intranasal administration.","authors":"G. Gianutsos, G. Morrow, John B. Morris","doi":"10.1093/TOXSCI/37.2.102","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.2.102","url":null,"abstract":"Manganese chloride (50-800 micrograms) 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 micrograms 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.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"18 1","pages":"102-5"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83324767","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}

{"title":"Potentiation of organophosphorus-induced delayed neurotoxicity following phenyl saligenin phosphate exposures in 2-, 5-, and 8-week-old chickens.","authors":"P. Harp, D. Tanaka, C. Pope","doi":"10.1093/TOXSCI/37.1.64","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.1.64","url":null,"abstract":"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.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"17 1","pages":"64-70"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83459030","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}

{"title":"Chloroform in drinking water prevents hepatic cell proliferation induced by chloroform administered by gavage in corn oil to mice.","authors":"M. A. Pereira, M. Grothaus","doi":"10.1093/TOXSCI/37.1.82","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.1.82","url":null,"abstract":"Chloroform administered by gavage in corn oil, but not when administrated in drinking water, has been shown to induce liver cancer in female B6C3F1 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 B6C3F1 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.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"195 1","pages":"82-7"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89292847","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}

{"title":"Modulation of the inflammatory effects of inhaled ozone in rats by subcutaneous prolactin-secreting, pituitary-derived tumors.","authors":"A. Gunnison, A. Bowers, C. Nadziejko, R. Adler","doi":"10.1093/TOXSCI/37.1.88","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.1.88","url":null,"abstract":"Rats are more sensitive to ozone-induced pulmonary inflammation and damage during late pregnancy and throughout lactation than in pre- or early pregnancy or postlactation. This window of sensitivity coincides with a period of elevated levels of pituitary-derived prolactin or placental lactogen. In this study, we investigated the hypothesis that prolactin exerts an enhancing effect on ozone-induced pulmonary inflammation and damage, thus presenting a plausible explanation for the sensitivity profile observed in rats. Hyperprolactinemia was achieved by using rats with subcutaneous tumors that were derived from the MMQ tumor model previously described by Adler and co-workers (Adler, R. A., Krieg, R. J., Farrell, M. E., Deiss, W. P., and MacLeod, R. M., Metabolism 40, 286-291, 1991). A variant of the MMQ tumor, the MMQr tumor, which appeared spontaneously from a single passage of MMQ tumor tissue, produced elevated levels of corticosterone in addition to high levels of prolactin. These two subcutaneous tumors had markedly different effects on adrenal, thymus, and spleen weights because of the different hormonal milieu they generated. There was also a significant difference between MMQ- and MMQr-bearing rats in their inflammatory response to acute ozone exposure as assessed by polymorphonuclear leukocytes (PMNs) in the airways. Rats with MMQ tumors were not significantly different from non-tumor-bearing controls in their baseline level of airway PMNs and PMN inflammation following ozone exposure, whereas MMQr-bearing rats had significantly elevated baseline PMNs in their airways and a greater PMN response to inhaled ozone. The hormonal milieu and elevated PMNs in the airways of both unexposed and ozone-exposed rats with MMQr tumors were similar to levels observed in lactating rats. The role of corticosterone in pulmonary inflammation in this model was investigated further by treating MMQ tumor-bearing rats with dexamethasone. Dexamethasone was effective in producing changes in organ weights similar to those observed in MMQr rats, but did not elicit higher airway PMN concentrations in unexposed rats as observed in the MMQr rats. We conclude that in this animal model prolactin did not significantly elevate airway PMN inflammation induced by ozone, and supplementation with exogenous glucocorticoid did not duplicate the endogenous airway PMNs numbers observed in MMQr-bearing rats or lactating rats.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"6 1","pages":"88-94"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86301456","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}

{"title":"Canalicular retention as an in vitro assay of tight junctional permeability in isolated hepatocyte couplets: effects of protein kinase modulation and cholestatic agents.","authors":"M. Roma, D. J. Orsler, R. Coleman","doi":"10.1093/TOXSCI/37.1.71","DOIUrl":"https://doi.org/10.1093/TOXSCI/37.1.71","url":null,"abstract":"A simple, fast method to evaluate acute changes of tight junctional permeability in isolated hepatocyte couplets is proposed. The method consists of the recording of the number of canalicular vacuoles able to retain the previously accumulated fluorescent bile acid analogue cholyl-lysyl-fluorescein (CLF), as visualized by inverted fluorescent microscopy, following acute exposure to the compounds under study. The method was validated by (i) making a systematic documentation of the effect on CLF retention of a variety of hormonal modulators (vasopressin and phorbol esters), as well as several cholestatic (taurolithocholic acid, cyclosporin A, and estradiol 17 beta-glucuronide) and hepatotoxic agents (menadione, A23187, and t-butyl hydroperoxide), all known to affect biliary permeability in intact liver, and (ii) carrying out a comparative analysis of the results obtained with those recorded using rapid canalicular access of horseradish peroxidase (HRP) as an alternative procedure. The compounds tested all decreased canalicular vacuolar retention of CLF in a dose-dependent manner. Vasopressin- and phorbol ester-induced decline in CLF retention were prevented by pretreatment with the protein kinase C inhibitors H-7 and staurosporine, thus confirming a role for this enzyme in canalicular permeability regulation. A significant direct correlation (r = 0.934, p < 0.001) was obtained when the decrease in canalicular retention of CLF was compared with the increment in the canalicular access of HRP. Image analysis revealed that cellular fluorescence was not increased following exposure to these compounds, suggesting a paracellular rather than transcellular route for CLF egress. These results all support canalicular vacuolar retention of CLF as a suitable method to readily evaluate acute changes in tight junctional permeability in isolated hepatocyte couplets induced by physiological modulators or hepatotoxic agents.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"46 1","pages":"71-81"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78861591","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}

{"title":"Perinatal methanol exposure in the rat. II. Behavioral effects in neonates and adults.","authors":"S Stern,&nbsp;C Cox,&nbsp;R Preston,&nbsp;A Sharma,&nbsp;G B Inglis,&nbsp;M Balys,&nbsp;B Weiss","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The use of methanol as a component of automobile fuel will increase perinatal exposures in the general population. Few studies have addressed questions concerning neurotoxicity stemming from such exposures. In the current study, four cohorts of pregnant Long-Evans rats, each cohort consisting of an exposure and a control group, were exposed to 4500 ppm methanol vapor in Rochester-type inhalation chambers for 6 hr daily beginning on Gestation Day 6. Exposure continued for both dams and pups through Postnatal Day 21 (PND 21) to model gestational and neonatal toxicity in humans. Several behavioral procedures were used to assess exposure effects in the offspring. Male-female littermates were studied whenever possible to examine sex differences, with one pair from a litter for each procedure. Exposure to methanol did not affect suckling latency and nipple attachment on PND 5 or performance on an aversive olfactory conditioning procedure on PND 10. Exposure to methanol did alter performances in a motor activity procedure. Methanol-exposed neonates were less active on PND 18, but more active on PND 25 than the equivalent control group pups. Two operant conditioning procedures, not used previously in this context, assayed other littermates as adults. A fixed ratio schedule required the rat to rotate a running wheel a specified number of revolutions to obtain food-pellet reinforcers. When the fixed ratio requirement changed, number of responses (revolutions) per 1-hr session displayed a complex interaction with treatment. Changes in performance over the course of training differed between males and females depending on exposure to methanol. Compared to initial baseline performances, methanol-exposed males showed decreases, and methanol-exposed females increases, in the rate of running. A stochastic spatial discrimination procedure permitted subjects to respond on any three levers, with the probabilities of food-pellet delivery determined by the location of the preceding response. A reinforcement matrix defined the response sequence required to maximize reinforcements. When the matrix was changed, the methanol-exposed subjects responded less efficiently at asymptotic levels of performance than controls. Across procedures, developmental exposure to 4500 ppm methanol vapor was associated with subtle behavioral changes in both neonates and adults.</p>","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"36 2","pages":"163-76"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091241","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}

{"title":"Biological markers of acute acrylonitrile intoxication in rats as a function of dose and time.","authors":"F. Benz, D. Nerland, D. Corbett, Junyu Li","doi":"10.1093/TOXSCI/36.2.141","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.2.141","url":null,"abstract":"Three markers of acute acrylonitrile (AN) intoxication, namely, tissue glutathione (GSH), tissue cyanide (CN), and covalent binding to tissue protein, were studied as a function of dose and time. Doses administered and responses expected were 20 mg/kg (LD0), 50 mg/kg (LD10), 80 mg/kg (LD50), and 115 mg/kg (LD90). Liver GSH was the most sensitive marker of AN exposure. At 80 mg/kg AN, virtually complete depletion of liver GSH was observed within 30 min with no recovery through 120 min. Kidney GSH showed a similar, but less intense depletion; while blood and brain GSH were more refractory to AN. Whole blood and brain CN rose progressively during the first 60 min in a dose-dependent fashion. At the lowest dose, CN levels decreased thereafter, whereas, at the three higher doses, CN levels were maintained or continued to increase through 120 min. At the highest dose, blood and brain CN remained at acutely toxic levels through 240 min. Covalent binding increased rapidly in all tissues during the first 30 min at all doses. At the lowest dose, little additional covalent binding was observed beyond 30 min, while at the three higher doses, covalent binding increased, although at a slower rate. The data indicate that these three biologic markers of acute AN intoxication respond dramatically in a time-dependent manner in the toxic dosage range. Furthermore, the data provide evidence that AN toxicity is gated by GSH depletion in liver with the resultant termination of AN detoxification.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"18 1","pages":"141-8"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73794748","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}