Fundamental and Applied Toxicology最新文献

{"title":"The American Health Foundation's 5th International Course on the Safety Assessment of Medicines","authors":"","doi":"10.1006/faat.1997.2304","DOIUrl":"https://doi.org/10.1006/faat.1997.2304","url":null,"abstract":"","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Page 100"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2304","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137441381","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":"Albert F. Gunnison ,&nbsp;Allen Bowers ,&nbsp;Christine Nadziejko ,&nbsp;Robert A. Adler","doi":"10.1006/faat.1997.2300","DOIUrl":"10.1006/faat.1997.2300","url":null,"abstract":"<div><p>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.,<em>Metabolism</em><strong>40,</strong>286–291, 1991). A variant of the MMQ tumor, the MMQ_rtumor, 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 MMQ_r-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 MMQ_r-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 MMQ_rtumors 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 MMQ_rrats, but did not elicit higher airway PMN concentrations in unexposed rats as observed in the MMQ_rrats. 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 MMQ_r-bearing rats or lactating rats.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 88-94"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139830","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}

{"title":"Canalicular Retention as anin VitroAssay of Tight Junctional Permeability in Isolated Hepatocyte Couplets: Effects of Protein Kinase Modulation and Cholestatic Agents","authors":"Marcelo G. Roma,&nbsp;Dominic J. Orsler,&nbsp;Roger Coleman","doi":"10.1006/faat.1997.2309","DOIUrl":"10.1006/faat.1997.2309","url":null,"abstract":"<div><p>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 17β-glucuronide) and hepatotoxic agents (menadione, A23187, and<em>t</em>-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 (<em>r</em>= 0.934,<em>p</em>&lt; 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.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 1","pages":"Pages 71-81"},"PeriodicalIF":0.0,"publicationDate":"1997-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20139828","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":"Effects of Lifetime Lead Exposure in Monkeys on Detection of Pure Tones","authors":"Deborah C. Rice","doi":"10.1006/faat.1996.2268","DOIUrl":"10.1006/faat.1996.2268","url":null,"abstract":"<div><p>Increased detection thresholds for pure tones were observed in a large cohort of children exposed to lead environmentally while smaller studies in lead-exposed workers have reported conflicting results on assessments of auditory function. Pure tone detection thresholds were determined in a group of monkeys (<em>Macaca fascicularis</em>) dosed with 2 mg/kg/day of lead from birth through testing at 13 years of age. Blood lead concentrations were stable at about 30 μg/dl until monkeys were 10–11 years of age, at which time they increased to between 50 and 170 μg/dl. Five age- and rearing-matched monkeys served as controls. Detection thresholds were determined at six frequencies between 0.125 and 31.5 kHz. Earphones were fit over both ears, and thresholds were determined for each ear separately. The monkey signaled detection of the tone by breaking contact with a stainless steel bar. Three lead-exposed monkeys exhibited normal pure tone detection functions. Three monkeys had thresholds outside of the control range at some frequencies; there was a tendency for higher frequencies to be differentially more affected. These findings are consistent with reports of elevated pure tone thresholds in humans exposed to lead developmentally, although the effect is smaller than might have been predicted given the concurrent blood lead concentrations of these monkeys.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"36 2","pages":"Pages 112-118"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1996.2268","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091341","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","authors":"Sander Stern ,&nbsp;Christopher Cox ,&nbsp;Ray Preston ,&nbsp;Archana Sharma ,&nbsp;Geoffrey B. Inglis ,&nbsp;Marlene Balys ,&nbsp;Bernard Weiss","doi":"10.1006/faat.1997.2288","DOIUrl":"10.1006/faat.1997.2288","url":null,"abstract":"<div><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></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"36 2","pages":"Pages 163-176"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88684871","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}

{"title":"Stimulation of Prostaglandin Production by Quinolone Phototoxicity in Balb/c 3T3 Mouse Fibroblast Cellsin Vitro","authors":"Kohji Shimoda,&nbsp;Nobuhiko Wagai,&nbsp;Michiyuki Kato","doi":"10.1006/faat.1996.2282","DOIUrl":"10.1006/faat.1996.2282","url":null,"abstract":"<div><p>Sparfloxacin (SPFX) and levofloxacin (LVFX) with ultraviolet-A (UVA) irradiation have been reported to induce skin inflammation due to phototoxicity in Balb/c mice. We examined the production of arachidonic acid metabolites induced by quinolone phototoxicity in Balb/c 3T3 mouse fibroblast cells<em>in vitro.</em>The cells were simultaneously treated with SPFX or LVFX at 1, 10, or 100 μ<span>m</span>and UVA irradiation for 5 min (0.5 J/cm²). They were then cultured in quinolone-free medium for 24 hr, and the concentrations of prostaglandin E₂(PGE₂), 6-ketoprostaglandin F_1α(6-keto-PGF_1α), and leukotriene B₄(LTB₄) in the incubation medium were measured. Furthermore, the effect of quinolone photoproducts on the production of the inflammatory mediators and that of indomethacin on PGE₂level were also examined. Treatment with SPFX at 100 μ<span>m</span>plus UVA irradiation markedly increased levels of PGE₂and 6-keto-PGF_1α, but not that of LTB₄. SPFX or LVFX alone at up to 100 μ<span>m</span>, 10 μ<span>m</span>SPFX, or 100 μ<span>m</span>LVFX, or less plus UVA irradiation, or UVA-preirradiated quinolone up to 100 μ<span>m</span>had no effect. Indomethacin even at 0.1 μ<span>m</span>completely inhibited the PGE₂elevation induced by 100 μ<span>m</span>SPFX with UVA. These results suggest that PGs released from dermal fibroblasts in the simultaneous presence of quinolone and UVA could contribute in part to the development of skin inflammation<em>in vivo.</em></p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"36 2","pages":"Pages 157-162"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1996.2282","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091346","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 Time1,2","authors":"Frederick W. Benz ,&nbsp;Donald E. Nerland,&nbsp;Donna Corbett,&nbsp;Junyu Li","doi":"10.1006/faat.1997.2294","DOIUrl":"10.1006/faat.1997.2294","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"36 2","pages":"Pages 141-148"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2294","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091344","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":"Dose Dependence of Covalent Binding of Acrylonitrile to Tissue Protein and Globin in Rats","authors":"Frederick W. Benz ,&nbsp;Donald E. Nerland,&nbsp;Junyu Li,&nbsp;Donna Corbett","doi":"10.1006/faat.1997.2295","DOIUrl":"10.1006/faat.1997.2295","url":null,"abstract":"<div><p>The dose dependence of acrylonitrile (AN) covalent binding to tissue protein, following a single acute exposure over a 100-fold range in dose, was measured. Covalent binding was a linear function of AN dose in the lower dose range (0.02–0.95 mmol AN/kg). The slopes of the dose–response curves indicated that tissues varied by nearly 10-fold in their reactivity with AN. The relative order of covalent binding was as follows: blood ⪢ kidney = liver &gt; forestomach = brain &gt; glandular stomach ⪢ muscle. Similar dose–response behavior was observed for globin total covalent binding and for globin<em>N</em>-(2-cyanoethyl)valine (CEValine) adduct formation. The latter adduct was found to represent only 0.2% of the total AN adduction to globin. Regression of tissue protein binding versus globin total covalent binding or globin CEValine adduct indicated that both globin biomarkers could be used as surrogates to estimate the amount of AN bound to tissue protein. At higher AN doses, above approximately 1 mmol/kg, a sharp break in the covalent binding dose–response curve was observed. This knot value is explained by the nearly complete depletion of liver glutathione and the resultant termination of AN detoxification. The toxicity of AN is known to increase sharply above this dose. The data suggest that a comparison of specific tissue proteins labeled by AN above and below this threshold dose may provide some insight into the mechanism of AN-induced toxicity.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"36 2","pages":"Pages 149-156"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091345","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":"Author Index for Volume 36","authors":"","doi":"10.1006/faat.1997.2303","DOIUrl":"https://doi.org/10.1006/faat.1997.2303","url":null,"abstract":"","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"36 2","pages":"Page 189"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136602683","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":"Bioavailability of Lead to Juvenile Swine Dosed with Soil from the Smuggler Mountain NPL Site of Aspen, Colorado","authors":"Stan W. Casteel ,&nbsp;Ross P. Cowart ,&nbsp;Christopher P. Weis ,&nbsp;Gerry M. Henningsen ,&nbsp;Eva Hoffman ,&nbsp;William J. Brattin ,&nbsp;Roberto E. Guzman ,&nbsp;Matthew F. Starost ,&nbsp;John T. Payne ,&nbsp;Steven L. Stockham ,&nbsp;Stephen V. Becker ,&nbsp;John W. Drexler ,&nbsp;James R. Turk","doi":"10.1006/faat.1997.2296","DOIUrl":"10.1006/faat.1997.2296","url":null,"abstract":"<div><p>Bioavailability of lead (Pb) has become an issue in quantifying exposure of sensitive populations and, where necessary, establishing cleanup levels for contaminated soil. Immature swine were used as a model for young children to estimate the degree to which Pb from two fully characterized composite samples from the Smuggler Mountain Superfund Site in Aspen, Colorado may be bioavailable to resident children. The composite soils contained 14,200 and 3870 μg Pb/g of soil. Relative and absolute enteric bioavailabilities of Pb in soil (oral dose groups of 75, 225, and 675 μg Pb/kg body wt/day) were estimated by comparison with an orally administered soluble Pb salt (lead acetate = PbAc₂·3H₂O) (dose groups of 0, 75, and 225 μg Pb/kg body wt/day) and an intravenously administered aqueous solution of Pb (100 μg Pb/kg/day) from the same trihydrate salt administered daily for 15 days to 50 juvenile swine. The biological responses (area under the blood Pb concentration–time curve, and the terminal liver–, kidney–, and bone–lead concentrations) produced by Pb from PbAc₂·3H₂O and lead-contaminated soils were determined. This study revealed Pb from soil containing 14,200 μg Pb/g of soil had a bioavailability relative to Pb from PbAc (RBA), ranging from 56% based on the area under the blood lead concentration–time curve (AUC) versus dose, to 86% based on calculations from liver–Pb loading versus dose. Similarly, Pb from soil containing 3870 μg Pb/g of soil had an RBA ranging from 58% based on the AUC versus dose, to 74% based on calculations from liver– and kidney–Pb loading versus dose. Bioavailability of Pb in soils may be more or less than EPA's default RBA of 60%, therefore, measuring site-specific RBAs provides a basis for improved exposure and risk assessment.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"36 2","pages":"Pages 177-187"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091242","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}