Effect of Inhaled Propylene Oxide on Reproductive Parameters in Fischer 344 Rats

Effect of Inhaled Propylene Oxide on Reproductive Parametersin Fischer 344 Rats. HAYES, W. C, KIRK, H. D., GUSHOW, T. S.AND YOUNG, J. T. (1988). Fundam. Appl. Toxicol 10, 82–88.Reproductive parameters in Fischer 344 rats were evaluated followinginhalation of propylene oxide (PO) for two successive generations.Thirty male and 30 female rats were exposed to 0, 30, 100, or300 ppm PO for 6 hr/day, 5 days/week for 14 weeks and then matedto produce the f, litters. After weaning, 30 randomly selectedf₁, pups/sex/group were exposed to PO for 17 weeks and subsequentlymated to produce the f₂ litters. Reproductive parameters examinedincluded fertility, litter size and neonatal growth, and survival.All adults and selected weanlings were examined for gross andhistologic lesions. Toxicity due to PO was demonstrated by decreasedbody weights of parental f_o and f₁, rats at 300 ppm. No treatment-relatedeffects on fertility (mating or conception) were observed ineither f_o or f₁ matings. Neonatal survival indices for f₁, orf₂ litters revealed no treatment-related effects. Litter sizewas decreased in the f₁, rats exposed to 100 ppm PO. However,the litter size in the 300 ppm group was comparable to the controlgroup, and no effect on litter size was shown in PO-exposedf₂ litters. Pup weights were unaffected by parental exposureto PO in either generation. Pathologic examination of adultsand weanlings revealed no changes considered due to PO. Basedon these results, it is concluded that inhalation exposure toPO at levels up to 300 ppm over two generations did not produceany adverse effects on reproductive function.     

Effects of the Herbicide 2,4,5-Trichlorophenoxyacetic Acid on Growth and Morphology of L 929 Cells

Abstract: A dose-dependent inhibition of growth was found when monolayer cultures of L 929 cells were grown in the presence of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) in concentrations from 0.25 to 2.25 mM. At 1.75 and 2.25 mM an almost immediate cessation of growth was found. On removal of the herbicide (2.25 mM) after incubation for 3 or 6 days, cell multiplication was resumed after a lag period of about 24 hours. In the presence of 0.5 to 2.25 mM 2,4,5-T an accumulation of particles in the cytoplasm was observed, and on prolonged incubation in the presence of 2.25 mM 2,4,5-T the cells became rounded and detached from the substratum. By replacing the test medium by the control medium, however, the particles in the cytoplasm disappeared and the cells resumed their fibroblast-like structure.     

Evaluation of the Immunotoxicity of Orally Administered 2-Methoxyacetic Acid in Fischer 344 Rats

Evaluation of the Immunotoxicity of Orally Administered 2-MethoxyaceticAcid in Fischer 344 Rats. SMIALOWICZ, R. J., RIDDLE, M. M.,ROGERS, R. R., COPELAND, C. B., LUEBKE, R. W., AND ANDREWS,D. L. (1991). Fundam. Appl. Toxicol. 17, 771–781. We previouslydemonstrated that the glycol ether 2-methoxyethanol (ME) isimmunotoxic in the rat. In this study, the immunotoxicity of2-methoxyacetic acid (MAA), the principal metabolite of ME,was evaluated in adult male Fischer 344 rats. Rats were dosedby gavage with MAA on 10 consecutive days at dosages rangingfrom 50 to 200 mg/kg/day. Thymic involution, in the absenceof body weight loss, was observed at 100 and 200 mg/kg/day MAA.Lymphoproliferative responses to the mitogens concanavalin A,phytohemagglutinin, and pokeweed mitogen were also reduced atthese dosages. The in vitro generated cytotoxic T lymphocyteresponse was reduced at 200 mg/kg/day MAA. The mixed lymphocytereaction and natural killer cell activity were unaffected byexposure to MAA. Enumeration of splenic lymphocyte populationsrevealed a reduction in the percentage of W3/25-positive cellsat 100 and 150 mg/kg/day and an increase in the percentage of0X39-positive cells at 200 mg/kg/day; however, no changes inthe absolute number of either of these subsets were observed.The plaque forming cell (PFC) response to trinitropheny-lipopolysaccharide(TNP-LPS) was suppressed at 50-200 mg/kg/day MAA, while thePFC response to sheep red blood cells (SRBQ was elevated at50 mg/kg/day. Immunization of rats with TNP-LPS or SRBC followedby oral exposure to MAA at 4 and 28 hr postimmunization resultedin the suppression of the PFC response to TNP-LPS and SRBC atdosages of 100 and 200 mg/kg and 200 and 400 mg/kg, respectively.Equal suppression of the PFC response to TNP-LPS was achievedat equimolar concentrations of ME and MAA. The effects of MAAon the immune system of the rat presented here are very similarto results reported from this lab for ME-induced immune alterations.These results, along with results of experiments in which ME-inducedsuppression of the PFC response to TNP-LPS was reversed by 4-methylpyrazole,an inhibitor of the oxidation of ME to MAA by alcohol dehydrogenase,indicate that MAA is the proximate immunotoxicant followingexposure to the glycol ether 2-methoxyethanol.     

1,3-Dichloropropene: Two-Generation Inhalation Reproduction Study in Fischer 344 Rats

1,3-Dichloropropene: Two-Generation Inhalation ReproductionStudy in Fischer 344 Rats. BRESLIN, W. J., KIRK, H. D., STREETER,C. M., QUAST, J. F.,AND SZABO, J. R. (1989). Fundam. Appl Toxicol.12, 129–143. This study evaluated the effects of inhaledtechnical-grade 1,3-dichloropropene (DCPT) on reproduction andneonatal growth and survival. Groups of 30 male and 30 femaleFischer 344 rats, approximately 6 weeks of age, were exposedvia inhalation to 0, 10, 30 or 90 ppm DCPT for 6 hr/day, 5 days/week,for two generations. The parental f₀ and f₁ generations wereeach bred twice. Reproductive and neonatal parameters evaluatedincluded indices of fertility and pup survival, gestation length,litter size, pup body weight, and pup sex ratio. Gross and histologicexaminations were conducted on all f₀ and f₁ adults. In addition,randomly selected f_1b and f_2b weanlings were given gross examinations.Parental effects were limited to rats exposed to 90 ppm DCPTand included decreased body weights and histopathologic effectson the nasal mucosa of adult male and female rats. The histopathologiceffects consisted of slight, focal hyperplasia of the respiratoryepitheium and/or focal degenerative changes in the olfactoryepithelium. No adverse effects on reproductive parameters orneonatal growth or survival were observed in the f_1a, f_1b, f_2a,or f_2b litters even at an exposure concentration which producedeffects in adult animals. Based on these results, it is concludedthat inhalation exposure of rats up to 90 ppm DCPT for two successivegenerations did not adversely affect the reproductive and neonatalparameters evaluated.     

Acute and Subchronic Inhalation Studies on Trifluoroiodomethane Vapor in Fischer 344 Rats

Trifluoroiodomethane (CF₃I) is being considered as a replacementcompound for halon fire suppressants. Its structure is similarto that of Halon 1301 (CF₃Br), but it has very low ozone depletionpotential compared to CF₃Br. As part of the process of developingenvironmental and health effects criteria, acute, 2-week, and13- week nose-only inhalation toxicity studies were conductedin Fischer 344 rats. In the acute study, three groups of 30male rats each were exposed to 0 (control), 0.5, or 1.0% (v/v)CF₃I for 4 hr and euthanized immediately following exposure,3 days postexposure, or 14 days postexposure. There were nodeaths and no clinical signs of toxicity throughout the study.Histopathologic examination of select tissues showed no lesionsof pathologic significance. In the 2-week study, four groupsof 5 male rats each were exposed for 2 hr/day, 5 days/week to0, 3, 6, or 12% CF₃I No deaths were observed, though lethargyand slight incoordination were noted in rats of the 6 and 12%groups at the conclusion of each daily exposure. Mean body weightgains were depressed in rats of the 6 and 12% groups. Serumthyroglobulin and reverse T₃ (rT₃) values were increased atall exposure levels. At necropsy, no gross lesions or differencesin absolute or relative organ weights were noted. Histopathologicexamination of the thyroid and parathyroid glands indicatedno morphological abnormalities in the CF₃I-exposed rats. Inthe 13-week study, four groups of 15 male and 15 female ratswere exposed to 0, 2, 4, or 8% CF₃I 2 hr/day, 5 days/week for13 weeks. Rats exposed to 4 or 8% CF₃I had lower mean body weightsthan the controls. Deaths observed in the 2 and 8% groups wereattributed to accidents resulting from the restraint systememployed. Hematologic alterations were minimal and consideredinsignificant. Increases in the frequency of micronucleatedbone marrow polychromatic erythrocytes were observed in ratsof all three CF₃I groups. Serum chemistry alterations observedin rats of all CF₃I exposure groups included decreases in T₃and increases in thyroglobulin, rT₃, T₄, and TSH. Relative organweight increases (8% CF₃I group) occurred in the brain, liver,and thyroid glands; decreases were observed in the thymus andtestes. A decrease in relative thymus weights and an increasein relative thyroid weights were observed also in rats of the2 and 4% groups. Histopathological findings included a mildinflammation in the nasal turbinates of rats exposed to 4 or8% CF₃I, mild atrophy and degeneration of the testes (4 and8% CF₃I groups), and a mild increase in thyroid follicular colloidcontent in rats of all CF₃I exposure groups. Though NOAELs wereobserved for select target organs (e.g., nasal turbinates, testes),NOAELs were not apparent in all target organs examined (e.g.,thyroid glands, bone marrow).     

Inhibition of Intercellular Communication in Cultures of Chinese Hamster V79 Cells by 2,4-Dichlorophenoxyacetic Acid and 2,4,5-Trichlorophenoxyacetic Acid

Inhibition of Intercellular Communication in Cultures of ChineseHamster V79 Cells by 2,4-Dicfalorophenoxyacctic Acid and 2,4,5-TrichlorophenoxyaceticAcid. RUBINSTEIN, C, JONE, C, TROSKO, J. E., AND CHANG, C. C.(1984). Fundam. Appt. Toxicol. 4, 731–739. Using the Chinesehamster V79 in vitro cell system designed to measure intercellularcommunication, 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyaceticacid (2,4,5-T), and several mixtures of these compounds weretested for their ability to inhibit this biological process.The ability of these chemicals to inhibit colony-forming abilityof these cells was tested prior to the studies to measure intercellularcommunication. 2,4-D was less cytotoxic than 2,4,5-T. Both 2,4,5-Tand 2,4-D were able to inhibit intercellular communication attheir respective noncytotoxic dose ranges. Various mixturesof both chemicals were also able to inhibit intercellular communication,snowing some kind of addititvity. No-effect levels were alsonoted in the intercellular communication assay. These resultswere interpreted as being consistent with the hypothesis thatthese compounds might be teratogenic by their ability to inhibitintercellular communication during development     

Developmental Toxicity of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T): I. Multireplicated Dose-Response Studies in Four Inbred Strains and One Outbred Stock of Mice

A large-scaled multireplicated developmental toxicity studywas conducted in various strains/stocks of mice with the herbicide,2,4,5-trichiorophenoxyacetic acid (2,4,5-T), by gavage on GestationalDays 6 through 14. The most important attributes of the studydesign were replicated test groups, a minimum of four dose levelsper replicate, use of multiple stocks/strains of animals toobtain an estimate of the range in sensitivities due to genotype,complete pathological evaluation of maternal animals, and histopathologicalas well as teratological evaluation of the fetuses. Developmentaltoxicity was observed at doses below those producing discernibleor measurable maternal toxicity. Regression and/or probit analyseswere conducted to determine whether a dose-response relationshipexisted. Reduced fetal weight and increased incidence of cleftpalate and embryolethality were the most significant prenataleffects of 2,4,5-T exposure observed in this study. Each strain/stockexhibited a dose-related decrease in fetal weight with the CD-1mice having the steepest slope and the A/J mice having the shallowestslope. There was a striking similarity among the slopes of thedose-response curves for the various strains/stocks. The meanincidence of embryolethality in the A/J strain was significantlygreater than that of the other strains or stocks. There wassubstantial variation among replicates within strains. The useof the replicated study design was logistically necessary dueto the magnitude of the study and it also served to increasethe statistical power of the study.     

Chlorpyrifos: A 13-Week Nose-Only Vapor Inhalation Study in Fischer 344 Rats

Fischer 344 rats were exposed by the nose-only inhalation routeto chlorpyrifos vapors at concentrations of 0, 5.2, 10.3, or20.6 ppb, 6 hr/day, 5 days/week for 13 weeks. The exposure concentrationswere limited by the low vapor pressure of chlorpyrifos (theoreticalmaximum vapor concentration of 25 ppb at 25?C). No treatment-relatedsigns of toxicity or changes in body weights were detected duringthe course of the study. Unnalysis, hematology, clinical chemistry,organ weights, gross pathologic, and histopathologic evaluationswere performed at the end of the study with no treatment-relatedeffects observed. In addition, no differences from controlswere noted in plasma, red blood cell, or brain cholinesteraseactivities. The results of this study indicate that the no-observed-effectlevel for chlorpyrifos vapor was the highest attainable concentration,20.6 ppb, in male and female Fischer 344 rats.     

Pathological and Biochemical Effects of Dimethyl Hydrogen Phosphite in Fischer 344 Rats

Pathological and Biochemical Effects of Dimethyl Hydrogen Phosphitein Fischer 344 Rats. NOMEIR, A. A., AND URAIH, L. C. (1988).Fundam. Appl. Toxicol 10, 114–124. In a chronic studyby the National Toxicology Program (NTP), dimethyl hydrogenphosphite (DMHP) caused neoplastic and nonneoplastic changesin the lungs and forestomach of F344/N rats following gavageadministration for 2 years. The current investigation was designedto study the effect of a short-term exposure on a series ofbiochemical systems in target and nontarget tissues which maybe involved in the metabolism and/or the manifestation of DMHPtoxicity. Rats were treated daily with a dose similar to thatused in the NTP study (200 mgkg) for 4, 5, or 6 weeks. Two groupsof animals were also treated /for 4 weeks and then treatmentwas discontinued and the rats were allowed to recover for 1or 2 weeks. An equal number of animals was treated similarlywith the vehicle and used as control. The microsomal and solublefractions were separated from liver, lungs, kidneys, forestomach,and glandular stomach from the 6-week treatment group. Anothergroup of rats treated for 6 weeks was prepared for pathologyexamination of the lungs, forestomach, and glandular stomach.There was a significant increase in the weight of the forestomachof rats treated for 4, 5, or 6 weeks relative to control animals,while no significant difference was observed in the weight ofliver, lungs, kidneys, and glandular stomach. The forestomachweight of rats treated for 4 weeks returned to the control valueafter 1 week of recovery. Microscopic examination of the forestomachof rats treated for 6 weeks revealed a thickened stratifiedsquamous epithelium characterized by hyperplasia, hyperkeratosis,and subepithelial inflammation and edema. There were no microscopicchanges in the lungs or glandular stomach of animals treatedfor 6 weeks. The activity of angiotensin converting enzyme inthe serum of rats treated for 4, 5, or 6 weeks was significantlyincreased over that of control animals. The activity of thisenzyme returned to near levels seen in the control animals after1 week of recovery following 4 weeks of treatment. No treatment-relatedeffect was observed in the activities of the microsomal p-nitroanisoledemethylase, soluble glutathione S-transferase, and solublesuperox-ide dismutase in the five tissues studied. There wasa significant increase in the level of nonpro-tein soluble sulfhydrylsin the forestomach but in no other tissue of rats treated for6 weeks. Also the activity of soluble carboxylesterase was significantlyreduced in the lungs and forestomach, but not in any other tissueof the 6-week-treated rats. Results of this study indicate thatearly pathological and biochemical changes are detected in targettissues of rats exposed to.     

Influence of phenobarbital pretreatment on methoxyflurane and sodium fluoride nephropathy in Fischer 344 rats

Adult male Fischer 344 rats were used to investigate the effect of phenobarbital on methoxyflurane- and sodium fluoride-induced nephropathy. Pretreatment consisted of the ip administration of phenobarbital sodium at a dose of 50 mg/kg/day for 5 days; control animals were given saline. Pretreated animals were exposed to anesthetic concentrations of methoxyflurane during a period of 2 or 4 hr, whereas other pretreated animals were exposed only to oxygen, the methoxyflurane carrier gas. For comparative purposes, other pretreated animals received sodium fluoride in saline at doses of 0, 4.2 and 8.4 mg/300g. The results show that phenobarbital pretreatment enhances the nephrotoxicity of methoxy-flurance as evidenced by a significant interaction between phenobarbital and methoxyflurane on plasma concentrations of sodium and potassium, urinary volume, urinary excretion of urea, and urinary concentration test. In contrast, the nephrotoxicity of sodium fluoride was not affected by phenobarbital. These results provide good evidence that the urinary concentration test is a reliable monitor of the potentiating effect of phenobarbital on methoxyflurane nephrotoxicity.     

Pulmonary Structural and Extracellular Matrix Alterations in Fischer 344 Rats Following Subchronic Phosgene Exposure

Phosgene, an acylating agent, is a very potent inducer of pulmonaryedema. Subchronic effects of phosgene in laboratory animalsare not well characterized. The purpose of the study was toelucidate potential long-term effects on collagen and elastinmetabolism during pulmonary injury/recovery and obtain informationabout the concentration x time (C x T) behavior of low levelsof phosgene. Male Fischer 344 rats (60 days old) were exposedeither to clean air or phosgene, 6 hr/day: 0.1 ppm (5 days/week),0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1day/week), for 4 or 12 weeks. A group of rats was allowed cleanair recovery for 4 weeks after 12 weeks of phosgene exposure.This exposure scenario was designed to provide equal C x T productfor all concentrations at one particular time point except for0.1 ppm (50% C x T). Phosgene exposure for 4 or 12 weeks increasedlung to body weight ratio and lung displacement volume in aconcentration-dependent manner. The increase in lung displacementvolume was significant even at 0.1 ppm phosgene at 4 weeks.Light microscopic level histopathology examination of lung wasconducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4and 12 and 16 weeks (recovery). Small but clearly apparent terminalbronchiolar thickening and inflammation were evident with 0.1ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminalbronchiolar thickening and inflammation appeared to be moreprominent when compared to the 0.1 ppm group and changes inalveolar parenchyma were minimal. At 1.0 ppm, extensive inflammationand thickening of terminal bronchioles as well as alveolar wallswere evident. Concentration rather than C x T seems to drivepathology response. Trichrome staining for collagen at the terminalbronchiolar sites indicated a slight increase at 4 weeks andmarked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5ppm was not examined), 1.0 ppm being more intense. Wholelungprolyl hydroxylase activity and hydroxyproline, taken as anindex of collagen synthesis, were increased following 1.0 ppmphosgene exposure at 4 as well as 12 weeks, respectively. Desmosinelevels, taken as an index of changes in elastin, were increasedin the lung after 4 or 12 weeks in the 1.0 ppm phosgene group.Following 4 weeks of air recovery, lung hydroxyproline was furtherincreased in 0.5 and 1.0 ppm phosgene groups. Lung weight alsoremained significantly higher than the controls; however, desmosineand lung displacement volume in phosgene-exposed animals weresimilar to controls. In summary, terminal bronchiolar and lungvolume displacement changes occurred at very low phosgene concentrations(0.1 ppm). Phosgene concentration, rather than C x T productappeared to drive toxic responses. The changes induced by phosgene(except of collagen) following 4 weeks were not further amplifiedat 12 weeks despite continued exposure. Phosgene-induced alterationsof matrix were only partially reversible after 4 weeks of cleanair exposure.     

Lack of Delayed Neurotoxic Effect after Tri-o-cresyl Phosphate Treatment in Male Fischer 344 Rats: Biochemical, Neurobehavioral and Neuropathological Studies

Lack of Delayed Neurotoxic Effect after Tri-o-cresyl PhosphateTreatment in Male Fischer 344 Rats: Biochemical, Neurobehavioral,and Neuropathological Studies. SOMKUTI, S. G., TIL-SON, H. A.,BROWN, H. R., CAMPBELL, G. A., LAPADULA, D. M., AND ABOU-DONIA,M. B. (1988). Fundam. Appl. Toxicol. 10, 199-205. Tri-o-cresylphosphate (TOCP), which produces a delayed neurotoxic syndromein humans and some animal species, was given to Fischer 344(F344) male (18 week old) rats to determine if it causes biochemical,sensorimotor, and neuropathological effects. Animals were givenTOCP by gavage in doses ranging from 10 to 100 mg of TOCP/kgdaily for a period of 63 days. The rats were subjected to aseries of neurobehavioral tests including fore- and hindlimbgrip strength, motor activity, tremor, and latency to respondto a thermal stimulus. Central and peripheral nervous tissueswere examined for damage characteristic of organophosphorouscompound-induced delayed neurotoxicity (OPIDN). Brain neurotoxicesterase and acetylcholinesterase activities were inhibitedin a dose-dependent fashion. A group of three chickens treatedwith 100 mg of TOCP/kg/day for 18 days was included as the positivecontrol for enzymatic and histopathological alterations associatedwith OPIDN. Rats showed no consistent neurobehavioral changesor evidence of neuropathological damage in nervous tissues associatedwith treatment. In contrast, chickens treated with TOCP developeddelayed neurotoxicity characterized by ataxia, which progressedto paralysis. These neurological changes included swelling,fragmentation, and degeneration of the axon and myelin in bothcentral and peripheral nervous tissues. This study concludesthat the F344 rat is not sensitive to the delayed neurotoxiceffects of TOCP. When studying OPIDN in rats, care must be exercisedin choosing the experimental animal since some strains, e.g.,F344, are not sensitive.     

Effect of Exposure Mode on Amounts of Radiolabeled Cigarette Particles in Lungs and Gastrointestinal Tracts of F344 Rats

Abstract

This study was designed to compare the internal and external deposition of cigarette smoke particles in F344IN rats after nose-only or whole-body exposures and to provide information on how grooming affects the amount of smoke particles that pass through the gastrointestinal (GI) tract. Female rats were exposed to mainstream cigarette smoke by - four different modes: nose-only, tube-restrained (NOT); pelt-only, tube-restrained (POT); whole-body, tube-restrained (WBT); and whole-body, cage-housed (WBC). Croups of rats were exposed simultaneously for 40 min by 1 of the 4 modes to [¹⁴C]ldotriacontane (DTC) labeled cigarette smoke at a mean mass concentration of 327 mglm³. Half of the rats from each group were sacrificed immediately after exposure, and the others were sacrificed 24 h later. Head skin, a sample of subcutaneous fat, GI tract, trachea/lobar bronchi, lungs, depelted head, depelted carcass, and remaining pelt were analyzed to determine their ^UC content. About 60% of the ¹⁴C activity in the respiratory tract in the NOT and WBT groups was deposited in the pulmonary region, and about 40% was in the head airways and trachea. The radiolabeled DTC was cleared very slowly from the pulmonary region. The initial total body burdens of ¹⁴C in the rats exposed by the WBT and WBC modes were higher than those in the rats exposed by the NOT mode as a consequence of pelt contamination by the ¹⁴C-DTC. Crooming resulted in the ingestion of about 80-90% and 60% of the ¹⁴C activity originally deposited on the head skin and pelt, respectively, by 24 h after exposure. The ratio of the amount of smoke particles either contained within or passing through the CI tract to the amount in lung after 24 h was 2.6 for WBC-exposed rats and 1.3 for NOT-exposed rats. We concluded that compared to rats exposed using the NOT mode, WBC exposures increased the amount of smoke particles passing into the CI tract by about a factor of two.     

Dispositiion,Toxicity, and Intestinal Absorption of Cobaltous Chloride in Male Fischer 344 Rats

Abstract

The absorption and disposition of inorganic cobalt salts after oral administration have not been well characterized. The objectives of this study were to compare in vivo results with cobalt transport through the in vitro everted small intestine and to relate the disposition results to a biochemical indicator of cobalt toxicity. Cobalt chloride was given to male Fischer 344 rats orally at 33.3 mg Co(II)/kg or intravenously at 4.16 mg Co(II)/kg. By 36 h, 74.5% of the oral dose was eliminated in the feces. The liver, kidney, and heart accumulated cobalt to the greatest extent Following the single oral dose, the blood cobalt concentration-time curve was triphasic, peaked at 3.2 h, and had an absorptive half-life of 0.9 h, an elimination phase half-life of 3.9 h, and a terminal elimination half-life of 22.9 h. Following intravenous administration, 10.1% of the dose was excreted in the feces, indicating that cobalt can be secreted in the bile. Following a single intravenous injection, the concentration-time curve displayed three segments. The first segment, which occurred during the first 4 h, had a rapid half-life of 1.3 h. The second phase, from 4 to 12 h, demonstrated a slower clearance rate with a half-life of 4.3 h. The final and slowest phase, from 12 to 36 h, had a half-life of 19 h. Intestinal jejunal ring experiments indicated that cobalt transport has both active and passive components; however, cobalt transport through the in vitro rat everted duodenum indicated that cobalt transport had almost exclusively passive components with facilitated diffusion. The finding that uptake was saturable may explain the small extent of absorption following oral dosing. Heme oxygenase studies following subcutaneous and intravenous administration resulted in an increase in activity (twofold) over controls, while oral administration did not. We concluded that the extent of cobalt absorption across the gastrointestinal tract is incomplete, and that the concentration administered and the route of exposure may determine its systemic toxicity.     

玛咖提取物对大鼠耐力和血抗氧化酶活性的影响

目的 探讨玛咖提取物对大鼠耐力和血抗氧化酶活性的影响。方法 采用循环水流自由游泳和/或给予大鼠8.0、16.0、32.0 g.kg_-1体重玛咖提取物,连续给药15 d,第16天测定耐力和血丙二醛(malondialdehyde,MDA)、 超氧化物歧化酶(superoxide dismutase ,SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-px)水平。结果 给予玛咖提取物8.0、16.0、32.0 g.kg_-1体重15 d,沉下前游泳时间和游泳总时间分别延长了34.38%、84.25%、126.07%和37.42%、47.03、107.24%( P<0.01),大鼠沉下次数比单纯游泳组分别减少了17.65%、33.28%、55.50%( P<0.01), MDA水平分别降低了34.63%、54.13%、63.73％(P<0.01),SOD和GSH-px水平分别升高了67.78%,108.25%、154.49％和48.57%、110.28%、154.86%(P<0.01)。结论 玛咖提取物具有抵抗疲劳,增强运动能力的作用。其机制与降低血MDA水平,提高血SOD和GSH-px活性作用有关。     

Influence of oral administration of sulfamethazine on thyroid hormone levels in Fischer 344 rats

Fischer 344 rats (810 of each sex) were divided into treatment groups and fed diets containing 0, 10, 40, 600, 1200, or 2400 ppm sulfamethazine. Serum samples were analyzed for levels of thyroid-stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), and T3 uptake after 12, 18, or 24 mo of continuous dosing. There were no statistically significant differences in T3 levels or percent T3 uptake for either sex after any of the exposure periods. The serum T4 levels were lower (p less than 0.05) for females dosed at 1200 and 2400 ppm for 18 mo and for males dosed at 600, 1200, or 2400 ppm sulfamethazine for 24 mo than for those dosed at levels of 40 ppm or less. Serum TSH levels showed a general increasing trend (but not statistically significant) among animals receiving 600 ppm or more sulfamethazine. There was a significant dose-related reduction in (T3 + T4)/TSH ratio for both sexes (p less than 0.05) after 18 and 24 mo of exposure at dose levels of 600 ppm or more. A lack of response at 12 mo may have been due to the shorter treatment time. At each sacrifice period both sexes of rats fed sulfamethazine at 1200 and 2400 ppm had significantly heavier (p less than 0.05) thyroid weights than animals fed control diet. The heavier thyroid weights in the dosed animals may have resulted from increased TSH levels. The cause of reduction in serum T4 was not clearly evident. Therefore, the thyroid hormone to pituitary feedback mechanism apparently compensated for sulfamethazine effects in most animals. This would suggest that the thyroid gland was not irreversibly affected.     

Polychlorotrifluoroethylene (PCTFE) Oligomer Pharmacokinetics in Fischer 344 Rats: Development of a Physiologically Based Model

The hydraulic fluid oil polychiorotrifluoroethylene (PCTFE)is hepato- and nephrotoxic in the rat. Male Fischer 344 ratswere exposed to PCTFE either for a single 6-hr exposure (0.5or 0.25 mg/liter) or daily 5 days/week, 6 hr/day, for 13 weeks(0.5, 0.25, or 0.01 mg/liter). Blood, tissue, and urinary PCTFEconcentrations measured postexposure were used to develop aphysiologically based pharmacokinetic (PB-PK) model. The PCTFEhydraulic fluid used was a mixture of trimeric and tetramericoligomers with minor amounts of other chain lengths. The PB-PKmodel was designed to describe the behavior, not of individualoligomers, but of total mass for the trimer and tetramer ineach tissue. Partition coefficients were estimated using themodel to optimize tissue/blood concentration ratios measuredat the end of the 13-week exposure. First-order metabolic rateconstants for both trimeric (2.0 ^hr–1) and tetrameric(1.0 ^hr–1) portions were estimated by optimization againsturinary fluoride data assuming release of 0.77 mole fluorideper mole trimer and 0.844 mole fluoride per mole tetramer metabolized.To obtain accurate simulation of pharmacokinetic data it wasnecessary to hypothesize two fat compartments with diffusion-limitedexchange of PCTFE oligomer with the blood. Relative concentrationsof trimer and tetramer in venous blood, liver, and fat aftera single 6-hr exposure were proportional to inhaled concentrations.Tetramer accumulated preferentially with multiple exposure.Components of PCTFE were metabolized to carboxylic acids withrelease of fluoride. Due to their persistence tetrameric oligomersappear to be more important than trimeric oligomers as causativeagents of PCTFE hepato and nephrotoxicity in the rat.     

Application of Microencapsulation for Toxicology Studies: II. Toxicity of Microencapsulated Trichloroethylene in Fischer 344 Rats

Application of Microencapsulation for Toxicology Studies. II.Toxicity of Microencapsulated Trichloroethylene in Fischer 344Rats. MELNICK, R. L., JAMESON, C. W., GOEHL, T. J., MARONPOT,R. R., COLLINS, B. J., GREENWELL, A., HARRINGTON, F. W., WILSON,R. E., TOMAS-ZEWSKI, K. E., AND AGARWAL, D. K. (1987). Fundam.Appl. Toxicol. 8, 432–442. Gelatin–sorbitol microcapsulescontaining 44.1% trichloroethylene (TCE) were prepared and mixedin NIH-07 rodent meal diet and provided at microcapsule concentrationsof 0 (untreated control group), 1.25,2.5, 5.0, or 10% (equivalentto 0, 0.55, 1.10, 2.21, or 4.41% TCE, respectively) to groupsof 10 male F344 rats for 14 days. An additional control groupreceived diets containing 5% empty capsules. For comparisons,TCE dissolved in corn oil was administered by gavage to differentgroups of 10 male rats for 14 consecutive days at dose levelsadjusted to correspond to those in the feed study. Treatment-relateddeaths occurred only in the highest dose group of the gavagestudy. Body weight gain and feed consumption were reduced inhigh-dose groups of both the feed and gavage studies. Therewas no measurable loss of TCE in feed sampled from the cagesduring the study. Dose-related increases in organ (liver andkidney) weight/body weight ratios, individual cell necrosisin the liver, and hepatic microsomal NADPH cytochrome c re-ductaseand peroxisomal palmitoyl-CoA oxidase and catalase activitieswere found in both the dosed-fed and gavage groups. Inductionof cytochrome P-450 occurred only in the dosed-feed study. Therewere no significant compound-related pathologic lesions observedin the kidneys, the only other organ examined microscopically.Differences in lethality, cytochrome P-450 levels, and inductionof microsomal or peroxisomal enzyme activities were attributedto differences in the method of dosing (gavage versus dosed-feed).The demonstration of no significant loss of TCE from the feedand of similar toxic effects produced by microencapsulated TCEvia feed and TCE in corn oil via gavage indicate that microencapsulationcan provide an excellent alternative exposure route for studyingthe oral toxicological properties of volatile chemicals, suchas TCE, in rats.     

健脾消胀片对大鼠胃酸含量、胃蛋白酶活力及胃肠电活动影响

目的探讨健脾消胀片对大鼠胃酸含量、胃蛋白酶活力及胃肠电活动的影响。方法结扎大鼠幽门与十二指肠结合部造模,测大鼠胃酸含量和胃蛋白酶活力;用EGEG-8D胃肠电图仪记录5 min大鼠胃电图,测量频率和幅值,以观察健脾消胀片对大鼠胃窦电活动、小肠电活动的影响。结果大、中剂量健脾消胀片组可使大鼠胃酸含量显著升高,大剂量健脾消胀片组可使大鼠胃蛋白酶活性显著升高,中剂量健脾消胀片组可使大鼠胃蛋白酶活性明显升高;大、中剂量健脾消胀片组可使大鼠胃窦电活动频率显著升高,小剂量健脾消胀片组可使大鼠胃窦电活动频率明显升高,大、中、小剂量健脾消胀片组可使大鼠胃窦电活动幅值显著升高;大、中、小剂量健脾消胀片组可使大鼠小肠电活动频率和幅值均显著升高。结论健脾消胀片具有消食和胃的临床意义。     

Developmental Toxicity Evaluation of Inhaled Methyl Isobutyl Ketone in Fischer 344 Rats and CD-1 Mice

Developmental Toxicity Evaluation of Inhaled Methyl IsobutylKetone in Fischer 344 Rats and CD-1 Mice. Tyl, R. W., FRANCE,K. A., FISHER, L. C., PRITTS, I. M., TYLER, T. R., PHILLIPS,R. D., and MORAN, E. J. (1987). Fundam. Appl. Toxicol. 8, 310–327.Pregnant Fischer 344 rats and CD-1 mice were exposed to methylisobutyl ketone vapor (CAS No. 108-10-1) by inhalation on GestationalDays 6 through 15 at concentrations of 0, 300, 1000, or 3000ppm (mean analytical values of 0, 305, 1012, and 2997 ppm, respectively).The animals were sacrificed on Gestational Day 21 (rats) or18 (mice), and live fetuses were examined for external, visceral,and skeletal alterations. In rats, exposure to 3000 ppm resultedin maternal toxicity expressed as clinical signs, decreasedbody weight and body weight gain, increased relative kidneyweight, and decreased food consumption, and in fetotoxicityexpressed as reduced fetal body weight per litter and reductionsin skeletal ossification. In mice, exposure to 3000 ppm resultedin maternal toxicity expressed as exposure-related increasesin deaths (12.0%, 3/25 dams), clinical signs, and increasedabsolute and relative liver weight, and in fetotoxicity expressedas increased incidence of dead fetuses, reduced fetal body weightper litter, and reductions in skeletal ossification. No treatment-relatedincreases in embryotoxicity or fetal malformations were seenin either species at any exposure concentration tested. Therewas no evidence of treatment-related maternal, embryo, or fetaltoxicity (including malformations) at 1000 or 300 ppm in eitherSpecies.