4-WEEK INHALATION TOXICITY STUDY WITH A MIXTURE OF DICHLOROETHYLENE AND PERFLUOROBUTYLETHYLENE IN RATS

Inhalation studies were conducted to determine the potential subchronic toxicity of a mixture of trans -1,2-dichloroethylene (70%), cis -1,2-dichloroethylene (5%), and perfluorobutylethylene (25%). Groups of rats were exposed to 0, 400, 2000, or 8000 ppm concentrations of the mixture vapor 6 h/day, 5 days/wk, for a total of 20 exposures. Subgroups of rats were further observed during a 1-mo recovery period. Functional observational battery (FOB) and motor activity (MA) behavioral tests were conducted prior to initiation of the exposures, during exposure wk 4, and after a 1-mo postexposure recovery period. Clinical pathology evaluations were conducted at the end of the exposure period and after a 1-mo recovery period. At the end of the 4-wk exposure period, tissues from rats were collected, histologically processed, and evaluated by light microscopy. Test substance-related, biologically significant decreased body weights and body weight gains occurred in male and female rats exposed to 8000 ppm. In addition, test substance-related, statistically significant decreases in food consumption and/or food efficiency were observed in male rats exposed to 8000 ppm. During exposures to 8000 ppm, some rats exhibited tremors and ataxia. Usually tremors and ataxia were observed within 1 h after initiation of the daily exposure period and were observed during each exposure day. Tremors were also observed during 1 exposure day in the 2000 ppm animals. In addition to the tremors and ataxia, rats exposed to 2000 ppm or 8000 ppm had a diminished and/or no alerting response to a sharp, sound stimulus during each of the daily exposure periods. These effects were transient since no clinical observations of compromised neurological function were detected when the rats were evaluated upon return to the animal room following exposure. Daily reoccurrence of this apparently acute effect in the 8000 ppm group did not produce enduring neurological changes since there were no test substance-related effects on FOB parameters or on MA conducted the day following the last exposure or during the recovery period. In addition, there were no toxicologically significant changes in hematology, clinical chemistry, or urinalysis parameters in either males or females for any exposure concentration; and there were no test substance-related gross or microscopic morphological changes in males or females administered any exposure concentration. Under the conditions of the study, the no-observed-effect level (NOEL) was 400 ppm in males and females based on clinical signs of toxicity during exposure to 2000 or 8000 ppm.     

A CHRONIC INHALATION TOXICITY/ONCOGENICITY STUDY OF METHYLETHYLKETOXIME IN RATS AND MICE

To evaluate the oncogenic potential of methylethylketoxime (MEKO), CD-1 mice (50/sex/group) and F-344 rats (50/sex/group) were coexposed 6 h/day, 5 days/wk for 18 mo (mice) or 26 mo (rats) via whole-body inhalation exposures to target vapor concentrations of 0, 15, 75, and 375 ppm (actual concentrations of 0, 15 ± 1, 75 ± 2, or 374 ± 10 ppm). Satellite groups of rats and mice (10/sex/group/interval) were exposed for 12 mo (mice) and 3, 12, or 18 mo (rats) to evaluate chronic toxicity. Methyl ethyl ketone (MEK), a possible hydrolysis product of MEKO, was present at less than 1%. Treatment-related effects included increased body weight (male rats only), methemoglobin formation, hematology and clinical chemistry changes, increased liver weight, and increased spleen and testes weights (rats only). A high incidence of cataracts and corneal dystrophy occurred in both control and MEKO-exposed rats, with an earlier appearance and slightly higher incidence for these ocular lesions in MEKO-exposed animals compared to controls. Degenerative and reparative changes of the olfactory epithelium in the nasal turbinates, primarily limited to the dorsal meatus, occurred in both rats (75 and 374 ppm) and mice (15, 75, and 374 ppm). In addition, in the mice, liver changes included increased incidences of pigment in reticuloendothelial cells, centrilobular hypertrophy, granulomatous inflammation, and a slightly increased incidence of necrosis (75 and 374 ppm). An increase in hepatocellular carcinomas occurred in male mice at 374 ppm. Additional MEKO-related findings in the rat included congestion of the spleen with pigment in reticuloendothelial cells and extramedullary hematopoiesis and a decreased incidence of lymphoreticular mononuclear cell leukemia. Effects observed in the liver of the rats included decreases in the incidence of both peribiliary fibrosis and hyperplasia/proliferation of the biliary duct, an increase of spongiosis hepatis in males, and an increase in the incidence of intracytoplasmic vacuoles and hepatocellular basophilic foci. The effects on the liver were generally most profound in the high-exposure groups and, with the exception of the spongiosis hepatis, occurred in both sexes. An increase in hepatocellular adenomas occurred in the male rats at 75 and 374 ppm, and hepatocellular carcinomas in the male rats at 374 ppm. In both species, the liver tumors appeared relatively late in the life of the animals, with no significant increase in tumors at 12 mo of exposure in mice and at 18 mo of exposure in rats. Lifespan shortening was not observed, as MEKO-exposed animals survived generally as well as, or slightly better than, the controls.     

TOXICOLOGIC EVALUATION OF HUMECTANTS ADDED TO CIGARETTE TOBACCO: 13-WEEK SMOKE INHALATION STUDY OF GLYCERIN AND PROPYLENE GLYCOL IN FISCHER 344 RATS

Glycerin (CAS no. 56-81-5) and propylene glycol (CAS no. 57-55-6) are commonly used as humectant ingredients in manufactured cigarettes to control and maintain the moisture content of the cut tobacco filler. The potential of these added humectants to affect the toxicity of cigarette smoke was investigated in a subchronic nose-only smoke inhalation study in rats. Filtered test cigarettes were prepared from an American-style tobacco blend containing either glycerin added at 5.1% w/w tobacco, propylene glycol at 2.2% w/w tobacco, or combinations of these humectants totaling 2.3%, 3.9%, and 7.2% w/w tobacco. Other groups of animals were exposed similarly to the smoke of reference cigarettes without added humectants, or to filtered air (sham control). Smoke exposures were conducted for 1 h/ day, 5 days/wk for 13 wk, at target smoke particulate concentrations of 350 mg/m 3. All smoke-exposed groups had equivalent increases in blood carboxyhemoglobin, serum nicotine, and serum cotinine relative to the air controls. Smoke-associated reductions in body weights and occasional increases in heart and lung weights were generally similar among the various exposure conditions at necropsy. Increases in serum alkaline phosphatase and decreases in serum glucose and cholesterol were observed among smoke-exposed females relative to air controls. However, no significant differences in these parameters were evident between the humectant-containing and reference cigarette smoke exposure groups. Assessments of respiration conducted after 3, 6, 9, and 12 wk of smoke exposure indicated an initial smoke-related but not humectant-related decrease in respiratory rate, tidal volume, and minute volume during the first 20 min of each smoke exposure. Respiratory-tract histopathology was consistent across sexes and smoke groups, comprising (1) diffuse and focal alveolar pigmented macrophages and chronic interstitial inflammation in the lung, (2) laryngeal epithelial hyperplasia, squamous metaplasia, and scab formation, and (3) epithelial hyperplasia in the anterior nose. Smoke-related histopathology resolved substantially during a 6-wk postexposure recovery period. Addition of the tested humectants to cigarettes, singly or in combination, had no meaningful effect on the site, occurrence, or severity of respiratory-tract changes or on the measured indices of pulmonary function. It was concluded that the addition of glycerin and propylene glycol to cigarettes does not significantly affect the biological activity of inhaled cigarette smoke in this rat model.     

INHALATION TOXICITY OF POTASSIUM OCTATITANATE FIBERS (TISMO) IN RATS FOLLOWING 13 WEEKS OF AEROSOL EXPOSURE

One hundred and forty male and 140 female rats were divided into 1 control and 3 test groups of 35 rats each, per sex, and exposed by whole-body inhalation to test compound at target concentrations of 0, 1 mg/m³ (1700 fibers/cm³, 123 WHO fibers/cm³), 10 mg/m³ (5900 fibers/cm³, 952 WHO fibers/cm³), and 100 mg/m³ (112,700 fibers/cm³, 7440 WHO fibers/cm³) for 6 h/day, 5 days/wk for 13 wk. Ten rats from each group were killed after 13 wk of exposure and 13 wk of recovery, respectively, for histopathological evaluation. The other 15 rats from each group were killed to study lung clearance after 91 days of exposure, and approximately 1.5 and 3 mo of recovery following the end of the 13 wk of exposure. The mean fiber length of the chamber atmosphere was 2.8, 2.7, and 2.8 µm, while the mean fiber width was 0.48, 0.48, and 0.45 µm for the 1-, 10-, and 100-mg/m³ chambers, respectively. In the 1-mg/m³ (123 WHO fibers/cm³) exposure group, inhaled particles were mostly retained in a few fiberladen alveolar macrophages (AMs) within the alveoli adjacent to alveolar ducts without any adverse tissue response throughout 13 wk of exposure and following 13 wk of recovery. This exposure concentration was considered to be a no-observable-adverse-effect level (NOAEL), since the alveoli containing fiber-laden AMs preserved normal structure. After 13 wk of exposure to 10 mg/m³ (952 WHO fibers/cm³), fiber-laden AMs were mainly retained at the alveoli adjacent to the alveolar ducts. Infrequently, slight fibrotic thickening was observed in the alveolar ducts and adjoining alveoli, with proliferating fibroblasts and hyperplastic Type II pneumocytes, and microgranulomas. Occasionally, trace amounts of collagenous material were deposited in the thickened alveolar ducts and adjoining alveolar walls. In addition, minimal alveolar bronchiolarization was occasionally found in the alveoli adjacent to the terminal bronchioles. The peribronchial lymphoid tissue and thymic lymph nodes contained migrated fiber-laden AMs. After 13 wk of recovery, fiber-laden AMs had mostly disappeared from alveoli located in the peripheral acini, but they localized in the alveolar ducts region, suggesting there was active lung clearance of fibers by the AMs via airways. Thickened alveolar ducts and adjacent alveoli were decreased in thickness, a reversible change manifested by reduction of proliferating Type II pneumocytes and fibroblasts. Collagenized fibrosis was slightly more pronounced in the thickened alveolar ducts and adjoining alveoli. The lung response following 13 wk of exposure to 100 mg/m³ (7440 WHO fibers/cm³) and after 13 wk of recovery was similar to those findings of the 952 WHO fibers/cm³ group but more pronounced, demonstrating a clear concentration-related response. Alveolar ducts and adjoining alveolar walls in the central acini were irregularly thickened with more frequent evidence of minimal collagenized fibrosis. The lung burden and clearance of fibers were estimated by measuring the total content of titanium (Ti) in the lungs, but high variability of Ti content in control and exposed groups prevented meaningful lung clearance analysis.     

DEVELOPMENTAL TOXICITY STUDY OF TETRAMETHYLUREA (TMU) IN RATS

The developmental toxicity of tetramethylurea (TMU) was assessed in rats by inhalation exposure of the test material over days 6–20 of gestation. Groups of 25 mated female Crl:CD®BR rats were exposed whole-body for 6 hours/day to concentrations of either 0, 2, 20 or 100 ppm TMU. The dams were euthanized on day 21 and the offspring were weighed, sexed, and examined for external, visceral, and skeletal alterations. Maternal toxicity was demonstrated at both 20 and 100 ppm. Maternal body weights, weight changes, and food consumption were statistically significantly reduced at these concentrations; effects were more pronounced at 100 ppm. There was evidence of developmental toxicity only at 100 ppm. The only finding was a decrease in mean fetal weight. No fetal malformations or variations occurred in fetuses derived from rats exposed to all 3 test concentrations (up to 100 ppm). The maternal no-observed-effect-level (NOEL) was 2 ppm, the fetal NOEL was 20 ppm. Thus, TMU was not considered to be uniquely toxic to the rat conceptus.     

INHALATION TOXICITY OF 4-ETHOXYANILINE (p -PHENETIDINE): CRITICAL ANALYSIS OF RESULTS OF SUBACUTE INHALATION EXPOSURE STUDIES IN RATS

This article addresses results from a single 4-h and repeated 1- and 4-wk inhalation exposure studies in Wistar rats with vapor and/or aerosol atmospheres of 4-ethoxyaniline (p -phenetidine). Groups of 10 rats/sex were exposed nose-only to mean analytical concentrations of 11.1, 86.2, and 882.6 mg p -phenetidine/m 3 using an exposure regimen of 6 h/day, 5 days/wk for 4 wk. Concentrations were selected based on results from a pilot study in which rats were exposed under identical conditions on 5 consecutive days for 6 h/day to mean analytical concentrations of 38.2, 133.0, and 1247.6 mg/m 3. In repeated exposure studies, the focus of endpoints was on hematotoxicity. The LC50 was not determined, but no rats died following a single 4-h exposure to 5085 mg/m 3 as a mixture of vapor and aerosol. No mortality was observed either in the 1- or 4-wk studies. Rats exposed to 882.6 mg/m 3 and above evoked characteristic signs of toxicity that included cyanosis, with no apparent progression of findings during the exposure period. Animals exposed to 86.2 mg/m 3 and above exhibited a concentration-dependent, significant increase in blood methemoglobin and reticulocyte counts as well as a significant decrease in hemoglobin, hematocrit, and red blood cell counts. Spleen weights were significantly increased in groups exposed to 133.0 mg/m 3 and above. Microscopic changes demonstrated an increased hematopoiesis (bone marrow smears) and splenic hemosiderosis at 86.2 and 882.6 mg/m 3 and a hepatic hemosiderosis only at 882.6 mg/m 3. These data suggest that the toxicity of p -phenetidine is similar to that of its structural analog aniline. Based on the erythrocytotoxicity occurring at 86.2 mg/m 3 and above, including the apparent reactive changes in bone marrow (increased erythropoiesis) and spleen (increased erythroclasia), the no-observed-adverse-effect level (NOAEL) of the 4-wk study was 11.1 mg/m 3 air and that of the 1-wk study was 38.2 mg/m 3 air. This difference in NOAELs is considered to be related to the selection of exposure concentrations rather than cumulative toxicity.     

CHRONIC TOXICITY AND ONCOGENICITY OF N-METHYLPYRROLIDONE (NMP) IN RATS AND MICE BY DIETARY ADMINISTRATION

A two-year feeding study in rats and an 18-month feeding study in mice were conducted to evaluate the potential chronic toxicity and oncogenicity of NMP in Crl : CD® (SD)BR rats and B6C3F1/CrlBR mice. Groups of 62 male and female rats were administered diets containing 0, 1600, 5000, or 15 000 ppm of NMP for approximately 2 years. Groups of 50 male and female mice were administered diets containing 0, 600, 1200, or 7200 ppm NMP for approximately 18 months. In vivo parameters were evaluated weekly during the first 3 months of the study, and every other week or monthly during the remainder of the study. For rats, an ophthalmoscopic examination was conducted prior to study start and near the end of the study. Periodically, blood samples were collected from rats and mice for determination of leukocyte differential counts, and from mice for red blood cell morphology. After approximately 2 years of dietary administration in rats and 18 months in mice, all surviving animals were sacrificed. Selected tissues were processed for morphological evaluation. Over the course of the two-year study in rats, test substance-related decrements in body weight and weight gain occurred in 15 000 ppm males and females, which correlated with decreased food consumption and food efficiency. A toxicologically significant, test substance-related increase in the incidence of severe chronic progressive nephropathy occurred in 15 000 ppm males. Several morphological changes noted grossly and/or microscopically were secondary to the increased severity of chronic progressive nephropathy. NMP was not oncogenic in male or female rats at dietary concen trations of 15000 ppm and below. A test substance-related decrease in the percentage of 15 000 ppm males surviving to the end of the two-year study compared to the control group resulted from the higher incidence of severe chronic progressive nephropathy. However, a sufficient population of 15000 ppm rats were at risk for potential oncogenicity, so the lower survival did not impair the ability to detect an oncogenic response in this study. There were no adverse, test substance-related effects on the incidences of clinical observations, ophthalmic observations, or differential leukocyte counts in males or females, or on survival of females at any dietary concentration. Male and female mice administered dietary concentrations of 7200 ppm had significantly increased liver weight, significantly increased incidence of hepatocellular adenoma, and significantly increased foci of cellular alteration in the liver. At 7200 ppm, male mice also had an increased incidence of hepatocellular carcinoma while the increased incidence of hepatocellular carcinoma in female mice fell within the historical control range. In addition, the incidence of hepatocellular hypertrophy was increased in 7200 ppm males. Liver weight and hepatocellular hypertrophy were also increased in 1200 ppm males. There were no adverse, test substance-related effects on the incidences of clinical observations, food consumption, body weight, differential leukocyte counts, red blood cell morphology, or survival in either males or females at any dietary concentration. Under the conditions of the study, the no-observed-effect level for NMP was 5000 ppm for male and female rats, 600 ppm for male mice, and 1200 ppm for female mice.     

REPRODUCTIVE AND REPEATED DOSE TOXICITY OF CYCLODODECATRIENE (CDDT) IN RATS FOLLOWING ORAL (GAVAGE) TREATMENT

ABSTRACT

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD®(SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1–2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.     

TWO-WEEK INHALATION TOXICITY OF POLYMERIC DIPHENYLMETHANE-4,4'-DIISOCYANATE (PMDI) IN RATS: Analysis of Biochemical and Morphological Markers of Early Pulmonary Response

The pulmonary response of Wistar rats to respirable polymeric diphenylmethane-4,4'-diisocyanate (PMDI) aerosol was examined in a 2-wk repeated nose-only inhalation exposure study. Exposure concentrations were 1.1, 3.3, and 13.7 mg PMDI/m³ (6 h/day, 15 exposures). The level of 13.7 mg/m³ was actually a combination of an initial target concentration of 10 mg/m³ in wk 1, which was raised to 16 mg/m³ in wk 2, due to a lack of signs suggestive of pulmonary irritation. An acute sensory irritation study on rats served as basis for selection of these concentrations. Shortly after the 2-wk exposure period, rats were subjected to pulmonary function and arterial blood gas measurements. Lungs were examined by light and transmission electron microscopy, and labeling indices in terminal bronchioles were measured. Bronchoalveolar lavage (BAL) was performed to assess various indicators of pulmonary inflammation, including neutrophil and macrophage numbers, protein, lactate dehydrogenase (LDH), gamma-glutamyltranspeptidase (gamma-GT), alkaline phosphatase (APh), acid phosphatase (ACPh), and beta-N-acetylglucosaminidase (beta-NAG). Phosphatidylcholine in BAL fluid and BAL cells was determined as aggregated endpoint suggestive of changes in pulmonary surfactant. Rats exposed to 3.3 and 13.7 mg/m³ experienced concentration-dependent signs of respiratory tract irritation. Determination of arterial blood gases, lung mechanics, and carbon monoxide diffusing capacity did not demonstrate specific effects. Analysis of BAL fluid and BAL cells revealed changes indicative of marked inflammatory response and/or cytotoxicity in rats exposed to 13.7 mg/m³, and the changes were characterized by statistically significantly increased activities of LDH, beta-NAG, and protein. Phospholipid concentrations were increased in rats exposed to 1.1 mg/m³ and above (elevated levels of lipid material in alveolar macrophages demonstrated by polychrome stain) and 3.3 mg/m³ and above (increased intracellular ACPh activity and intracellular phospholipids). In these groups, gamma-GT was statistically significantly increased. These findings suggest that changes in phospholipid homeostasis appear to occur at lower levels than those eliciting inflammation and cytotoxicity. Light and transmission electron microscopy suggest that exposure to 3.3 and 13.7 mg/m³ resulted in focal inflammatory lesions and an accumulation of refractile, yellowish-brownish material in alveolar macrophages with concomitant activation of type II pneumocytes. In the terminal bronchioles a concentration-dependent increase of bromodeoxyuridine (BrdU)-labeled epithelial cells was observed in all PMDI exposure groups. In summary, it appears that respirable PMDI aerosol interacts with pulmonary surfactant, which, in turn, may stimulate type II pneumocytes to increase their production of surfactant and to proliferate.     

反相高效液相色谱法测定大鼠血浆中左旋黄皮酰胺及其主要代谢产物和药代动力学

目的　探讨左旋黄皮酰胺［（-）clau］及其主要代谢产物6-OH-clau在大鼠体内的药代动力学。方法　建立了RP-HPLC-UV法。固定相为Kromasil-100 C₁₈（5 μm）色谱柱,流动相为乙腈-甲醇-水（21∶16.5∶62.5), DM-9384作内标,氯仿作提取溶剂。结果　测得（-）clau的回收率为96.91%～105.74%,日内、日间RSD低于7%,最低检测浓度为24 ng.mL^-1,（-）clau和6-OH-clau分别在0.047～968 μg.mL^-1和0.049～200 μg.mL^-1,线性关系良好(γ=0.999); （-）clau和6-OH-clau血浆浓度-时间曲线符合二室开放模型,同时求得两者的药代动力学参数。结论　数据表明（-）clau在大鼠血浆中的分布、代谢转化和消除均较快。     

(+),(-)和(±)棉酚在雌大鼠抗早孕作用的研究

妊娠第6～9天大鼠,分别ig(±)和(-)棉酚80mg·kg^-1·d^-1和40mg·kg^-1·d^-1,结果有明显的抗早孕作用。然而(+)棉酚40mg·kg^-1·d^-1对大鼠生育无明显影响。(-)棉酚30μg·ml^-1能抑制体外培养黄体细胞孕酮的分泌。(+)棉酚10μg·ml^-1能促进黄体细胞分泌孕酮。hCG1IU·ml^-1能明显刺激体外培养颗粒细胞孕酮的分泌。(±)棉酚10和30μg·ml^-1皆能明显降低颗粒细胞对hCG的反应性。     

GENDER DIFFERENCES IN ACUTE N -(3,5- DICHLOROPHENYL)-2-HYDROXYSUCCINIMIDE (NDHS) AND N -(3,5-DICHLOROPHENYL)-2-HYDROXYSUCCINAMIC ACID (2-NDHSA) NEPHROTOXICITY IN FISCHER 344 RATS

N -(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide that induces nephrotoxicity as its major toxicity. NDPS is also a more potent nephrotoxicant in female than in male rats. The purpose of this study was to examine the nephrotoxic potential of the two NDPS metabolites N -(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N -(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) in agematched male and female Fischer 344 rats to determine if gender differences exist for the nephrotoxicity induced by the two NDPS metabolites. Rats (4 per group) were administered a single intraperitoneal (ip) injection of NDHS or 2-NDHSA (0.025 or 0.05 mmol/kg) or vehicle, and renal function was monitored for 48 h. Neither compound induced significant nephrotoxicity in male rats at the doses tested. However, in female rats both metabolites induced marked nephrotoxicity at the 0.05 mmol/kg dose level, and treatment with 0.025 mmol/kg 2-NDHSA induced some changes in renal function (transient diuresis, transient proteinuria, decreased organic ion accumulation). Little effect on renal function was induced in females by treatment with 0.025 mmol/kg NDHS. At toxic levels in female rats, the renal lesions were located primarily in the S2 and S3 segments of the proximal tubule. These results indicate that, like the parent compound, gender differences exist in the nephrotoxic potential of NDHS and 2-NDHSA. The results also suggest that in females, as in males, NDPS nephrotoxicity is mediated via NDHS and/or 2-NDHSA. However, it is not clear if the ultimate nephrotoxicant species following NDPS exposure is different in males and females or if the same ultimate nephrotoxicant species is produced in both species but handled differently by male and female kidneys. Thus, further studies are needed to determine the exact nature of the ultimate nephrotoxicant species and the mechanisms of the observed gender differences.     

DISPOSITION OF 3-CHLORO-4-(DICHLOROMETHYL)-5-HYDROXY-2(5 H )-FURANONE (MX) IN B6C3F1 MICE AND F344 RATS

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5 H )-furanone (MX) is a mutagenic by-product of chlorination of drinking water, particularly where the water contains humic matter. MX has been estimated to account for 50% of the mutagenic activity in some drinking water. A bioassay in rats demonstrated an increased tumor incidence, primarily in liver and thyroid glands. This study was designed to provide disposition/metabolism information in mice to evaluate the necessity of a National Toxicology Program chronic bioassay and to provide data for female rats. Radioactivity was rapidly absorbed and excreted near equally in urine (42-54%) and feces (40-51%) 72 h following oral administration of 14 C-labeled MX at single doses from 0.2 to 20 mg/kg to male and female mice and female rats. A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 h postdosing. MX was transformed to urinary and biliary metabolites. A major extremely polar urinary metabolite was tentatively identified as 1-hydroxy-1,2,2-ethanetricarboxylic acid. This metabolite is likely transformed from the MX degradation product 2-hydroxy-3-formyl-4-oxo-2-butenoic acid. Oral administration produced highest tissue/blood ratios in the following order: forestomach (>100), glandular stomach, intestine, and kidney. Intravenous administration resulted in high, prolonged levels of radioactivity in blood compared to oral dosing. Therefore, MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration.     

7-甲氧基-4′-羟基-3′-二乙胺甲基异黄酮(MHDF)对大鼠血流动力学和主动脉的作用

本实验观察了MHDF对整体大鼠血流动力学和离体大鼠胸主动脉的作用。结果表明iv MHDF(3～12.8 mg/kg)能降低大鼠左心室±dp/dt_(max),V_(max),V_(pm)和LVSP,延长T-dp/dt_(max),减慢心率。MHDF还能舒张大鼠胸主动脉,ED_(50)为6.5×10~(-6)mol/L;非竞争拮抗NA和CaCl_2致主脉收缩,pD_2′为3.11±0.21和3.73±0.07;抑制高K~ 致主动脉收缩,IC_(50)为1.76×10~(-5)mol/L。提示MHDF对血管的作用与α受体阻断剂不同,而可能与钙拮抗有关。     

7-甲氧基-4′-羟基-3′-二乙胺甲基异黄酮(MHDF)对大鼠血流动力学和主动脉的作用

本实验观察了MHDF对整体大鼠血流动力学和离体大鼠胸主动脉的作用。结果表明iv MHDF(3～12.8 mg/kg)能降低大鼠左心室±dp/dt_max,V_max,V_pm和LVSP,延长T-dp/dt_max,减慢心率。MHDF还能舒张大鼠胸主动脉,ED₅₀为6.5×10^-6mol/L;非竞争拮抗NA和CaCl₂致主脉收缩,pD₂′为3.11±0.21和3.73±0.07;抑制高K⁺致主动脉收缩,IC₅₀为1.76×10^-5mol/L。提示MHDF对血管的作用与α受体阻断剂不同,而可能与钙拮抗有关。     

消旋（15R）－15甲基PGE_2甲酯（PG_6E）对大鼠实验性胃溃疡的保护作

用实验性胃溃疡模型研究了ＰＧ＿６Ｅ的抗溃疡作用，结果表明ＰＧ＿６Ｅ有抗胃酸分泌作用，而对胃肠运动无明显影响；ＰＧ＿６Ｅ在剂量为１０一８０μｇ·ｋｇ－１时，对无水乙醇型、盐酸型、消炎痛型、慢性醋酸型和幽门结扎型胃溃疡有明显保护作用，并能显著减少幽门结扎大鼠的胃液体积、胃酸分泌、胃蛋白酶活性和ＤＮＡ含量。小鼠ｐｏＰＧ＿６Ｅ３０～６０μｇ·ｋｇ－１，３ｄ后粘膜氨基己糖含量显著增加。研究结果提示ＰＧ＿６Ｅ能抑制对胃粘膜的攻击性因素，增加保护性因素的作用，可望成为一种新型抗胃溃疡药     

强啡肽A(1-17)在脊髓的致瘫作用及其与神经毒作用的相关性

在以行为学为观察指标(甩尾镇痛和斜板实验)的基础上,用组织学方法探讨大剂量强啡肽A在脊髓水平的致瘫作用与其神经毒作用的关系。结果表明,给大鼠蛛网膜下腔(it)注射强啡肽A(1-17)20nmol·L^-1,共10μl,给药后5～10min即引起大鼠后肢不可逆性瘫痪、甩尾反射被抑制长达40h以上。大鼠脊髓组织学检查发现,腰、骶段脊髓前角运动神经元大量坏死或严重变性、以腰段损伤最为显著(运动神经元减少87.2%),其次是骶段(减少69.6%),胸段损伤不明显(减少8.2%)。     

5-乙基-5-对氟苯甲酰丙基巴比妥酸在兔体内的代谢产物研究

用高效液相色谱法对5-乙基-5-对氟苯甲酰丙基巴比妥酸在家兔体内的代谢物进行了分离,用二极管阵列检测器测定了原药及代谢物紫外图谱,得出代谢物的紫外吸收性质;同时测试了原药及代谢物的质谱,推测出代谢物的可能结构,并用化学方法合成了代谢物对照品,通过核磁和质谱的测定进一步确证了结构。     

丙氨瑞林对大鼠,兔异位内膜的抑制作用

采用异位内膜模型大鼠和兔，以那法瑞林、达那唑、双侧卵巢切除（ＯＶＸ）作为阳性对照，观察了丙氨瑞林（１）对异位内膜的抑制作用。结果表明皮下或肌肉注射１１０～１００μｇ／ｋｇ有明显抑制作用，且具一定的剂量相关性。该作用较达那唑强，可达ＯＶＸ水平。但较那法瑞林为弱。这一作用是１的药物性去势作用的结果。     

STUDIES OF THE INTERACTION OF BOVINE NEUROPHYSIN-II WITH [1-HEMI-d-(3-13 C)CYSTINE] OXYTOCIN AND [1-HEMI-(3-13 C)CYSTINE] OXYTOCIN

The interactions of [1-hemi-(3-¹³C)cystine]oxytocin and [1-hemi-D-(3-¹³C) cystine]oxytocin with bovine neurophysin-II have been studied in aqueous solution under various conditions of pH using carbon-13 (¹³C) nuclear magnetic resonance spectroscopy (n.m.r.). We have monitored changes in ¹³C chemical shifts (δ), spin-lattice relaxation times (T₁) and linewidths (πT₂*)^-1 of the [1-hemi-(3-¹³C)cystine] oxytocin as a function of the concentration of added neurophysin. [1-Hemi-d -(3-¹³C)cystine]oxytocin does not interact with neurophysin and shows no changes in the above spectral parameters as a function of increasing protein concentrations. The ¹³C chemical shifts have been monitored as a function of pH for both ¹³C-enriched, diastereoisomeric oxytocin analogs in the presence and absence of neurophysin. The midpoints of the pH-titration curves for [1-hemi-(3-¹³C)cystine]oxytocin and [1-hemi-d -(3-¹³C) cystine]oxytocin in the absence or presence of neurophysin are 6.2 and 5.5, respectively. T₁ values are independent of pH for both peptides in free solution, and the rotational correlation times (t_c) obtained for the peptides are of the order of magnitude expected from the Stokes-Einstein relation (5.0 times 10^-10 sec rad^-1). T₁ values decrease and linewidths increase for [1-hemi-(3-¹³C)cystine]oxytocin in the presence of neurophysin. Fast-exchange on the n.m.r. time scale occurs at low pH. Only broad lines can be detected at neutral pH rendering ¹³C T₁ measurements difficult. It appears that increasing the concentration of neurophysin in the presence of [1-hemi-(3-¹³C)cystine]oxytocin leads to aggregation of the system as judged by the ¹³C T₁ results and corresponding rotational correlation times. In light of the significant changes in T₁ values and small changes in δ values, it would seem that T₁ measurements are more accurate monitors of peptide-protein interactions than are ¹³C chemical shifts when the interaction of the peptide with the protein does not involve any changes in steric constraints of the peptide being monitored.