Acid and alkaline phosphatase activities in a novel phosphorothionate (RPR-11) treated male and female rats. Evidence of dose and time-dependent response

The effect of a novel phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) was studied on membrane bound target enzymes Acid (AcP) and Alkaline (AkP) Phosphatases in different tissues of male and female albino Wistar rats. Three sub-chronic doses 0.014 (low), 0.028 (medium) and 0.042 (high)mg/kg-1 were administered to the rats daily for a period of 90 days. The long term and repeated administration of RPR-II caused significant increase of AcP and AkP in serum and kidney (AcP), whereas these enzymes simultaneously decreased significantly in liver, kidney (female rat AkP) and lung tissues in both male and female rats after 45 and 90 days of treatment. However, the kidney AcP increased significantly in both the sexes which is suggestive of an increase in synthesis of this enzyme which may be an adaptive mechanism to the toxicant stress. The changes in serum, liver, kidney and lung of both male and female rats by this compound were statistically significant when compared with two way Anova showing that they are dose and time dependent. The alterations in male rats were statistically insignificant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days of post treatment (withdrawal study) indicating reversal of the toxic symptoms once the toxicant is removed. High degree negative correlation was observed for serum versus liver and lung and in other cases substantial correlation was observed. The changes observed in these enzymes showed that liver was most susceptible followed by lung and kidney. There are marker enzymes and their increase in different tissues might be due to the increased permeability of plasma membrane or cellular necrosis, showing the stress condition of the treated rats. This investigation elucidates the effect of these biomarker enzymes which increased in blood, might be due to the necrosis of liver, kidney and lung tissues by this compound.     

Effects of Vepacide (Azadirachta indica) on aspartate and alanine aminotransferase profiles in a subchronic study with rats

The aim of this study was to ascertain the long-term effects of Vepacide, a neem-based pesticide on biochemical profiles. Albino Wistar rats were treated orally with 80 (low), 160 (medium) and 320 mg/kg (high) doses of Vepacide in coconut oil for 90 days. Control rats received the same volume of the vehicle. Vepacide caused increase of aspartate and alanine aminotransferase in serum, kidney and lung, and these enzymes decreased in liver in both male and female rats when measured after 45 and 90 days of treatment. The two-way analysis of variance (ANOVA) showed that the alterations in these enzymes were dose- and time-dependent. Sexual dimorphism was observed when male rats were compared with female rats (Student t-test at P< 0.05). Positive correlation was observed with regard to these enzymes between serum, kidney and lung, whereas in the case of serum and liver, a negative correlation was recorded. These enzyme profiles elucidate that they increased in serum with simultaneous decrease in liver, indicating necrosis of liver, whereas in other tissues, the level of enzymes increased, showing an adaptive mechanism due to the chemical stress. The affected enzymes were recovered to normal conditions after 28 days of post-treatment (withdrawal study). Due to the Vepacide treatment, lung was more affected followed by liver and kidney. This study has indicated that these enzymes could be useful as biomarkers for the insult of any toxicant. Besides, they can also help in predictive toxicology.     

Biochemical Changes Induced in Liver and Serum of Diplodiatoxin (Stenocarpella maydis) Treated Male and Female Rats

Abstract

Present study was conducted to investigate the acute and sub-acute toxic effect of diplodiatoxin with special reference to biochemical membrane bound enzymes like aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and RBC acetylcholinesterase (AChE) in male and female rats. For acute study, rats were treated with a single oral dose of 5.7 mg/kg of diplodiatoxin, whereas for sub-acute study, the rats received 0.27 mg/kg/day for 21 days. Acute and sub-acute diplodiatoxin treatment caused loss in body weight and feed intake along with symptoms including irritation, dullness, tremors and convulsions. Diplodiatoxin caused a significant increase in serum ASAT and ALAT and a decrease in activity in the liver in both acute and sub-acute studies. This compound also significantly inhibited RBC AChE. Sexual dimorphism was observed when male rats were compared with female rats (p<0.05). The enzyme alterations observed in the affected enzymes recovered to the normal levels by day 7 post treatment (withdrawal study) in both acute and sub-acute treated rats. A negative correlation was observed with regard to these enzymes when serum was compared with liver. These enzyme profiles show increases in serum with parallel decrease in liver, indicating necrosis of liver. These results suggest that diplodiatoxin has potential to affect hepatic end-points.     

Biochemical changes induced in liver and serum of diplodiatoxin (Stenocarpella maydis) treated male and female rats

Present study was conducted to investigate the acute and sub-acute toxic effect of diplodiatoxin with special reference to biochemical membrane bound enzymes like aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and RBC acetylcholinesterase (AChE) in male and female rats. For acute study, rats were treated with a single oral dose of 5.7 mg/kg of diplodiatoxin, whereas for sub-acute study, the rats received 0.27 mg/kg/day for 21 days. Acute and sub-acute diplodiatoxin treatment caused loss in body weight and feed intake along with symptoms including irritation, dullness, tremors and convulsions. Diplodiatoxin caused a significant increase in serum ASAT and ALAT and a decrease in activity in the liver in both acute and sub-acute studies. This compound also significantly inhibited RBC AChE. Sexual dimorphism was observed when male rats were compared with female rats (p < 0.05). The enzyme alterations observed in the affected enzymes recovered to the normal levels by day 7 post treatment (withdrawal study) in both acute and sub-acute treated rats. A negative correlation was observed with regard to these enzymes when serum was compared with liver. These enzyme profiles show increases in serum with parallel decrease in liver, indicating necrosis of liver. These results suggest that diplodiatoxin has potential to affect hepatic end-points.     

Sex difference in inhalation toxicity of p-dichlorobenzene (p-DCB) in rats

The organ distribution and toxicity of p-dichlorobenzene (p-DCB) were compared in male and female rats after inhalation of 500 ppm of p-DCB for 24 h in a whole-body chamber. Concentrations of p-DCB in the serum, liver, kidney and fatty tissues were measured by gas chromatography at intervals during and up to 24 h after the treatment. Though no significant differences in the serum levels were observed between male and female rats, the p-DCB values in the livers of female rats were significantly higher than those of male rats. Conversely, significantly higher levels were found in the kidneys of male than of female rats. The distribution results thus appeared to correlate with the fact that nephrotoxic changes were observed only in male rats and that the appearance of minor hepatotoxic changes was limited to females.     

The cytochromes P-450 concentrations in microsomes of liver, kidney and duodenal mucosa of the camel, sheep and goat

The concentration of microsomal cytochromes P-450, and of protein in the homogenate, cytosol and microsomes were measured in the liver, kidney and duodenal mucosa of healthy well-fed male and female camels, sheep and goats. For comparison, data from the liver of male and female rats were also obtained. The protein concentrations in the tissues of adult animals were broadly similar in the four species. The concentration of cytochromes P-450 was highest in the liver, followed by the kidney, then the duodenal mucosa in all the species. No cytochromes P-450 were detected in the tissues of immature (less than 1 mo) male goats, whereas the female goat had the highest concentrations of these enzymes in the liver and kidney when compared with the respective tissues in the other species studied. Males had higher activity of cytochromes P-450 than females in the three tissues, except in the duodenal mucosa of sheep, where males had lower activity than females. In camel liver and sheep kidney, the amount of cytochromes P-450 were similar in the two sexes. The present results suggest that the mature female goat is the species best equipped to handle xenobiotics which are detoxified by the cytochromes P-450 and other drug metabolizing enzymes in diseased or malnourished animals is suggested as these two conditions are known to modify drug metabolizing enzymes.     

Induction of aryl hydrocarbon hydroxylase by 3-methylcholanthrene in liver,lung and kidney of gonadectomized and sham-operated wistar rats

Detailed dose-response curves have been obtained for the induction of aryl hydrocarbon hydroxylase (AHH) m liver, lung and kidney by intraperitoneally administered 3-methylcholanthrene (3-MC) in Wistar rats. The effects of gonadectomy also were studied. Lung was the tissue most sensitive to induction, followed by liver, and then kidney in all cases. Although liver exhibited the greatest overall activity, the per cent increase over control AHH levels was much higher in the two extrahepatic tissues. Gonadectomy did not affect either control or induced AHH activity in any of the three organs in the female, or in the male lung. However, castration of the males decreased control liver enzyme levels and increased these levels in kidney. The AHH levels reached after maximal 3-MC induction were the same in castrated and sham-operated male rat livers. A different pattern was seen in male kidney enzyme levels where significantly increased maximal induction was observed in castrated animals.     

Metabolic alterations after chronic exposure to -chlordane

Daily injection of α-chlordane (5 mg/kg) for 45 days significantly stimulated the activities of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphosphatase and glucose-6-phosphatase in liver and kidney cortex of male rats. Statistically significant increases in the quartet of the key, rate-limiting gluconeogenic enzymes in two tissues were noted within 20 days when the daily amount of α-chlordane was raised to 25 mg/kg. Long-term exposure to either dose of the insecticide for 45 days also elevated the concentration of serum urea. The present results together with our previous findings suggest that chronic administration of α-chlordane is as effective as DDT in enhancing the gluconeogenic capacity of both kidney cortex and liver.     

Interaction of monocrotophos and its novel thion analogues with microsomal cytochrome P-450: in vivo and in vitro studies in rat.

The binding of monocrotophos (MCP) and its two thion analogues (coded as RPR-II and RPR-V) to rat hepatic microsomal cytochrome P-450 (HMC) were investigated in vitro by difference spectroscopy. These three organophosphorus insecticides were found to bind stoichiometrically to HMC with very high affinity (Ks 34-50 microM). RPR-V showed the highest binding affinity followed by RPR-II and MCP. Association of these compounds with HMC occurred within 2 min of addition in the cuvette and therefore, appeared to be tight binding ligands of cytochrome P-450. In vivo studies at equitoxic doses of the three compounds 24 h after oral treatment in rats revealed that they all caused reduction in MC content in liver, lung, kidney and brain, as against induction in cardiac and splenic cytochrome P-450. These in vivo results suggest organ specificity in modulating the microsomal cytochrome P-450 (MC) content of hepatic and extra-hepatic tissues by the three compounds. Apparently, their binding affinity with HMC is strongly correlated with their LD50 value and has a substantial co-relationship with the cytochrome P-450 level in the liver.     

性别差异对异补骨脂素在大鼠体内吸收和分布的影响

目的：目的研究异补骨脂素（iopsoralen,IPO）在雌雄大鼠体内药动学和组织分布特征,探讨性别差异对IPO体内吸收和分布的影响。方法：通过单次灌胃给予雌雄大鼠80 mg·kg^-1IPO溶液,采用HPLC法测定不同时间点雌雄大鼠血浆和主要脏器（肝、肾、心、脾、肺）中IPO的含量,应用DAS 2.0计算主要药动学参数、SPSS 19.0进行统计学分析。结果：血浆药动学结果发现,雌雄大鼠血浆中IPO浓度变化趋势基本一致,但雌鼠血浆中AUC显著高于雄鼠。组织分布结果发现,IPO在雌雄大鼠肝肾组织中暴露量高于其他组织,其中IPO在雌鼠肝脏中AUC_0-t为（1 439.08±84.27） mg·h·L^-1,显著高于雄鼠（1 239.55±26.25） mg·h·L^-1（P<0.05）。结论：IPO在雌雄大鼠体内进程存在显著性别差异,主要表现为雌性大鼠血浆和肝组织中暴露量显著高于雄鼠,这可能是IPO易引起雌性大鼠肝损伤的原因。     

SD大鼠经鼻腔给予神经干细胞方法初探

目的：采用大鼠鼻腔给药,建立可模拟干细胞给药新途径的临床前给药方法,为开展干细胞临床前安全性评价奠定基础。方法：将32只Sprague Dawley(SD)大鼠,随机分为2组：溶媒对照组、受试物组,每组16只动物,雌雄各半。采用鼻腔给药法,溶媒对照组给予生理盐水,受试物组给予人源神经干细胞(Neural Stem Cells,NSCs),给药剂量为1×107 cells·kg-1。于给药后24 h和6 d,对大鼠实施麻醉后暴露心脏,完成心脏采血并进行心脏灌流固定,取脑(纹状体、黑质、皮层、海马、小脑)、血、 心、肝、脾、肺、肾、睾丸及附睾(雄性)、卵巢(雌性),脏器、组织进行固定,取材后进行免疫荧光试验,研究神经干细胞在上述组织器官中的分布情况。结果：大鼠鼻腔给予神经干细胞后24 h和6 d, 脑组织的纹状体、黑质、皮层、海马、小脑部位均可见神经干细胞分布。外周组织心、肝、脾、肺、 肾、睾丸及附睾(雄性)、卵巢(雌性)、外周血均未见有阳性细胞。结论：临床前研究表明,神经干细胞可以通过鼻腔给药方式吸收入脑治疗脑部疾病。     

Effect of tobacco-leaf extract administration on liver,lung, intestine,and serum enzymes

Tobacco-leaf extract induced benzpyrene hydroxylase activities of liver and lung of male albino rats after 7, 30, and 62 days of oral administration. Aniline hydroxylase activity of liver and lung showed an increase after 30 days of administration, while the N-demethylase activity of liver showed a small increase at the first phase and a decrease after 62 days. Of the lysosomal enzymes investigated, β-glucuronidase activity of both liver and lung showed a significant increase. Increased activities of hepatic lysosomal acid phosphatase was observed at 7 and 30 days of leaf-extract administration. A decrease was observed in sucrase and maltase activities of intestinal brush border after 7 and 30 days of tobacco-leaf extract administration. No significant change in serum enzymes was observed under the conditions of the present study.     

Inhalation Toxicity of Phosphine for Fischer 344 Rats and B6C3F1 Mice

Abstract

Because of the potential increased use of phosphine (PH₃) as a fumigant and the lack of adequate toxicity data, short-term inhalation studies were conducted to characterize the toxicity of PH₃ for Fischer 344 (F344) rats and B6C3F1 mice. Male rats and mice were exposed to 0, 1, 5, or 10 ppm PH₃ for up to 4 days, and males and females to 0, 1.25, 2.5, or 5 ppm for 2 wk. In the 4-day study, all rats died by the end of the third exposure to 10 ppm, and all mice were euthanized in moribund condition after the fourth exposure to 10 ppm. Clinical pathology data were obtained only for mice, due to early mortality of rats. There were no significant treatment-related effects in hematological indices in mice exposed to 1 or 5 ppm; at 10 ppm there was a moderate anemia, and leukocyte counts were significantly decreased. There were significant biologically relevant increases in serum activity of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) and in the concentration of urine nitrogen (UN) at 10 ppm. Flectrophoretic evaluation of hemoglobin from mice exposed to 10 ppm did not reveal any differences in banding patterns from controls. Moribund mice euthanized after 4 exposures to 10 ppm had minimal to mild degeneration and necrosis of the renal tubule epithelium, minimal myocardial degeneration, and minimal to mild subcapsular foci of hemorrhage and necrosis in the liver. Bound PH₃ could not be detected in blood, lung, liver, or kidney of mice or lungs of rats exposed to 10 ppm for 3–4 days. There were no treatment-related mortalities in rats or mice exposed for 2 weeks. Lung weights of male rats and mice were significantly decreased and heart weights of female rats and mice were significantly increased after 2 wk of exposure to 5 ppm. Slight but statistically significant increases were observed in serum UN in male mice exposed to 5 ppm. There was no microscopic evidence of treatment-related effects in any of the tissues examined from rats or mice exposed to 5 ppm for 2 wk. Bound PH₃ could not be detected in blood, lung, liver, or kidney of mice or rats exposed to 5 ppm for 2 wk. These studies demonstrated that PH₃ inhalation does not cause a specific target organ toxicity in the B6C3F1 mouse or F344 rat, and that the primary hazard of subchronic inhalation in these species is lethality.     

Constitutive and induced expression by pyridine and β-naphthoflavone of rat CYP1A is sexually dimorphic

Adult male and female Sprague-Dawley rats were compared in terms of the constitutive levels and inducibility of CYP1A1 and CYP1A2 (CYP1A) in lung, kidney, and liver. CYP1A were induced by i.p. treatment with pyridine (75 mg/kg per day) or β-naphthoflavone (βNF; 25 mg/kg per day) for two consecutive days and analyzed catalytically (via O-dealkylation of resorufin ethers), at the protein level (by Western blot analysis) and at the mRNA level (by Northern blot analysis). In untreated rats, CYP1A1 protein and its mRNA were detectable only in the lung and kidney of females but not males, whereas CYP1A2 protein and its mRNA were detectable only in the liver in either gender. Pyridine treatment upregulated CYP1A1 mRNA and its protein in the lung, kidney and liver in female rats, and upregulated the mRNA but not the protein in the lung and liver in male rats. Conversely, pyridine induced both CYP1A2 mRNA and protein in the liver in female rats, whereas it induced the protein but not its mRNA in the liver in male rats. No gender difference was observed in the plasma elimination rate of administered pyridine. βNF, in contrast to pyridine, induced CYP1A proteins, activities, and mRNA to higher levels in male than in female rats. The results show that the constitutive as well as inducible expression of CYP1A is sexually dimorphic in the Sprague-Dawley rat, with females being more responsive than males to induction by pyridine but with males being more responsive than females to induction by βNF. The findings support the involvement of different mechanisms in CYP1A induction by pyridine and βNF. Received: 20 January 1999 / Accepted: 13 April 1999     

Cadmium Induced Changes in Gluconeogenic Enzymes in Rat Kidney and Liver

Male Sprague-Dawley rats were administered cadmium chloride 0, 50, 100, 150 and 200 ppm for 30 days. At the end of the treatments, the body weight gains, serum glucose, serum protein, serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were determined. Renal and hepatic key gluconeogenic enzymes; viz., pryuvate carboxylase, phosphoenol pyruvate carboxykinase, fructose-1, 6-diphosphatase and glucose-6-phosphatase were also determined. A significant decrease in body weight gain in rats treated with cadmium was observed. The serum glucose and protein levels were increased in rats receiving cadmium through feed. All four key gluconeogenic enzymes were increased in both kidney and liver tissues of rats treated with cadmium. The present results indicate that cadmium may induce gluconeogenesis from non-carbohydrate sources.     

14-Week toxicity and cell proliferation of methyleugenol administered by gavage to F344 rats and B6C3F1 mice.

Methyleugenol, a food flavor and fragrance agent, was tested for toxicity in male and female F344/N rats and B6C3F1 mice. Groups of 10 males and 10 females per sex per species were administered 0, 10, 30, 100, 300 or 1000 mg methyleugenol/kg body weight in 0.5% aqueous methylcellulose by gavage, 5 days per week for 14 weeks. Additional groups of rats and mice of each sex were dosed similarly and used for hematology and clinical chemistry studies. Groups of 10 male and 10 female rats and mice received the vehicle by gavage on the same dosing schedule and served as vehicle controls. For serum gastrin, gastric pH and cell proliferation studies groups of 10 female rats were given 0, 37, 75 or 150 mg/kg, once daily 5 days per week for 30 or 90 days or 300 or 1000 mg/kg for 30 days; male mice were given 0, 9, 18.5, 37, 75, 150 or 300 mg/kg for 30 or 90 days. For the gastrin, pH and cell proliferation studies, groups of 10 female rats and 10 male mice were given the vehicle for 30 or 90 days and served as controls. Methyleugenol administration to rats induced erythrocyte microcytosis and thrombocytosis in male and female rats. It also caused an increase in serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentration, suggesting hepatocellular injury, cholestasis or altered hepatic function. Additionally, methyleugenol induced hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations in both male and female rats, suggesting in inefficiency of dietary protein utilization due to methyleugenol-induced toxic effects on the liver and glandular stomach of rats and mice. The increase in gastrin and gastric pH of rats and mice given methyleugenol suggests that gastrin feedback was impaired and resulted in conditions not conducive to protein digestion. In rats, methyleugenol caused an increase in the incidences of hepatocyte cytologic alteration, cytomegaly, Kupffer cell pigmentation, mixed foci of cellular alteration and bile duct hyperplasia of the liver and atrophy and chronic inflammation of the mucosa of the glandular stomach. In mice, it caused an increase in the incidence of cytologic alteration, necrosis, bile duct hyperplasia and subacute inflammation of the liver and atrophy, degeneration, necrosis, edema, mitotic alteration, and cystic glands of the fundic region of the glandular stomach. The increased incidences of adrenal gland cortical hypertrophy and/or cytoplasmic alteration in the submandibular salivary glands, adrenal glands, testis and uterus of rats were considered secondary to the chemical-related effects observed in the liver and glandular stomach. Based on mortality, body weight gain, clinical chemistry and gross and microscopic evaluation of tissues of rats and mice, the no-observed-effect level (NOEL) of methyleugenol for both species was estimated at 10 mg/kg.     

Sex- and organ-specific toxicity in normal and malnourished rats fed thermoxidized palm oil.

The effects of free radical toxicity as induced by chronic consumption of thermoxidized palm oil (TPO) diet on organ size of normal animals, their first filial offspring and malnourished rats, were studied. Tissue- and sex-specific toxicity was revealed. The TPO diet significantly (P<0.01) reduced lung and kidney mass in normal male rats but female rats remained unaffected. Hearts of first filial offspring of both male and female rats were, however, enlarged while lung, liver and kidneys of first filial female offspring were additionally reduced in size (P<0.01). This information suggests that the observed toxicities could be cumulative for female offspring. Malnutrition protected against toxic injury because none of the kwashiorkoric animals rehabilitated on the toxic diet showed any overt symptoms of toxicity.     

Hematological and Clinical Chemistry Changes Induced by Subchronic Dosing of a Novel Phosphorothionate (RPR-V) in Wistar Male and Female Rats

A novel phosphorothionate [2-butenoic acid-3-(diethoxy phosphinothioyl)-ethyl ester; RPR-V] synthesized at Indian Institute of Chemical Technology (Hyderabad, India) was studied using subchronic doses of 0.033 (low), 0.066 (medium), and 0.099 (high) mg kg^{? 1} in male and female rats daily for 90 days. Continuous treatment with RPR-V caused significant (p < 0.05) decreases in body-weight gain, feed intake, hemoglobin (Hb), hematocrit (Hct), and total erythrocyte count (TEC), whereas total leukocyte count (TLC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were increased. Similarly, RPR-V caused significant elevation in serum clinical chemistry parameters calcium, phosphorus, creatinine, and chloride contents, whereas protein and glucose levels were depressed in both male and female treated rats after 45 and 90 days of treatment. These alterations were significant when compared with two-way ANOVA showing that these changes were dose- and time-dependent. The effects of low dose were generally not statistically significant, whereas medium and high doses caused significant effects. The changes in male rats were not significant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days post-treatment (withdrawal study), indicating that the compound entered into the system was eliminated from the body, and the blood parameters were improved. Hematological and clinical chemistry parameters can be detected rapidly and hence can be used for prediction and diagnosis of pesticide toxicity. Alterations in these parameters show toxic stress in the treated animals especially on blood and blood-forming organs.     

Toxicity of 3,3',4,4'-tetrachloroazoxybenzene in rats and mice

The toxicity of 3,3',4,4'-tetrachloroazoxybenzene (TCAOB) was evaluated in 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included clinical chemistry, hematology, thyroid hormone analyses, and effects on sperm morphology and estrous cycle length. Groups of 10 rats and 10 mice of each sex were exposed to TCAOB at dose levels of 0, 0.1, 1, 3, 10, or 30 mg/kg 5 days a week for 13 weeks. In the rat studies, the major effects included death in the 30 mg TCAOB/kg dose group; at lower exposure levels, a decrease in body weight gain, a decrease in thymus weight, an increase in liver weight, an increase in hematopoietic cell proliferation in the spleen and liver, a responsive anemia, a decrease in platelet counts, a chronic active inflammation of the vasculature in the lung, an increase in cardiomyopathy, hyperplasia of the forestomach, and a marked decrease in circulating thyroxine concentrations were observed. In male rats a decrease in sperm motility in the epididymides was observed. In addition, in female rats an increase in lung, spleen, kidney, and heart weights and nephropathy was observed. Furthermore, the estrous cycle length was increased. In the mouse studies, the major effects for males and females included a decrease in thymus weights, an increase in liver and kidney weights, centrilobular hypertrophy in the liver, hematopoietic cell proliferation, hyperplasia of the forestomach, and dilatation of hair follicles. The spectrum of effects in both rats and mice after exposure to TCAOB indicates that dioxin-like effects occur in addition to effects that have not been observed with dioxin-like compounds. No no-observed-adverse-effect level was reached in male or female rats or mice.     

Development of a short-term model of decalin inhalation nephrotoxicity in the male rat

Fischer 344 male rats and C57BL/6 male mice were exposed 'continuously' (22 hr/day, 7 days/wk) for 20, 28 or 35 days to a model compound, decalin, at 0, 25, 62.5 or 125 ppm. Fischer 344 female rats were exposed 'continuously' to decalin at 0 or 125 ppm for 28 days. No histopathological changes were observed in selected organs of female rats or male mice exposed to up to 125 ppm decalin for 28 or 35 days, respectively. However, kidney lesions were observed in all three test groups of male rats after 20, 28 and 35 days' exposure. The nephrotoxicity was characterized by the formation of hyaline droplets in the cytoplasm of proximal convoluted tubule epithelial cells, by the presence of granular casts at the outer zone of the medulla, and by chronic nephrosis. These changes were time and dose dependent and were identical to the renal toxicity that has been reported to occur in male rats following 90 days of continuous exposure to decalin by inhalation. No histopathological effects were observed in the heart, liver, lung or nasal turbinates of male rats. Our results indicate a sex and species specificity for the kidney toxicity. This leads to questions with regard to the appropriateness of using the male rat to assess the potential inhalation toxicity of volatile hydrocarbons. By producing nephrotoxicity in less than 90 days, decalin may now be used to examine, in a well-defined manner, the effect on nephrotoxicity of variables such as dose, exposure regimen, sex, species, and route of exposure. Data from these studies can be used to ascertain whether or not the male rat is an appropriate test animal for predicting potential human nephrotoxic responses to volatile chemicals such as perfumes and perfume raw materials.