A comparative study on the reliablility of toxicokinetic parameters for predicting hepatotoxicity of DDT in rats receiving a single or repeated administration

A comparative study on the reliability of toxicokinetic parameters for predicting hepatotoxicity was conducted in male F344 rats receiving a single (106 mg/kg by gavage) or 7-day repeated (1000 ppm in feed, 97 mg/kg/day) administration of p,p'-DDT. DDT was selected as the test substance because it is known as a hepatotoxic agent and its metabolic pathway is well documented. Concentrations of DDT and its metabolites (DDE and DDD) in the plasma, brain, and liver were measured at various time intervals during the study and the results were compared with the area under the concentration-time curve (AUC) in relation to hepatotoxic response. Increases in the absolute and relative (ratio to body weight) liver weights were observed as a typical toxic response after a single or repeated exposure to DDT. The coefficient (R2) of correlation between the increases in the relative liver weight and the concentrations or AUC of DDT and its metabolites in the plasma and liver was estimated. The values of R2 between the relative liver weight and AUC of DDT or the total DDT (T-DDT) in the plasma and liver were found to be more consistent and higher than those with their concentrations in the repeated dose study. In addition, the R2 values in correlation with their AUCs after a single exposure were lower than those in the repeated dose study. These results indicate that the AUC of DDT or T-DDT in the plasma and liver would be more reliable than their concentrations for predicting hepatotoxicity caused by DDT, especially in the repeated dose study.     

A repeated dose 90-day oral toxicity study of cyflumetofen,a novel acaricide, in rats

Cyflumetofen is a novel acaricide which is highly active against phytophagous mites. As a part of safety assessment, a repeated dose 90-day oral toxicity study of cyflumetofen was conducted in Fischer (F344/DuCrj) rats of both sexes. Technical grade cyflumetofen was administered in feed to groups of 10 males and 10 females at dose levels of 0, 100, 300, 1,000, and 3,000 ppm. Prothrombin time was prolonged in males at 3,000 ppm and plasma globulin levels were decreased in females at 1,000 and 3,000 ppm. At necropsy, enlarged and whitish adrenals were observed in females at 3,000 ppm. There were statistically significant increases in relative liver weight (ratio to body weight) in males and relative adrenal weight in females in the 1,000 ppm group; increased relative liver and kidney weights in both sexes at 3,000 ppm, and increased absolute and relative weights of adrenals in females at 3,000 ppm. Increased absolute liver weight was also noted in males at 3,000 ppm. Histopathologically, at 1,000 and 3,000 ppm males had diffuse vacuolation and females had diffuse hypertrophy of adrenal cortical cells. In addition, vacuolation of ovarian interstitial gland cells was noted in females at 1,000 and 3,000 ppm. There were no treatment-related changes in any parameters for either sex in other dose groups. Based on these results, the no-observed-adverse-effect level (NOAEL) of cyflumetofen was judged to be 300 ppm for both sexes (16.5 mg/kg/day for males and 19.0 mg/kg/day for females).     

Effect of taurine on toxicity of cadmium in rats

A study was undertaken to investigate the effect of taurine on the toxicity of cadmium in male Wistar rats. The rats were divided into six groups and fed different diets with or without supplement of 5% taurine and 150-300 ppm cadmium for 2 months. It was found that the body weight of rats, the ratios of liver and kidney weight to body weight, and the level of glutathione in the liver were decreased with increasing the dose of cadmium. The levels of cadmium in the liver and kidney, the levels of thiobarbituric acid-relative substances (TBARS) in the plasma and liver, the activities of aspartate transaminase (AST) and alanine transaminase (ALT) in the plasma, and the levels of blood urea nitrogen (BUN) and creatinine in the plasma of rats were increased with the increasing dose of cadmium. Hence, symptoms of cadmium toxicity in rats included loss of body weight, hepatotoxicity and nephrotoxicity. However, these toxic effects of cadmium were significantly reduced when the rats fed diet with supplement of taurine. Furthermore, the level of cadmium in the feces of rats treated with taurine and cadmium was higher than that of rats treated with cadmium alone. It indicated that taurine might play a role in reducing the toxic effect of cadmium in rats.     

Distribution and biochemical effects of DDT, DDD and DDE in penned double-crested cormorants

Concentrations, distribution and chronic effects of DDT, DDD and DDE were determined in penned cormorants (Phalacrocorax a. auritus) treated with 2, 5 and 10 mg of a combination of these compounds daily in their diet. Birds stressed by a one-half decrease in food after the cessation of 9 weeks of treatment and birds that died of DDT toxicity showed a marked increase in brain and liver residues and a decrease in carcass residues. Higher brain residue levels were significantly correlated with decreased body weight (p < 0.01) and carcass lipid content (p < 0.05). DDD concentrations in the brain were found to be the best indicator of DDT toxicity. Brain concentrations ranged from 24 to 85 ppm in birds that died of toxic effects and from 0.4 to 29 ppm in survivors, indicating that 30 ppm was diagnostic of toxicity. Brain concentrations of DDT and metabolites in wild cormorants indicated no immediate danger of toxicity. Average residue levels in the carcass of wild adult cormorants was 1.00 ppm for DDD and 10.6 ppm for the total of DDT, DDD and DDE. This represents a total body burden of 2.2 mg of DDD and 23.3 mg of the DDT complex as adult cormorants averaged 2200 g in body weight. Analysis of total liver vitamin A indicated a significant decrease of vitamin A due to treatment. An analysis of variance showed a significant decrease in liver (p < 0.05) and heart weights (p < 0.05) due to treatment but not brain or spleen weights when analyzed as percentage of body weight. A significant negative correlation was found between liver weight and brain concentrations of DDE + DDD + DDT (p < 0.05). No significant effects due to treatment were found on blood chemistry values.     

Subchronic toxicity of photomirex in the female rat: results of 28- and 90-day feeding studies

Photomirex (8-monohydromirex) was administered to female Sprague-Dawley rats at dietary levels of 0.2, 1.0, 5.0, 25.0 and 125 ppm. Food intake and body weight gain were significantly depressed at the 125 ppm level in the 28- but not in the 90-day study. Significant alterations were observed in some hematological and biochemical parameters at the highest dietary level in the 90-day study. Photomirex residues accumulated in a dose-dependent manner in perirenal fat, liver, brain, kidney, and spleen. Dose-dependent histotoxic effects were observed in liver and thyroid at and above 1 ppm; hepatomegaly was observed at 25.0 and 125 ppm. These results indicate that photomirex was approximately five times more toxic than mirex in terms of liver histology. When these results are compared with those observed in an earlier study in the male rat, it is evident that the female is less susceptible to photomirex than the male.     

Enhanced proliferative response of hepatocytes to combined inhalation and oral exposures to N,N-dimethylformamide in male rats

Male Wistar rats were exposed by inhalation to N,N-dimethylformamide (DMF) at 0 (control), 200 or 400 ppm (v/v) for 6 hr/day, 5 days/week and 4 weeks, and each inhalation group received DMF-formulated drinking water at 0, 800, 1,600 or 3,200 ppm (w/w) for 24 hr/day, 7 days/week and 4 weeks. Both the combined inhalation and oral exposures and the single-route exposure through inhalation or ingestion induced centrilobular hypertrophy and single-cell necrosis of hepatocytes, increased plasma levels of alanine aminotransferase (ALT), increased percentage of proliferating cell nuclear antigen (PCNA)-positive hepatocytes without glutathione-S-transferase placental form (GST-P)-positive liver foci, and increased relative liver weight. Those hepatic parameters of the DMF-induced effects were classified into hypertrophic, necrotic and proliferative responses according to the pathological characteristics of affected liver. While magnitudes of the hypertrophic and necrotic responses were linearly increased with an increase in amounts of DMF uptake in the single-route exposure groups, those dose-response relationships tended to level off in the combined-exposure groups. Saturation of the hypertrophic and necrotic responses at high dose levels might be attributed to suppression of the metabolic conversion of DMF to its toxic metabolites. Percentage of PCNA-stained hepatocytes classified as the proliferative response was increased more steeply in the combined-exposure groups than in the single-route exposure groups. It was suggested that the proliferative response of hepatocytes to the combined exposures would be greater than that which would be expected under an assumption of additivity for the component proliferative responses to the single-route exposures through inhalation and ingestion.     

Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats

RATIONALE: Following an oral dose of risperidone (RSP), concentrations of its major metabolite 9-hydroxyrisperidone (9-OHRSP) were high in plasma and tissues but disproportionately lower in the brain compared to RSP, indicating that 9-OHRSP may have different pharmacokinetic properties. OBJECTIVES: To investigate non-compartmental pharmacokinetics of RSP and 9-OHRSP in plasma, brain and other tissues after separate administration of a single oral dose of 6 mg/kg RSP and 9-OHRSP to rats. METHODS: Plasma, brain, liver, lung, kidney and spleen tissues were collected at pre-dose and at 0.5, 1, 2, 5, 6, 12, 24, 36 and 48 h post-dose, homogenized in saline and assayed for RSP and 9-OHRSP using a sensitive and specific liquid chromatography tandem mass spectrometry method. RESULTS: The concentration-time curve of RSP and 9-OHRSP showed that they were readily absorbed and followed a multiphase elimination pattern. The terminal elimination half-life (t(1/2) ) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The t(1/2)of 9-OHRSP after the RSP dose was shorter in plasma (3.4 h) and other tissues (approximately 8-11 h) than that for RSP but it was longer in the spleen. However, the t(1/2) of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the t(1/2) of 9-OHRSP after the RSP dose. The area under the concentration-time curve (AUC) of RSP and 9-OHRSP was 6-67 times higher in the plasma and tissues than in the brain. AUCs of 9-OHRSP in tissues after the RSP dose were 2-5 times higher than those for RSP, except in the brain, where AUCs of RSP and 9-OHRSP were similar. CONCLUSION: Pharmacokinetics of 9-OHRSP in many tissues were different after RSP and 9-OHRSP doses. The reason for disproportionate brain levels of 9-OHRSP is not clear. The overall exposure to active drug in the brain as represented by AUC was similar after the RSP and 9-OHRSP doses and the 9-OHRSP is probably an equal contributor to the pharmacological actions of RSP.     

Gene expression profile in the livers of rats orally administered ethinylestradiol for 28 days using a microarray technique

To identify genes showing responses to estrogen exposure in the livers of animals in a repeated oral dose toxicity study, dose-dependent gene expression profiles were analyzed using high-density oligonucleotide microarrays in Sprague–Dawley rats of both sexes administered ethinylestradiol (EE) for 28 days at concentrations of 0, 0.01, 0.1, and 1.0 ppm in the diet. Among 3776 genes examined, examples showing increased expression on EE-treatment were detected predominantly in females. Genes showing dose-dependent up-regulation with greater than five-fold change at 1.0 ppm from the control levels were found to, respectively, number 4 in males, and 24 in females. Most of the latter exhibited relatively high basal expression as well as low variability, and many exhibited clear dose-dependence. Genes showing dose-dependent down-regulation were rather few, and many of those affected exhibited relatively low expression levels with large variation between animals, like genes showing dose-unrelated expression patterns in both sexes or dose-dependent up-regulation in males. Considering that detection of changes in endocrine-linked organs and estrous cyclicity is only possible at the high dose of 1.0 ppm, up-regulation of genes dose-dependently in females provides a sensitive tool to detect estrogenic effects in the rat liver in the framework of the 28-day toxicity study.     

Lack of hepatotoxicity or promotion of enzyme-altered liver foci development in rats treated with harman or norharman

The modifying effects of harman or norharman on liver carcinogenesis were investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given harman or norharman at dietary levels of 1000 and 200 parts per million (ppm), or sodium phenobarbital (PB) at 500 ppm as a positive control, for 6 wk. At wk 3 following DEN administration, all animals were subjected to partial hepatectomy. Marked retardation of body weight gain was observed in rats treated with harman or norharman at 1000 ppm, but not at 200 ppm. Increased relative kidney but not liver weights were associated with harman or norharman treatment, especially in the higher dose groups. Although no toxicity-related hepatocyte lesions were found, severe renal toxic tubular lesions and regeneration were evident. Neither harman nor norharman significantly increased the numbers or areas of glutathione S-transferase placental form (GST-P) positive foci observed after DEN initiation, in clear contrast to PB. The results thus demonstrated that harman and norharman are nontoxic for the liver and lack modifying potential for liver carcinogenesis in our medium-term bioassay system.     

Evaluation of hepatic and thyroid responses in male Sprague Dawley rats for up to eighty-four days following seven days of dietary exposure to potassium perfluorooctanesulfonate

In a prior 28-day dietary study in rats with 20 and 100 ppm K? PFOS, activation of PPARα and CAR/PXR were concluded to be etiological factors in K? PFOS-induced hepatomegaly and hepatic tumorigenesis. The objective of this study was to evaluate persistence/resolution of K? PFOS-induced, liver-related effects in male Sprague Dawley rats following a 7-day dietary exposure to K? PFOS at 20 or 100 ppm. Groups of 10 rats per treatment were observed on recovery Day(s) 1, 28, 56, and 84 following treatment. Changes consistent with hepatic PPARα and CAR/PXR activation noted on recovery Day 1 included: increased liver weight; decreased plasma cholesterol, alanine aminotransferase, and triglycerides; decreased liver DNA concentration and increased hepatocellular cytosolic CYP450 concentration; increased liver activity of acyl CoA oxidase, CYP4A, CYP2B, and CYP3A; increased liver proliferative index and decreased liver apoptotic index; decreased hepatocellular glycogen-induced vacuoles; increased centrilobular hepatocellular hypertrophy. Most effects resolved to control levels during recovery. Effects on plasma cholesterol, hepatocellular cytosolic CYP450 concentrations, liver apoptotic index, CYP3A, and centrilobular hepatocellular hypertrophy persisted through the end of the recovery period. Thyroid parameters (histology, apoptosis, and proliferation) were unaffected at all time points. Mean serum PFOS concentrations on recovery Day 1 were 39 and 140 μg/mL (20 ppm and 100 ppm K? PFOS, respectively), decreasing to 4 and 26 μg/mL by recovery Day 84. Thus, hepatic effects in male rats resulting from K? PFOS-induced activation of PPARα and CAR/PXR resolved slowly or were still present after 84-days following a 7-day dietary treatment, consistent with the slow elimination rate of PFOS.     

Comparative metabolism of methyl isobutyl carbinol and methyl isobutyl ketone in male rats

Methyl isobutyl carbinol (MIBC) is an oxygenated solvent that is metabolized to methylisobutyl ketone (MIBK) and then to 4-hydroxymethyl-4-methyl-2-pentanone (HMP). Plasma levels of MIBC, MIBK and HMP were determined up to 12 h after a single oral 5 mmol/kg dose of MIBC or MIBK to male rats. The major material in the plasma in both cases was HMP, with similar areas-under-the-curve (AUC) and C(max) at 9 h after dosing. MIBK plasma levels and AUC were also comparable after MIBK or MIBC administration. MIBC AUC was only about 6% of the total material in the blood after MIBC, and insignificant after MIBK administration. No other metabolites were detected in the plasma under the analytical conditions used. The extent of metabolism of MIBC to MIBK, by comparing combined AUCs for MIBK and HMP, was at least 73%. The limited systemic toxicity data for MIBC are consistent with those for MIBK, which has been well studied. The metabolic equivalency of MIBC with MIBK indicates that MIBC will have a low potential for toxicity similar to that of MIBK, and reduces the need for additional animal studies.     

Relationship between AUC of 5'-DFUR and toxicity of capecitabine, fluoropyrimidine carbamate analogs, and 5'-DFUR in monkeys, mice, and rats

Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/kg and the AUCs of 5'-DFUR were approximately 40 to 60 microg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5 microg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10 microg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2 microg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.     

Monochlorodiisobutylene Vapor: Acute and 9-Day Inhalation Studies in Fischer-344 Rats and B6C3F1 Mice

Monochlorodiisobutylene Vapor Acute and 9-Day Inhalation Studiesin Fischer-344 Rats and B6C3F1 Mice. SNELUNGS, W. M., DODD,D. E., GRICE, H. C, AND PHILLIPS, R. D. (1985) Fundam. Appl.Toxicol. 5, 506–514. Acute and 9-day repeated exposuresto monochlorodiisobutylene (CDIB) were conducted in male andfemale Fischer-344 rats and B6C3F1 mice. The 4-hr LC50 valuesfor these animals ranged between 1400 and 2100 ppm. Animalsin the 9-day study were exposed at a mean concentration of 478,97, or 25 ppm of CDIB for 6 hr per day. Treatment-related effectsdiffered between species in this study. Body weight change wasdecreased in rats. Morphologic changes in the kidneys with accompanyingpolyuria and hematuria/hemoglobinuria were observed in malerats. The only effect observed at 25 ppm was a low incidenceof hematuria/hemoglobinuria in male rats. Mice appeared unaffectedby exposure to CDIB at levels as high as 478 ppm     

Comparative Toxicity of Arsine Gas in B6C3F1 Mice, Fischer 344 Rats, and Syrian Golden Hamsters: System Organ Studies and Comparison of Clinical Indices of Exposure

Comparative Toxicity of Arsine Gas in B6C3F₁ Mice, Fischer 344Rats, and Syrian Golden Hamsters: System Organ Studies and Comparisonof Clinical Indices of Exposure. BLAIR, P. C, THOMPSON, M. B.,MORRISSEY, R. E., MOORMAN, M. P., SLOANE, R. A., AND FOWLER,B. a. (1990). Fundam. Appl. Toxicol. 14, 776–787. In orderto examine possible species differences in response to arsineexposure, multiple inhalation studies consisting of acute (1-day),subacute (14- and 28-day), and subchronic (90-day) exposuresto this agent were conducted using three different species ofrodents. Evaluations of hematopoietic organs and alterationsin the heme biosynthetic pathway were the focus of these studies.Species used were B6C3F₁ mice (exposed 1, 14, or 90 days), Fischer344 rats (exposed 14, 28, or 90 days), and Syrian Golden hamsters(exposed 28 days). All arsine exposures were at concentrationsof 0.5, 2.5, or 5.0 ppm except for 90-day studies, in whichconcentrations were lowered to 0.025, 0.5, or 2.5 ppm. No changesin body weight gain were observed in either sex of mice or hamsters.The only decrease in body weight gain occurred in male ratsexposed to 5.0 ppm arsine for 28 days. Significant exposure-relatedincreases in relative spleen weights occurred in both sexesof mice and rats in the 0.5 (except 14-day female rats), 2.5,and 5.0 ppm exposure groups from all studies and in hamstersin the 2.5 and 5.0 ppm exposure groups. Generally, increasesin relative liver weight occurred in fewer exposure groups andwere of a lesser magnitude than increases in spleen weight.Other parameters affected included decreased packed cell volumes(mice, rats, and hamsters), hematol-ogy profiles (rats), andan increase in 6-aminolevulinic acid dehydratase activity inall species. Arsenic content was measured in livers of ratsafter 90 days of exposure. Concentrations increased in relationto atmospheric concentrations of arsine. Histopathological changesincluded increased hemosiderosis and extramedullary hematopoiesisin spleen and intracanalicular bile stasis (mice only) in liver.Additionally, bone marrow hyperplasia was observed in rats.Effects on other organs were not observed, suggesting that thehematopoietic system is the primary target for arsine. In conclusion,we have determined that the effects of arsine exposure uponmice, rats, and hamsters are similar. Most importantly, eventhough no effects on the hematopoietic system were observedfollowing a single exposure to 0.5 ppm arsine which is 10 timesthe Threshold Limit Value (TLV) set by the American Conferenceof Governmental Industrial Hygienists, repeated exposure to0.025 ppm (one-half the TLV) caused a significant anemia inrats.     

Single- and repeated-dose pharmacokinetics of eplerenone,a selective aldosterone receptor blocker,in rats

1. The pharmacokinetics of eplerenone (EP) were examined in rats following single or repeated dosing with (14)C-labelled or unlabelled EP to characterize absorption, metabolism and excretion. Rates of EP metabolism and cytochrome P450 activities were determined in vitro after repeated dose administration of EP. 2. Following a single i.v. dose (15 mg kg(-1)), the elimination half-life of EP was 0.80 and 1.14 h in male and female rats, respectively. Plasma clearances (CL) of EP were 1.62 and 1.20 l kg(-1) h(-1) in males and females, respectively. Following a single oral dose (15 mg kg(-1)), C(max) and T(max) of EP were 1.71 micro g ml(-1) and 0.5 h in male rats. The corresponding values in female rats were 3.54 micro g ml(-1) and 1.0 h. The systemic availability of EP was 25.6% in male rats and 66.4% in female rats, demonstrating sex differences in the pharmacokinetics of EP. 3. In the 8-day study, the AUC(0-24h)'s of total EP (closed lactone ring form plus open form) following 100 and 200 mg kg(-1) oral doses were approximately half those on day 1 in male rats. After repeated dosing for 13 weeks, the pharmacokinetics of total EP did not change with study duration at the 20 mg kg(-1) dose in both males and females. However, at the 100 mg kg(-1) dose, AUC(0-24h)'s were notably reduced on day 24 but progressively increased on subsequent days to approximate day 1 levels by day 86 in both sexes. At the 500 mg kg(-1) dose, the AUCs on day 86 remained lower than those on day 1. Reductions in AUCs on days 8 and 24 appeared to be the result of metabolism induction. 4. EP was extensively metabolized in male rats and most faecal and urinary radioactivity was in the form of metabolites. In female rats, the vast majority of urine and faecal radioactivity was associated with total EP. Thus, the sex difference in the pharmakokinetics of EP was due to more extensive metabolism in male rats. 5. The major metabolite in the rat was 6beta-OH EP. EP 6beta-hydroxylase activity was well correlated with testosterone 6beta-hydroxylase activity, indicating that EP metabolism to 6beta-OH EP was mediated primarily by CYP3A in the rat. 6. After repeated dose administration, EP increased 6beta-hydroxylase activities of testosterone and EP itself in a dose-dependent manner in both male and female rats, indicating that EP was a CYP3A inducer in the rat. There appeared to be no effects on activities of CYP1A1, 2B and 2E1.     

Toxicity of 2-methyl-5,6-cyclopentapyrimidine (MCPP).

2-Methyl-5,6-cyclopentapyrimidine (MCPP, CAS No. 36274-29-0) is a white dusty solid with a powerful lingering odor and is formed as a by-product in the polymer synthesis of an experimental polymer. The acute toxicity following both oral and inhalation exposures and the effects of repeated inhalation exposures in rats were determined. Mutagenic activity was assessed using Salmonella as the indicator organism. The chemical is moderately toxic, with the lethal dose following a single oral administration being 90 mg kg-1. Doses greater than or equal to 130 mg kg-1 produced strong convulsions. Excessive salivation, hyperactivity and twitching were seen at 90 mg kg-1 and only mild initial weight loss was seen in surviving rats (less than or equal to 60 mg kg). Liver injury was produced at doses as low as 17 (but not at 12) mg kg-1. The material was highly toxic by inhalation, with the approximate lethal concentration in rats following single 4-h exposures being 9 ppm. Convulsive-like movements were seen at greater than or equal to 9 ppm (not at 2 ppm). Histological findings suggest that MCPP causes dilation of blood vessels with hyperemia of various organs apparent in rats exposed to 1 ppm and sacrificed 1 or 2 days post-exposure. No evidence of liver or central nervous system damage was seen. Repeated (nine daily 4-h exposures) inhalation of 2 ppm MCPP failed to produce any signs of a toxic response. No mutagenic activity was seen. The material needs to be considered as a potent acute toxin.     

Effect of a single oral dose of ddt on lipid metabolism in rat

A single oral dose of 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane (DDT) (600 $\text{mg}\text{kg}$ body weight) was given to rats and the levels of various lipids in adipose tissue, liver and plasma were studied. No alteration was observed in the levels of various lipid classes in these tissues except for a decrease in the phospholipid and triglyceride fractions of liver. Lipoprotein lipase activity of post-heparin plasma (protamine-sensitive and -resistant) was significantly decreased, whereas in liver and adipose tissue, the activity of this enzyme remained unchanged.     

Single- and repeated-dose pharmacokinetics of eplerenone,a selective aldosterone receptor blocker,in rats

1. The pharmacokinetics of eplerenone (EP) were examined in rats following single or repeated dosing with 14 C-labelled or unlabelled EP to characterize absorption, metabolism and excretion. Rates of EP metabolism and cytochrome P450 activities were determined in vitro after repeated dose administration of EP. 2. Following a single i.v. dose (15?mg kg ? 1), the elimination half-life of EP was 0.80 and 1.14?h in male and female rats, respectively. Plasma clearances (CL) of EP were 1.62 and 1.20?l kg ? 1?h ? 1 in males and females, respectively. Following a single oral dose (15?mg kg ? 1), C max and T max of EP were 1.71 µg ml ? 1 and 0.5?h in male rats. The corresponding values in female rats were 3.54 µg ml ? 1 and 1.0?h. The systemic availability of EP was 25.6% in male rats and 66.4% in female rats, demonstrating sex differences in the pharmacokinetics of EP. 3. In the 8-day study, the AUC 0-24h 's of total EP (closed lactone ring form plus open form) following 100 and 200?mg kg ? 1 oral doses were approximately half those on day 1 in male rats. After repeated dosing for 13 weeks, the pharmacokinetics of total EP did not change with study duration at the 20?mg kg ? 1 dose in both males and females. However, at the 100?mg kg ? 1 dose, AUC 0-24h 's were notably reduced on day 24 but progressively increased on subsequent days to approximate day 1 levels by day 86 in both sexes. At the 500?mg kg ? 1 dose, the AUCs on day 86 remained lower than those on day 1. Reductions in AUCs on days 8 and 24 appeared to be the result of metabolism induction. 4. EP was extensively metabolized in male rats and most faecal and urinary radioactivity was in the form of metabolites. In female rats, the vast majority of urine and faecal radioactivity was associated with total EP. Thus, the sex difference in the pharmakokinetics of EP was due to more extensive metabolism in male rats. 5. The major metabolite in the rat was 6 β -OH EP. EP 6 β -hydroxylase activity was well correlated with testosterone 6 β -hydroxylase activity, indicating that EP metabolism to 6 β -OH EP was mediated primarily by CYP3A in the rat. 6. After repeated dose administration, EP increased 6 β -hydroxylase activities of testosterone and EP itself in a dose-dependent manner in both male and female rats, indicating that EP was a CYP3A inducer in the rat. There appeared to be no effects on activities of CYP1A1, 2B and 2E1.     

Induction of apoptosis and CYP4A1 expression in Sprague-Dawley rats exposed to low doses of perfluorooctane sulfonate

In previous studies, perfluorooctane sulfonate (PFOS), an environmental organic compound, was reported to cause hepatotoxicity and hypolipidemia in rodents. However, the low dose toxicity of PFOS and the toxic mechanisms involved remain to be determined. To clarify the low dose toxicity and action mechanism in the target organ toxicity, Sprague-Dawley (SD) rats were orally administered with PFOS at the doses of 0, 1.25, 5, 10 mg/kg/day for 28 days. As a result, no death or abnormal symptoms were observed in all groups. The significant loss of mean body weight was observed in female rats treated with 10 mg/kg PFOS and the relative liver weight of 10 mg/kg PFOS-treated group was significantly greater compared to control. Histopathological examination revealed that fatty change was evident in the liver of male rats treated with PFOS (5 and 10 mg/kg) and hypertrophy and cellular swellings in females at the dose of 10 mg/kg, which showed different pattern of pathological lesions. In addition, we demonstrated the expression induction of hepatic caspase-3 and cytochrome P450 4A1 (CYP4A1) related with apoptosis and lipid metabolism, respectively. This study suggested that no-observed-adverse-effect level (NOAEL) of PFOS was 1.25 mg/kg in 28-day repeated toxicity study and, however, the toxic response showed gender differences. The possible toxic mechanism of PFOS was the induction of apoptosis and altering lipid metabolism which resulted in hepatotoxicity.