Dietary toxicity of picloram herbicide in rats

The toxicity of orally administered technical-grade picloram was evaluated in male and female Fischer 344 rats. Dietary dose levels were up to 2000 mg/kg body weight (bw) X d for 2 wk, 500 mg/kg bw X d for 13 wk, or 200 mg/kg bw X d for 12 mo. Routine indices of toxicity were evaluated at all of the respective time periods. Body weight, food consumption, clinical chemistries, urinalyses, and hematological determinations were considered unaffected by treatment. The only treatment-related effect, regardless of the duration of exposure, was in the liver of both male and female rats. This was generally manifested as an increase in the liver-to-body weight ratio and slight hypertrophy and pallor of the centrilobular hepatocytes. These effects were consistently present in rats receiving 1000 mg/kg bw X d for 2 wk, 300 mg/kg bw X d for 13 wk, or 200 mg/kg bw X d for 6 or 12 mo. Similar effects were marginally evident for rats receiving 500 mg/kg bw X d for 2 wk, 150 mg/kg bw X d for 13 wk, or 60 mg/kg bw X d for 6 or 12 mo. At 60 mg/kg bw X d, the effects were not progressive from 6 to 12 mo. The no-observable-effect level (NOEL) was 20 mg/kg bw X d for male and female rats fed picloram for 12 mo.     

Involvement of nonparenchymal cells in oxygen-dependent hepatic injury by allyl alcohol.

Allyl alcohol injury to hepatocytes in the perfused liver is oxygen-dependent. It is not known if this injury involves direct action of allyl alcohol on hepatocytes or requires participation of other cell types (e.g., Kupffer cells) present in the liver. Accordingly, the action of allyl alcohol (100-500 microM) on isolated hepatocytes was studied using cells maintained at either 95 or 21% O2. Allyl alcohol toxicity, as indexed by trypan blue uptake, lactate dehydrogenase release, and ATP content, did not differ in the two groups of cells, suggesting that O2 dependency of allyl alcohol toxicity involves other cell types. Administration of allyl alcohol (30 or 40 mg/kg, ip) to rats caused extensive hepatic necrosis localized primarily to periportal regions. To test the involvement of Kupffer cells in the genesis of this injury, male rats (200-350 g) were treated with gadolinium chloride (GdCl3, 10 mg/kg, iv) which diminishes Kupffer cell function and number. The extent of hepatic damage assessed by light microscopy and serum enzymes, aspartate aminotransferase and alanine aminotransferase, was markedly attenuated by pretreatment of rats with GdCl3 24 hr prior to allyl alcohol injection. Thus, O2-dependent hepatic necrosis caused by allyl alcohol involves the presence of Kupffer cells. Since GdCl3 did not prevent toxicity in the perfused liver, circulating blood elements may also contribute to injury of the liver by allyl alcohol in vivo.     

Toxicological response of rats to a novel monoamine oxidase type-A inhibitor, (5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011), orally administered for 13 weeks.

(5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011) is a novel monoamine oxidase type-A (MAO-A) inhibitor. In order to assess toxicological profiles of E2011, doses of 0 (as controls), 30, 100 mg/kg of E2011 were administered to male and female Sprague-Dawley rats once a day for 13 weeks orally by gavage. No mortality or any toxic signs except salivation occurred due to E2011 treatment. Decreased body weight gain and food consumption, increases of alkaline phosphatase and increases of liver weight were the major treatment-related findings observed predominantly in the 100 mg/kg group. Histological examination revealed nuclear enlargement of hepatocytes with appearance of altered cell foci in some cases, and acinar atrophy in Harderian glands in the 100 mg/kg group. Since the histopathological findings in the liver were indicative of an ongoing carcinogenic process, glutathione S-transferase placental form (GST-P) positive hepatic foci were identified immunohistochemically and examined morphometrically. Although GST-P positive hepatic foci were detected in all groups including controls, the number and area of GST-P positive hepatic foci were significantly higher in female rats treated with 100 mg/kg than those in controls. In this paper, possible mechanisms of specific lesions in the liver and Harderian glands will be discussed.     

The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity

The pharmacokinetic and macromolecular interactions of perchloroethylene were evaluated in B₆C₃F₁ mice and Sprague-Dawley rats in an attempt to explain, mechanistically, the sensitivity of the mouse and the resistance of the rat to perchloroethylene-induced hepatocellular carcinoma. When compared to rats, mice were found to metabolize 8.5 and 1.6 times more perchloroethylene per kilogram of body weight following inhalation of 10 ppm or a single oral dose of 500 mg/kg perchloro[¹⁴C]ethylene, respectively. Since the initial metabolism of perchloroethylene is an activation process, the increased extent of metabolism in the mouse resulted in a greater extent of irreversible binding of radioactivity in hepatic macromolecules of the mouse compared to that in the rat after inhalation of 10 or 600 ppm or a single oral dose of 500 mg/kg perchloro[¹⁴C]ethylene. Repeated oral administration of perchloroethylene for 11 days resulted in histopathological changes in the liver of mice at doses as low as 100 mg/kg/day, while minimal treatment-related effects were observed in the liver of rats only at the 1000 mg/kg/day level. Approximately a twofold increase in hepatic DNA synthesis, indicative of hepatic regeneration, was observed in mice but not in rats after repeated oral administration of perchloroethylene at dose levels which are tumorigenic to mice in lifetime studies. The absence of any pronouced direct interaction of perchloroethylene with hepatic DNA in mice at times of peak hepatic macromolecular binding suggests that hepatic tumors are induced in B₆C₃F₁ mice by recurrent cytotoxicity which enhances the spontaneous incidence of liver tumors in this highly susceptible strain of mouse. The implication of these results for hazard assessment is that recurrent tissue damage is necessary for tumors to be induced. Thus, levels of perchloroethylene which do not induce organ toxicity are not likely to pose a carcinogenic risk to man.     

Developmental Toxicity of Dinitroaniline Herbicides in Rats and Rabbits

The potential developmental toxicity of trifluralin was evaluatedin rats and rabbits. Pregnant rats and rabbits were dosed oncedaily by gavage on Gestation Days 6–15 and 6–18,respectively. Doses for rats were 0, 100, 225, 475, or 1000mg/kg; doses for rabbits were 0, 100, 225, or 500 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 28, respectively. In rats, maternal toxicity was indicatedin the 475 and 1000 mg/kg treatment groups by depression ofbody weights and food consumption. Fetal viability and morphologywere not adversely affected at any dose level. Developmentaltoxicity was indicated at the 1000-mg/kg dose level by depressionof fetal weight. The NOAEL for maternal toxicity in the ratwas 225 mg/kg the NOAEL for developmental toxicity in the ratwas 475 mg/kg. In rabbits, maternal toxicity was indicated atthe 225 and 500 mg/kg dose levels by abortions and/or deathsin conjunction with anorexia and cachexia. Developmental toxicitywas indicated at the 500 mg/kg dose level by depressed fetalviability and weight. Fetal morphology was not adversely affectedat any dose level. The NOAELs for maternal and developmentaltoxicity in the rabbit were 100 and 225 mg/kg, respectively.Based on these data, trifluralin did not exhibit selective toxicitytoward the developing conceptus.     

Toxic responses to acute, subchronic, and chronic oral administrations of monochlorobenzene to rodents

Acute (single exposure), 14-d repeated exposure, 91-d subchronic, and 103-wk chronic toxicity studies of orally administered (gavage, in corn oil) monochlorobenzene were conducted in male and female Fischer-344 rats and B6C3F1 hybrid mice. A single exposure to 4000 mg/kg was lethal to male and female rats, while a single exposure to a dose as low as 1000 mg/kg was lethal to mice. Fourteen daily exposures to 1000 mg/kg caused death in rats of both sexes, but neither survival nor clinical health were compromised at 500 mg/kg in rats or mice. In the 91-d studies, wherein monochlorobenzene was administered once daily, 5 d/wk, survival was reduced by doses of 500 mg/kg and higher in rats, and by doses of 250 mg/kg and higher in mice. Dose-dependent necrosis of the liver (hepatocytes), degeneration or focal necrosis of the renal proximal tubules, and lymphoid or myeloid depletion of the spleen, bone marrow, and thymus (mild to severe) were produced by doses of 250 mg/kg or greater of monochlorobenzene in both sexes of rats and mice, although the incidences of these lesions varied considerably by sex and species. Consistent changes in the circulating blood components were not observed, but a mild porphyrinuria was detected at the higher doses. No toxic effects were observed at doses of 125 mg/kg or less. In the 2-yr studies, wherein monochlorobenzene was administered once daily, 5 d/wk, doses of 30 or 60 mg/kg in male mice and 60 or 120 mg/kg in female mice and male and female rats did not produce any evidence of toxicity. Doses of 60 or 120 mg/kg caused slight (statistically significant at 120 mg/kg; p less than 0.05) increases in the frequencies of male rats with neoplastic nodules of the liver. Increased tumor frequencies were not observed in female rats or in male or female mice receiving monochlorobenzene.     

A NO-releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway

NCX-701 is a nitric oxide (NO)-releasing acetaminophen (APAP) derivative. In the present study we demonstrated that NCX-701 is as effective as APAP in controlling body temperature in a rat model of endotoxin-induced fever. Liver toxicity is a major complication of APAP overdosing. To investigate whether NCX-701 is hepatotoxic, BALB/C mice were injected with 100 - 500 mg kg(-1) APAP or NCX-701 alone or in combination (i.e. 500 mg kg(-1) of both compounds). Our results demonstrated that although APAP caused a dose-dependent liver injury, NCX-701 was completely devoid of liver toxicity. At the dose of 500 mg kg(-1) APAP caused an approximately 40 fold increase of AST plasma levels and extensive centrilobular necrosis. APAP and NCX-701 share the same metabolic pathway as demonstrated by the time-course of APAP-glucuronide concentrations in plasma and liver. NCX-701 was safe in mice with pre-existing chronic liver disease. Indeed, while C57BL6 transgenic mice expressing the hepatitis B virus (HBV) at the age of 8 months were significantly more susceptible to liver damage induced by APAP (500 mg kg(-1)) than their congenic littermates, treating HBV-transgenic mice with NCX-701, 500 mg kg(-1), caused no damage. Co-administration of NCX-701 at the dose 500 mg kg(-1) to mice treated with APAP, 500 mg kg(-1), completely protected against liver damage induced by APAP. APAP, but not NCX-701, upregulated liver Fas and Fas Ligand mRNA expression in vivo. Incubating mouse hepatocytes with APAP, but not with NCX-701, increased cell surface Fas expression and sensitized hepatocytes to death induced by challenge with a Fas-agonistic antibody. Collectively, these observations suggest that APAP toxicity is Fas mediated and that NCX-701 spares the liver by acting at several checkpoints in the Fas pathway.     

Evaluation of the toxicity of polyvinylacetate phthalate in experimental animals.

Polyvinylacetate phthalate (PVAP) is used in the pharmaceutical industry as an ingredient in coating systems for oral solid dosage forms and in inks for monogramming capsules. PVAP has been evaluated in both sexes of several species in a number of toxicological studies including acute, repeated dosing, subchronic, chronic and reproductive and developmental. The acute oral toxicity is low in rats and mice (LD(50) > 8000 mg/kg body weight), although it appears to be more toxic in the dog. The gastrointestinal tract appears to be the target organ and effects seen (irritation, laxation, colitis with erosions and submucosal fibrosis in the dog and ulcers, polyps, and cecal wall thickening in rats) were dose dependent. There were no consistent treatment-related adverse effects on reproductive performance or development (not teratogenic). The no-observed-adverse-effect levels (NOAELs) ranged from 100 mg/kg body weight/day in the rabbit developmental toxicity study, to 500 mg/kg body weight/day in 24 month rat and dog studies, to 1000 mg/kg body weight/day in a one-generation reproduction study in the rat.     

Dermal toxicity of a medium-boiling (154-378 degrees C) coal liquefaction product in the rat--Part I

The subchronic dermal toxicity of a medium-boiling coal liquefaction product (CLP, 154-378 degrees C) was investigated in the rat. CLP was applied to the shaved backs of rats at dose levels of 50, 100, 200, or 400 mg/kg body weight.d, 7 d/wk for a period of 13 wk. Control groups received 0.4 ml/kg of normal saline. Signs of dermal irritation were observed at sites of application in males dosed at 200 and 400 mg/kg body weight and were characterized by thickened, focally necrotic and ulcerative skin. All animals survived the full length of the treatment period. Growth depression was observed in males at all dose levels, but no significant decrease in weight gain was observed in females. An increase in liver/body weight ratios was observed in all treatment groups of both sexes. The organ/body weight ratios for the spleen, heart, kidney, and brain were also increased in the upper dose groups of both sexes. Treatment with CLP caused a dose-dependent decrease in hemoglobin and packed cell volume in both sexes of all dose groups. The number of erythrocytes was decreased and that of neutrophils was increased in some CLP-treated groups of both sexes. There was a mild myeloid hyperplasia with increased myeloid/erythroid ratios in the 200- and 400-mg/kg groups of both sexes. Hepatic microsomal ethoxyresorufin deethylase activity was increased in all treatment groups of females, and in males dosed at 100 mg/kg and higher. In the renal tubules mild treatment-related histological changes occurred, which consisted of eosinophilic inclusions, increased cytoplasmic volume, and pyknosis. These changes were noted in the high-dose groups of both sexes. These data indicate that the medium-boiling CLP could produce systemic toxicity when applied dermally at 50 mg/kg body weight.d.     

A preliminary 13-week oral toxicity study of ginger oil in male and female Wistar rats

Zingiber officinale Roscoe, ginger, is a major spice extensively used in traditional medicine. The toxicity profile of ginger oil was studied by subchronic oral administration for 13 weeks at doses of 100, 250, and 500 mg/kg per day to 6 groups of Wistar rats (5/sex per dose). Separate groups of rats (5/sex per group) received either paraffin oil (vehicle) or were untreated and served as comparative control groups. There was no mortality and no decrease in body weight or food consumption as well as selective organ weights during the study period. Administration of ginger oil to rats did not produce any treatment-related changes in hematological parameters, hepatic, renal functions, serum electrolytes, or in histopathology of selected organs. The major component of ginger oil was found to be zingiberene (31.08%), and initial studies indicated the presence of zingiberene in the serum after oral dosing. These results confirmed that ginger oil is not toxic to male and female rats following subchronic oral administrations of up to 500 mg/kg per day (no observed adverse effect level [NOAEL]).     

Prechronic Toxicity Studies on 2-Ethylhexanol in F334 Rats and B6C3F1 Mice

Data on the subchronic toxicity of 2-ethylhexanol (2EH) wererequired to establish the dose vehicle and dose levels for oncogenicitystudies. In preliminary studies 2EH was given subacutely (11days) to male and female Fischer 344 rats and B6C3F1 mice asan aqueous emulsion by oral gavage (0, 100, 330, 1000, and 1500mg/kg/day). Clinical observations were made, body weights, foodconsumption, clinical chemistries, hematologies, and selectedorgan weights were measured, and gross and micropathologieswere performed. Target organs were the central nervous system,liver, forestomach, spleen, thymus, and kidney in rats and thecentral nervous system, liver, and forestomach in mice. 2EHwas then administered by oral gavage to male and female F344rats and B6C3F1 mice as an aqueous emulsion (0, 25, 125, 250,and 500 mg/kg/day) for 13 weeks. At 500 mg/kg/day in the ratthere was reduced body weight gain (6% male, 7% female), increasedrelative liver (29% male, 15% female), kidney (16% male, 6%female), stomach (11% male, 16% female), and testes (6%) weights,and moderate gross and microscopic changes in the liver andforestomach. There were no behavioral effects or effects onthe spleen or thymus. A no-effect level for target organ effectsin the rat was 125 mg of 2EH/kg/day. At 500 mg of 2EH/kg/dayin the mouse the only effects were increased relative stomachweights in males (13%) and a low incidence of gross and microscopicfindings in the forestomach (male and female) and liver (female).A no-effect level for target organ effects in the mouse was125 mg of 2EH/kg/day. 2EH was a peroxisome proliferator in therat but not in the mouse at subchronic dose levels of 500 mg/kg/day.Dose levels in oncogenicity studies were set at 50 mg/kg/dayfor the absence of treatment-related effects in rats and mice,and 500 and 750 mg/kg/day, respectively, in rats and mice ashigh doses producing minimal toxicity without altering the lifespan.     

Evaluation of the Reproductive Toxicology of 2,4,6-Trichiorophenol in Male and Female Rats

Evaluation of the Reproductive Toxicology of 2,4,6-Trichlorophenolin Male and Female Rats. BLACKBURN, K., ZENICK, H., HOPE, E.,MANSON, J. M., GEORGE, E. L., AND SMITH, M. K. (1986). Fundam.Appl. Toxicol. 6, 233–239. The toxicity of chlorinatedorganic compounds which may be generated as a by-product ofdrinking water chlorination has been an issue of increasingconcern. Relatively few data are available concerning theirreproductive toxicity. The present study was designed to evaluatethe reproductive effects of one of these compounds, 2,4,6-trichlorophenol(TCP), in male and female rats. Adult males were treated witheither 0, 100. 500, or 1000 mg/kg of TCP (po) for 10 weeks,at which time semen evaluations were conducted on ejaculatesrecovered from the genital tract of receptive females. Fertilitywas assessed in the 0- and 1000-mg/kg groups. Females were treatedwith identical doses for 2 weeks prior to pregnancy then throughoutgestation. Dams were allowed to litter and pup development wasmonitored until Day 42 postpartum. TCP had no effect on anysperm parameter or male fertility. Treatment of females with1000 mg/kg of TCP produced gross maternal toxicity as reflectedin increased lethality and decreased weight gains in the dams.However, no treatment-related differences were seen in littersizes or pup survival. Male and female birth weights were significantlydepressed in the 500- and 1000-mg/kg groups; these differencesdisappeared by Day 4 postpartum, suggesting that they were areflection of maternal toxicity. To this extent, the reproductiveprocesses of male and female rats do not appear to be a primarytarget for the effects of TCP.     

Acute, subchronic and chronic toxicity studies of a synthetic antioxidant, 2,2'-isobutylidenebis(4,6-dimethylphenol) in rats

General toxicity studies on 2,2'-isobutylidenebis(4,6-dimethylphenol)(IBBMP) were conducted using male and female Wistar rats. In the acute test, the oral LD50 values were 119 mg/kg BW in males and 103 mg/kg BW in females. Hypersensitivity, loss of righting reflex and abdominal position were observed. In the subchronic test, rats were fed a diet containing IBBMP at levels of 0, 20, 100 or 500 ppm for 13 weeks with interim sacrifice at 4 weeks (equal to 0, 1.1, 5.5 or 27.9 mg/kg BW/day in males and 0, 1.1, 5.9 or 29.6 mg/kg BW/day in females). In both sexes, there were no changes in general condition, body weight gains and food intakes in all groups. No deaths were observed in all groups. Significant increase in AST was observed in 500 ppm males at Week 4. However, the change was not observed at Week 13. Slight but significant decreases in creatinine were also observed in 100 ppm females at Week 13 and 500 ppm males and females at Weeks 4 and 13. Total cholesterol (T-CHO) was significantly elevated in females of the 500 ppm group at Weeks 4 and 13. Absolute and relative liver weights were increased in 500 ppm of both sexes at Week 4. In females, the increases were also observed at Week 13. However, no remarkable histopathological findings were observed in all treated groups. In the chronic test, rats were fed a diet containing IBBMP at levels of 0, 100, 500 and 1500 ppm for 18 months with interim sacrifices at 6 and 12 months (equal to 0, 3.8, 19.4 or 59.4 mg/kg BW/day in males and 0, 4.3, 20.9 or 67.5 mg/kg BW/day in females). No remarkable changes in general appearance were observed in any rats. Body weight gains, food intakes and survival rates in all treated animals were comparable to those of the control. No remarkable changes in the hematological parameters were observed. T-CHO was significantly elevated in females of the 1500 ppm groups throughout the experiment. Significant increases or tendencies for increase in relative liver weights were observed in the 500 and 1500 ppm animals of both sexes. Increased incidences of swelling in liver cells were observed in 1500 ppm males at 6 months and 1500 ppm females at 12 and 18 months. At 18 months, dose-dependent increases in thickness of basement membrane of renal tubules and Bowman's capsule and cell infiltration to the interstitium of the kidney were observed in males. Significant increases of hyaline cast and basophilic change were also observed in 1500 ppm males. In females, increased incidences of hyaline cast were observed at 500 ppm and higher at 18 months. No other toxicity was apparent. No neoplastic lesions that could be attributed to IBBMP were observed in any organs of either sex. From the result of the chronic toxicity test, the no-observed-adverse-effect level (NOAEL) for IBBMP was concluded to be 100 ppm in the diet (4.26 mg/kg BW/day) in female rats on the basis of induction of hyaline cast in renal tubules at 500 ppm, whereas, in males, only a lowest-observed-adverse-effect level (LOAEL) was given as 100 ppm (3.84 mg/kg BW/day) on the basis of induction of thickening of basement membrane in renal tubules at 100 ppm.     

Toxicology of Indecainide Hydrochloride in Mice, Rats, and Dogs

Toxicology of Indecainide Hydrochloride in Mice, Rats, and Dogs.SANDUSKY, G. E., AND MEYERS, D. B. (1985). Fundam. Appl. Toxicol.5,175–181. Indecainide is a new (investigational) drugfor treating cardiac arrhythmias. When given orally to eitheryoung adult rats or mice, the LD50 was ca. 100 mg/kg. Leg weakness,tremors, and occasional convulsions were seen in rodents givendoses in the lethal range. Dogs and monkeys survived a singleoral dose of 25 mg/kg; however, there was a pronounced increasein duration of the PR and QRS intervals. In a 3-month subchronictoxicity study, rats fed dietary levels equivalent to 20 mg/kg/dayindecainide were unaffected. Body weight gain was slightly depressedin both sexes of the 40-mg/kg dose group and moderately reducedin both sexes of the 85-mg/kg dose group. Alkaline phosphatasevalues were minimally increased in females of the 85-mg/kg dosegroup. In a 3-month subchronic toxicity study, dogs were givendaily doses of 0, 6.25, 12.5, or 25 mg/kg indecainide. One malein the 12.5-mg/kg dose group and two females in the 25-mg/kgdose group died during the study. EKG recordings showed a prolongationof the PR and QRS intervals in all treated dogs. In addition,there was a notch in or just prior to the R wave. There wereno histopathology findings related to treatment in rats anddogs in the 3-month Subchronic rat and dog Studies.     

Subacute toxicity of alpha-ergocryptine in Sprague-Dawley rats. 2: metabolic and hormonal changes.

The present study describes the metabolic changes observed in a dietary subacute toxicity experiment with the ergot alkaloid alpha-ergocryptine in Sprague-Dawley rats. The observed effects on metabolic and hormonal parameters were described separately from the general toxicological effects, in view of the important role of dopamine agonists in metabolism (e.g. ergot alkaloids in fescue toxicosis). The rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28-32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). Total cholesterol and high-density lipoprotein (HDL)-cholesterol were decreased dose dependently in females but the ratio HDL-cholesterol/total cholesterol was only decreased at 20 mg/kg body weight. Triglycerides and glucose concentrations were decreased in the highest dose groups of both sexes. Serum urea concentrations were increased in the 20, 100 and 500 mg/kg dose groups. Insulin, glucagon and liver glycogen were increased in the highest dose group at the end of the study, when the animals were allowed to eat prior to blood sampling and necropsy. Prolactin, T4 and FT4 were decreased in the 20, 100 and 500 mg/kg dose groups of both sexes. Follicle-stimulating hormone (FSH) was decreased in the 20, 100 and 500 mg/kg female dose groups and luteinizing hormone (LH) was increased in the 20, 100 and 500 mg/kg male dose groups. It is postulated that the observed effects on food intake, metabolism (lipid and carbohydrate) and hormonal parameters are due to an interaction of ergocryptine with central dopaminergic activities, which comprise a major functional component of a central regulatory system for metabolism.     

Biologic Activity of 5′-Deoxy-5-fluorouridine by Rectal Administration

5-Deoxy-5-fluorouridine (dFUR) is used orally to treat human malignancies. This study compared the antitumor activity and toxicity of rectally and orally administered dFUR. A 7-day treatment of dFUR (350 or 700 mg/kg/day) was infused rectally over 30 min or administered by oral gavage (500 mg/kg/day) to rats bearing transplanted dimethylhydrazine-induced colon tumors. The oral treatment was previously shown to produce a 82% cure of the tumor-bearing animals. The tumor weight after 7 day treatment was compared to that before treatment. The size of the tumor in the saline-treated control group (N = 6) increased by 55%. The maximum tumor size reductions by drug treatments were 40% for the 350-mg/kg rectal dose (N = 5), >99% for the 700-mg/kg rectal dose (N = 10), and 100% for the 500-mg/kg oral dose (N = 4). The 350-mg/kg rectal dose did not produce any cures, while the 700-mg/kg rectal dose produced 80% cures and the 500-mg/kg oral dose 100% cures. The cured animals remained tumor-free during the observation period of 163 to 243 days. The tumor-bearing rats were euthanized between 46 and 132 days when they appeared moribund or when the tumor began to ulcerate. The 700-mg/kg rectal and 500-mg/kg oral treatments produced greater weight loss than saline, suggesting a drug-induced intestinal toxicity. After rectal drug treatment, the animal weight returned to pretreatment level within 3 days, indicating a rapidly reversible intestinal toxicity. The oral group suffered a greater weight loss than the rectal group and took more than 10 days to recover. This suggests that the intestinal toxicity of the rectal treatment was less severe than the oral treatment. The leukocyte and thrombocyte counts after drug treatments were not significantly different from the pretreatment levels, which suggests an absence of myelosuppression. In summary, these results indicate that dFUR by rectal administration had antitumor activity with minimal host toxicity.     

Toxicity of Toxaphene in the Rat and Beagle Dog

Toxicity of Toxaphene in the Rat and Beagle Dog. CHU, I., VILLENEUVE,D.C, SUN, C., SECOURS, V., PROCTER, B., ARNOLD, E., CLEGG, D.,REYNOLDS, L., AND VALLI, V.E. (1986). Fundam Appl. Toxicol.7, 406-418. Residues of the insecticidal mixture, toxaphene,have been found in Great Lakes fish. The purpose of the presentstudy was to assess the subchronic toxicity of toxaphene inthe rat and beagle dog. In the rat study, groups of 10 maleand 10 female animals were fed diets containing 0, 4, 20, 100,or 500 ppm of the test compound for 13 weeks. No clinical signsof toxicity or spontaneous deaths were observed. Toxaphene treatmentup to 500 ppm had no effects on weight gain or food consumption.The liver/body weight ratio and hepatic microsomal enzyme activities(phenobarbital type) were increased in both sexes fed 500 ppmof the test compound. Toxaphene at the highest dose also causedkidney enlargement in male but not in female rats. Dose-dependenthistological changes were seen in the kidney, thyroid, and liver.Changes in the liver and thyroid were considered to be adaptativebut the injury in the proximal tubules of the kidney was focallysevere. Groups of six male and six female beagle dogs were fedtoxaphene in gelatin capsules at 0, 0.2, 2.0, and 5.0 mg/kgbody wt/day for 13 weeks. Food consumption and growth rate werenot affected. All animals survived the entire treatment period.No clinical signs of toxicity were observed. The liver/bodyweight ratio and serum alkaline phosphatase were increased indogs of both sexes fed 5.0 mg/kg. Mild to moderate dose-dependenthistological changes were observed in the liver and thyroid.Toxaphene was accumulated in a dose-dependent manner in thefat and liver of dogs and rats. Based on the biochemical, histological,and residue data, it was concluded that the no-adverse-effectlevels of the pesticide were 4.0 ppm (0.35 mg/kg) for the ratand 0.2 mg/kg for the dog.     

Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes

Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were obtained in all the in vivo assays as well as in the in vitro assay. In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes. In the liver of rats given flutamide as initiating agent at the dose of 500 mg/kg/week for 6 successive weeks, gamma-glutamyltraspeptidase-positive foci were detected only in 3 of 10 rats. There was no evidence of a promoting effect on the development of aberrant crypt foci in rats given 100 mg/kg flutamide on alternate days for 8 successive weeks. In primary cultures of human hepatocytes from one male and one female donor DNA fragmentation as measured by the Comet assays, and DNA repair synthesis as revealed by quantitative autoradiography, were absent after a 20 hr exposure to flutamide concentrations ranging from 18 to 56 microM. Taken as a whole, our results seem to indicate that flutamide is a non-genotoxic drug.     

Gender-Related Difference in the Toxicity of Ultraviolet Absorber 2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole in Rats

2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as an ultraviolet absorber. Previously, we showed that male rats had more than a 100 times higher susceptibility to the toxic effects of DBHCB than females. In order to investigate the role of sex steroids in the mediation of this gender-related difference, DBHCB (0 or 250?mg/kg/day) was given to male and female young intact and castrated rats by gavage for 28 days in the current study. In intact rats, relative liver weight increased to more than two times that of the control in males, while the rate of change was less than 10% in females. On histopathology, hypertrophy of hepatocytes was observed in males but not in females. In castrated rats, an approximately 40% increase in the relative liver weight was found only in males, and no histopathological changes in the liver were detected in either sex. The gender-related difference was also determined in preweaning rats administered DBHCB at 0, 250, or 500?mg/kg/day by gavage from postnatal days 4 to 21. Blood biochemical changes, including increases in the levels of AST, ALT, and ALP, 80–95% increase in the relative liver weight and histopathological changes in the liver, such as hypertrophy and single cell necrosis of hepatocytes, were observed at both doses in both sexes. In conclusion, the gender-related difference in the toxicity of DBHCB, which was observed in young rats, was markedly reduced by castration and abolished in preweaning rats.     

Combined repeated-dose and reproductive/developmental toxicity screening test of 1-tert-butoxy-4-chlorobenzene in rats

We have carried out animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade, and Industry of Japan. Here, we tested 1-tert-butoxy-4-chlorobenzene in a combined repeat-dose and developmental and reproductive toxicity test. The test chemical was administered daily by gavage to 9-week-old Crl:CD (SD) rats at doses of 0, 20, 100, and 500 mg/kg/d. Males were treated for 42 d beginning 14 d before mating. Females were treated from 14 d before mating to day 4 of lactation. Decreased spontaneous locomotion, decreased respiratory rate, and incomplete eyelid opening were observed at 500?mg/kg/d (both sexes), but resolved within 30?min of administration, suggesting central nervous system depression. No notable changes were observed in body weight, food consumption, functional battery tests, or blood test. Increased liver weight with centrilobular or diffuse hepatocyte hypertrophy was observed at 100 and 500?mg/kg/d (both sexes). There were no biochemical or histopathological changes related to hepatotoxicity. Increased kidney weight with basophilic tubules, tubule dilatation, and increased hyaline droplets were observed in males dosed at 100 and 500?mg/kg/d. Immunohistochemical staining indicated α_2u-globulin nephropathy, a male rat-specific toxicity. Although kidney weight was also increased in females dosed at 500?mg/kg/d, it was not considered to be an adverse effect because there were no histopathological changes. Pup weights on postnatal day 0 were decreased at 500?mg/kg/d and still decreased on postnatal day 4. Our data indicated the no-observed-adverse-effect-level for repeated-dose and reproductive/developmental toxicity for 1-tert-butoxy-4-chlorobenzene was 100?mg/kg/d.