Subchronic toxicity study of liquid paraffin in F344 rats

A 13-week oral toxicity study of liquid paraffin was carried out in F344 rats at the dose levels of 5, 2.5, 1, 0.5, 0.2 and 0% in the powdered diet to select a suitable dose range for a 2-year carcinogenicity study. Each group consisted of 10 males and 10 females. No animals showed decrease in body weights and food intakes in any group, and all animals were surviving at the end of the experiment. Changes indicating obvious toxicity of liquid paraffin were not observed in the hematological-, serum biochemical- and histopathological-examinations. Based on these data, a concentration of 5% or more in the diet was considered as the maximum tolerable dose of liquid paraffin for both sexes in F344 rats.     

Subchronic inhalation toxicity study of a water-dispersible polyester in rats

AQ55 is a high molecular weight, water-dispersible, amorphous polyester used in applications where the exclusion of solvents and conventional surfactants is desirable, such as water-based adhesives, coatings, emulsions, paint primers, cosmetics and detergents. Potential health effects were evaluated in rats exposed by inhalation for about 13 wk to mean concentrations of 0, 2.4, 19.6 or 199 mg/m3 AQ55 polymer. No mortality occurred and body weights were unaffected. Mean relative liver weights in all treated male groups were slightly higher than control weights, but were not judged to be treatment related. Absolute liver weights and all other organ weights except lung weights were normal. Haematology, clinical chemistries and gross pathology were unremarkable. Exposure-related changes in the 199 mg/m3 groups included increased mean absolute and relative lung weights, accumulations of macrophages and acute inflammatory cells in alveolar and bronchial lumina, and increased numbers of macrophages in sinusoids of peribronchial lymph nodes. Minor accumulation of macrophages in alveolar lumina was the only exposure-related change in the 19.6 mg/m3 group. No exposure-related effects were seen in the 2.4 mg/m3 group. AQ55 produced no systemic toxicity, and aerosols of AQ55 do not appear to be toxic to pulmonary tissues following subchronic inhalation exposure.     

Subchronic dietary toxicity of strychnine: bobwhite quail are less sensitive than mallard ducks

PURPOSE: This study was undertaken to evaluate in vivo the effect of recombinant hirudin (r-hirudin [HBW 023]), a potent thrombin inhibitor, on the process of microvascular thrombus formation and recanalization. METHODS: Thrombosis was induced photochemically in distinct arterioles (n = 25) and venules (n = 30) of the ear of 16 hairless hr/hr mice (8 to 10 weeks old, 25 to 30 g of body weight). r-Hirudin (1 mg/kg of body weight) was administered intravenously directly before thrombus induction; saline-treated animals served as controls. Thrombus formation (i.e., first platelet deposition at the endothelial lining [FPD]; inner luminal diameter reduction to 50% [D/2]; complete vessel occlusion [CVO]), vessel recanalization, microcirculatory parameters, and leukocyte-endothelial cell interaction were analyzed by means of intravital fluorescence microscopy. RESULTS: Hirudin significantly delayed the process of thrombus formation compared with saline-treated controls in both arterioles (FPD: 381 +/- 80 vs 137 +/- 25 seconds, P < 0.05; D/2: 627 +/- 49 vs 501 +/- 71 seconds; CVO: 925 +/- 78 vs 854 +/- 60 seconds) and venules (FPD: 173 +/- 11 vs 59 +/- 4 seconds; D/2: 342 +/- 54 vs 228 +/- 27 seconds; CVO: 541 +/- 85 vs 344 +/- 43 seconds; P < 0.05). In addition, r-hirudin-treated animals showed an increased rate of vessel recanalization at 24 hours after thrombus induction (arterioles: 54% [7 of 13] vs 0% [0 of 12], P < 0.05; venules: 77% [10 of 13] vs 53% [9 of 17]), whereas microcirculatory parameters and leukocyte-endothelial cell interaction were not affected. CONCLUSION: Our data indicate that r-hirudin not only counteracts the process of thrombus formation but also promotes vessel recanalization, thus supporting its use in clinical microvascular surgery.     

Subchronic toxicity of PCB 105 (2,3,3'',4,4''-pentachlorobiphenyl) in rats

Increases in the intracellular free calcium concentration are of great importance to the initiation of development in deuterostomes. Their involvement has not yet been clearly defined in protostomes. We used endogenous ligands (IP3, cADPR, ryanodine and NAADP) and pharmacological agents (thapsigargin [Tg], thimerosal, caffeine and heparin) to study smooth endoplasmic reticulum Ca2+ pump and release mechanisms in eggs of an annelid, Chaetopterus. Oocyte homogenates effectively sequestered Ca2+ and released it in response to IP3 in a concentration-dependent manner. Repeated additions of IP3 were unable to cause further release. Heparin inhibited Ca2+ release in response to IP3. The homogenates also released Ca2+ in response to thimerosal, and this release was sensitive to heparin. Two antibodies to IP3 receptors recognized an appropriate band in Chaetopterus egg lysates. These results indicate that the oocytes possess type-1 IP3-gated Ca2+ channels. Neither calcium itself, nor strontium, cADPR, ryanodine, caffeine nor NAADP released appreciable Ca2+. At low concentrations, Tg caused a slow release of Ca2+; at higher concentrations, it elicited a rapid release. Release of Ca2+ by Tg activated development. Since one theory of fertilization invokes the introduction of a Ca2+ releasing soluble protein into the egg upon sperm-egg fusion, we also tested whether soluble extracts of Chaetopterus sperm could stimulate Ca2+ release in Chaetopterus egg homogenates. There was no Ca2+ release when the sperm extract was added to the homogenate; however, homogenates exposed to sperm extract became refractory to IP3. Thus, Ca2+ release at fertilization in these oocytes occurs through IP3-gated channels.     

Subchronic toxicity of a medium-chain chlorinated paraffin in the rat

Groups of ten male and female weanling Sprague-Dawley rats were fed diet containing 0, 5, 50, 500 or 5000 ppm of a medium-chain chlorinated paraffin (C14-17, 52% chlorination) for a period of 13 weeks. Increased relative liver weight was observed at 500 and 5000 ppm in females and at 5000 ppm in males. Relative kidney weight was increased at 5000 ppm in both sexes. Serum cholesterol was increased in the females in a dose-related manner starting at 50 ppm. At 5000 ppm, animals of both sexes had elevated hepatic UDP-glucuronosyltransferase activity while only females showed increased aminopyrine N-demethylase activity. Increased urinary N-acetylglucosaminidase activity occurred at 5000 ppm in females. Increased urinary ascorbic acid excretion monitored at week 12 and a decreased hepatic vitamin A level were detected in females receiving the 500 ppm diet and male and female rats at 5000 ppm. Mild, adaptive histopathological changes were detected in the liver of rats of both sexes at 500 and 5000 ppm, and in the thyroid of males and females starting at 500 and 50 ppm respectively. Minimal changes were observed in the kidney proximal tubules of male rats fed the 5000 ppm diet and in the inner medulla tubules of female rats fed the 500 and 5000 ppm diets. These data indicate that the medium-chain chlorinated paraffin produces biochemical and histological changes at dietary levels of greater than or = 50 ppm in females and greater than or = 500 ppm in males.     

Sodium appetite in adrenalectomized rats following dietary sodium deprivation.

Experimented with operated, sham-operated, and comparison male Sprague-Dawley rats (N = 74). Adrenalectomized (Adrex) rats adjusted well during adrenal insufficiency when saline solutions were available. Despite continuous uncontrolled losses of relatively large amounts of sodium in their urine, they managed to maintain body fluids at approximately normal levels by replacing crucial sodium losses, if only temporarily, through frequent intakes of saline. It is concluded that the threshold for sodium appetite in Adrex rats is associated with relatively small sodium deficits, and roughly similar deficits also are effective in stimulating sodium appetite in intact Ss. When more pronounced losses result from maintenance on a sodium-free diet, Adrex Ss rapidly drink more than enough saline to replace their deficits. Thus, it seems evident that mineralocorticoids need not have a vital role in either the initial salt-drinking response of intact Ss to minor sodium deficits or their overcompensation for moderate sodium deficits. (32 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine-induced place preferences following prior nicotine exposure in rats

The motivational properties of morphine and nicotine were investigated in an automated conditioned place preference (CPP) procedure using a two-compartment apparatus. The accuracy of the photocell recording system was assessed by correlation with direct observation. In a counterbalanced conditioning design, graded doses of morphine (0.1-3.2 mg/kg SC) produced dose-related CPP. Under similar conditions, a dose of nicotine (0.6 mg/kg SC) previously reported to produce CPP failed to show an effect. Increasing the number of conditioning trials from 4 to 12 did not facilitate CPP with nicotine. After pretreatment with nicotine (0.4 mg/kg SC) daily for 7 days prior to conditioning, nicotine (0.4-0.8 mg/kg) produced increasing magnitudes of CPP. Locomotor activity was assessed during both conditioning and extinction tests. During conditioning, nicotine but not morphine decreased activity in the first conditioning trial, but by the fourth trial, marked stimulation was apparent following administration of either drug. Activity in the drug-paired compartment was not increased during tests for CPP carried out in the undrugged state following 4 conditioning trials with either morphine or nicotine, but there was evidence for conditioned hyperactivity after 12 conditioning trials with nicotine. The results suggest that motivational properties of nicotine can be detected in counterbalanced CPP procedures, but only in subjects with a history of nicotine exposure. The CPP produced by morphine or nicotine does not appear to be an artefact associated with conditioned changes in locomotor activity.     

Subchronic toxicity study of tetrahydroisohumulone and hexahydroisohumulone in the beagle dog

Hops and hop extracts are approved and widely used bittering agents in the brewing of beer. During recent years, preisomerized alpha hop acids and reduced preisomerized alpha hop acids have been introduced as effective and economical bittering agents that may be added late in the brewing process. Although hops have been used for centuries, there are few studies in the literature on the safety of this ingredient. The study herein was conducted to determine the effects associated with subchronic oral administration of the reduced preisomerized hop acids, hexahydroisohumulone and tetrahydroisohumulone, in the dog. The results show that these materials are generally well tolerated in the dog. At high dose levels they induce vomiting, and much of the material administered was excreted in the faeces. The no-observed-adverse-effect level (NOAEL) of the compounds were 50 and 100 mg/kg body weight, respectively. Consumption of these ingredients by adult humans drinking 1 litre of beer daily is less than 0.25 mg/kg body weight; their use is thus associated with wide safety margins.     

Subchronic toxicity studies with the leukotriene D4 antagonist RG 12525

Preclinical safety studies with the leukotriene D4 antagonist RG 12525 were conducted by the oral route in mice, rats, and monkeys. Oral administration of RG 12525 was repeated daily in studies up to 6 months in duration. RG 12525 was shown to have limited high-dose toxicity after repeated oral administration. The effects of RG 12525 were strongly dependent upon the species considered. High doses of RG 12525 caused significant increases in liver weight in mice, rats, and monkeys that were associated with diffuse hepatocellular hypertrophy in mice and rats but not in monkeys. No related clinical chemistry changes were observed in any of the species and hepatic activities of peroxisomal enzymes or cytochrome P450 were increased only slightly. Proliferation of brown adipose tissue (BAT) was observed in rats and mice but not in monkeys. The BAT reaction was more pronounced in the interscapular area but it was also observed in other subcutaneous locations as well as in mediastinal and bone marrow fat. In all locations, the RG 12525-induced BAT had some morphological similarities with cold-adapted BAT. Repeated administration of RG 12525 at high doses to female rats resulted in a lack of progression to the luteal phase of the estrous cycle that was reversible after discontinuation of treatment. Finally, RG 12525 was nephrotoxic in mice with males being more sensitive than females.     

Brain stimulation reward following chronic lead exposure in rats.

Adult male rats were exposed to drinking water containing either 500 parts per million (ppm) lead acetate or an equal concentration of sodium acetate for 80 days. Bipolar electrodes were then implanted into the medial forebrain bundle (MFB), and rats were allowed to recover for 7 days. On Day 8 postsurgery, control and lead-treated rats were placed in an operant chamber and shaped to press a lever to receive 200-msec trains of current. Data from a range of current intensities and frequencies were recorded to obtain threshold values for each rat, defined as the stimulation needed to support half-maximal lever responding. Results indicated that chronic lead exposure attenuated the reinforcing effect of brain stimulation. Because of the large number of reward systems mediated by the MFB nucleus accumbens pathway, these data suggest that a variety of motivational phenomena may be affected by contaminant exposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disorders in the development of offspring following exposure of rats to hydrogen chloride

Female Wistar rats were subjected to the influence of hydrogen chloride before and on the ninth day of pregnancy. Apart from marked lung lesions there were functional disturbances in the kidneys and the liver in both groups of the experimental animals. Changes in the state of maternal organs caused changes in the development of organs in the progeny (functional derangement of these organs during the postnatal period). Disturbances in the lungs (after an additional load) and in the kidneys were noted in the male progeny of both groups; there were also disturbances of the hepatic function in the male progeny when their mothers were acted upon by HC1 before the occurrence of pregnancy.     

Choline supplementation following third-trimester-equivalent alcohol exposure attenuates behavioral alterations in rats.

Despite the known adverse consequences of prenatal alcohol exposure, some pregnant women continue to drink alcohol, making it imperative to identify treatments for children with fetal alcohol spectrum disorders. The authors recently reported that perinatal choline supplementation can reduce some fetal alcohol effects (J. D. Thomas, M. Garrison, & T. M. O'Neill, 2004), and the present study examined whether choline supplementation is effective when administered after third-trimester-equivalent ethanol treatment. Rat pups were exposed to 6.0 g/kg/day ethanol during the neonatal brain growth spurt (Postnatal Days [PD] 4-9) and treated with choline chloride (0, 10, 50, or 100 mg/kg) from PD 10-30. Behavioral testing occurred after choline treatment had ceased. Female subjects exposed to ethanol were overactive and exhibited spatial learning deficits, effects that were attenuated with all doses of choline supplementation. These data indicate that choline supplementation can alter brain development following a developmental insult. Moreover, the data suggest that early dietary interventions may reduce the severity of some fetal alcohol effects, even when administered after birth. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subchronic MK-801 treatment to juvenile rats attenuates environmental effects on adult spatial learning

Forty eight primary and 20 secondary chondrosarcomas were treated surgically 1975 through 1991. An evaluation of the data of the Bone Tumor Register of the Semmelweis Medical University proved that the incidence of the malignant transformation and development of secondary chondrosarcomas is 3% and 2.6% among solitary osteochondromas. The authors summarize the clinicopathological characteristics of the malignant transformation. A retrospective evaluation of the histological grade of the malignancy proved that 67% of tumors were classified as grade I; 18% as grade II and 15% as grade III. The survival of the patients was mainly determined by the grade of the malignancy. A 95% 5-years survival was found in the grade I group and a 10% survival only in the grade II and III groups. In the cases of highly malignant chondrosarcomas radical surgical intervention i.e. amputation is recommended, considering the most often extra-compartmental location of the tumors. Low malignant and intra-compartmental highly malignant chondrosarcomas should be treated, however, by limb saving surgery. In the cases of large inresecable but low malignant chondrosarcomas debulking surgery is also acceptable.     

Pathomorphologic changes in the organs of rats following chronic inhalation exposure to liquid polyethylsiloxane

A chronic 90-day inhalation of polyethylsiloxane fluid at a concentration of 10 and 2 mg/m3 produced local irritation and general toxic effect on rats. Local irritation induced catarrhal-desqueamative tracheitis that was accompanied by a microfocal interstitial process in the lungs. The general toxic effect gave rise to interstitial myocarditis that was followed by focal cardiosclerosis and dystrophic lesions of vascular walls and areas of liver parenchyma. Changes in the thymus-lymph system and adrenal structure suggested prolonged protective tension of the animal body. A chronic 90-day inhalation of polyethylsiloxane at a concentration of 0.2 mg/m3 brought about no pathological lesions in the microstructure of animal organs.     

Developmental toxicity of 1,2-dichloropropane (PDC) in rats and rabbits following oral gavage

The ST-16 antigenic specificity of the HLA-B locus is defined as a B39 variant of Mexican-Americans. Nucleotide sequencing of cDNA shows the ST-16 allele (B*3905) differs from B*39011 by a single substitution that substitutes tyrosine for aspartic acid at position 74 of the mature class I heavy chain. The complete coding region sequence for the common caucasoid allele encoding the B38 antigen has been determined. This B*3801 allele differs from B*3802 at two nucleotide substitutions within the Bw4 sequence motif. B*3801 and B*3802 may have been derived independently from B*39011 by conversion events with B alleles donating distinctive Bw4 motifs. A novel allele B*39022 derived from a Colombian Indian differs from the B*39021 allele of Japanese origin at two widely separated silent substitutions. Comparison of sequences for the known B16 alleles suggest that B*39021 and B*39022 were independently derived by recombination from B*39013 and B*39011 respectively.     

Subchronic feeding study of four white mineral oils in dogs and rats

Subchronic 90-day feeding studies were conducted on four highly refined white mineral oils to determine any potential for toxicity in Long-Evans rats (20 per sex per dose level) and beagle dogs (4 per sex per dose level). Each oil was fed at dietary dose levels of 300 ppm and 1500 ppm (w/w). No treatment-related effects of toxicological importance were detected in daily observations of general health or in periodic assessments of food consumption and body weight, hematology, serum clinical chemistry, and urinalysis. Observations in dogs suggested that the white oils produced mild laxative effects. Gross and histopathologic examinations, as well as measurements of organ weights, did not reveal any macroscopic or microscopic changes which could be due to treatment. In addition, special staining by Oil Red O of liver, mesenteric lymph nodes, spleen, gastrointestinal tract, stomach, and kidneys indicated no evidence of oil or lipid deposition. A special re-examination of tissues from female and male rats, in response to more recent conflicting data from the Fischer 344 strain, found no histopathologic signs of macrophage accumulation and/or microgranuloma formation in liver, spleen, or mesenteric lymph nodes. These data indicate that repeated exposure to relatively high levels of white mineral oils in the diets does not produce significant subchronic toxicity in Long-Evans rats or beagle dogs.     

The influence of dietary lipids on nephrolithiasis in rats

PURPOSE: The influence of dietary lipids on nephrolithogenesis is unclear. In the present study, I investigated the role of dietary lipids concerning both the etiology and the prevention of nephrolithiasis using 9-week-old male Wistar rats. METHODS: Study 1: The rats were divided into five groups and reared on standard, low protein, high protein and high cholesterol diets for 23 weeks. Study 2: The effects of cholesterol on nephrolithiasis was examined. The animals were given a 30 intraperitoneal injection of 2 ml of 8.5% calcium gluconate. Study 3: A nephrolithiasis model was prepared by intraperitoneal administration of 40 mg/kg of glyoxylic acid and 0.25 microgram of vitamin D3 daily for 2 weeks. The inhibitory effects of eicosapentaenoic acid (EPA) on nephrolithiasis were studied. RESULTS: Study 1: In the groups given the high protein and high cholesterol diets, an increase in renal osteopontin-mRNA, one of the major matrix ingredients of stones containing calcium, was observed. Study 2: Microlith was more frequently observed in the high cholesterol group than in the standard diet group. Study 3: In the EPA group, lithiasis was less extensively than in the groups administered distilled water or olive oil, and this was assumed to be caused by factors other than inorganic substances such as calcium and oxalic acid in the urine. When the renal tissue specimens in Studies 2 and 3 were examined, initial calcium deposition was found to start from the basement membrane of renal tubular cells and gradually spread throughout the cells. CONCLUSION: These results suggested that cholesterol is a risk factor in nephrolithiasis, and EPA is effective in its prevention. The elimination of hyperlipidemia should be included in dietary instructions for nephrolithiasis patients.     

Reproductive and thyroid hormone levels in rats following 90-day dietary exposure to PCB 28 (2,4,4''-trichlorobiphenyl) or PCB 77 (3,3''4,4''-tetrachlorobiphenyl)

It has been reported that suramin, an anthelminthic, trypanocidal agent and an inhibitor of P2 receptors, may antagonise N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptors. Both NMDA receptors and P2X subclass of P2 receptors are ligand-gated Ca2+-selective channels and, since the increased influx of Ca2+ into neurons has been linked to neurotoxicity, simultaneous inhibition of P2X and NMDA receptors in vivo by suramin could represent an effective neuroprotective treatment. We have found that suramin inhibited the binding of [3H]CGP 39653 to NMDA receptor binding sites in vitro and reduced the frequency of NMDA channel openings in patch-clamp studies. Suramin (1 mM) had no effect on [3H]kainate binding in vitro. In vivo, intracerebroventricular (I.C.V.) injections of suramin (70 nmol/brain) antagonised convulsive effects of the NMDA agonist (RS)-(tetrazol-5-yl)-glycine (TZG, LY 285265). Suramin, however, did not prevent neurotoxic lesions in the hippocampus caused by I.C.V. administration of TZG. Increasing the dose of suramin resulted in death from severe respiratory depression.