Dose Levels In Rats Research Articles

PBK models to predict internal and external dose levels following oral exposure of rats to imidacloprid and carbendazim

Monitoring oral exposure to pesticides in wildlife is crucial for assessing environmental risks and preventing adverse effects on non-target species. Traditionally, this requires invasive tissue sampling, raising ethical, regulatory, and economic concerns. To address this gap, our study aims to develop a method for assessing external oral dose levels in rats using physiologically-based kinetic (PBK) modeling based on blood concentration levels of two pesticides, imidacloprid and carbendazim, and one of their primary metabolites. We utilized in vitro metabolic kinetic data from hepatic microsomal and S9 incubations to inform our models. These models were then evaluated by comparing their predictions with existing in vivo experimental data from the literature. Our results demonstrate that the models provide accurate predictions, presenting a novel in vitro and in silico approach for environmental exposure and risk assessment of pesticides. This methodology has the potential for application in wildlife species, advancing the frontier of knowledge in non-invasive pesticide exposure assessment.

Carcinogenicity assessment of baricitinib in Tg.rasH2 mice and Sprague-Dawley (Crl:CD) rats

Baricitinib is a potent and selective Janus kinase (JAK)1 and JAK2 inhibitor, and is approved for the treatment of moderately to severely active RA in adults in Europe, Japan, and other countries. This study evaluated the carcinogenic potential of baricitinib in Tg. rasH2 mice and Sprague-Dawley (Crl:CD) rats. Baricitinib was administered daily by oral gavage to Crl:CD rats for up to 94 weeks (dose levels of 0, 1, 3, or 8 mg/kg for males and 0, 3, 8, or 25 mg/kg for females) and to Tg. rasH2 mice for 26 weeks (dose levels of 0, 15, 40, or 300 mg/kg for males and 0, 10, 30, or 150 mg/kg for females). Baricitinib was well tolerated with no incidence of compound-related neoplasms at any dose levels in rats and mice. In mice, non-neoplastic events observed were bone marrow hypocellularity and increased adipocytes. In rats, baricitinib administration was associated with a dose-dependent increase in survival, with a decreased incidence of neoplasm (hematopoietic and mammary), potentially secondary to drug-related decreased weight gain. The incidence of proliferative changes such as neoplastic and hyperplastic lesions in the mammary glands of females and in the livers of males and females also decreased. In conclusion, baricitinib is not considered to be carcinogenic.

Acute and subchronic toxicity study of Tamra Bhasma (incinerated copper) prepared with and without Amritikarana

BackgroundTamra Bhasma (TB) is one among herbo-metallic preparations extensively used in routine ayurvedic practice. In the present era, Bhasma preparations used in ayurvedic system of medicines are always under stern observations for containing heavy metals which may raise the question of safety aspect. ObjectiveIn the present study, TB prepared with and without Amritikarana was subjected to toxicity study to ascertain the role of Amritikarana on safety profile of TB in rats. Materials and methodsBoth the samples of TB were administered to rats for 28 consecutive days at the doses of 5.5, 27.5, and 55 mg/kg. The effects of both drugs were assessed on ponderal changes, hematological, serum biochemical, and histopathology of various organs. ResultsResults showed that both the samples of TB did not produce any sign and symptoms of toxicity at therapeutic dose level (5.5 mg/kg) and therapeutic equivalent dose (TED) × 5 (27.5 mg/kg) while at higher dose of TED × 10 (55 mg/kg) TB has mild toxicity in liver, kidney, heart, and thymus on repeated administration for 28 days in rats. The sample without Amritikarana has more magnitude of toxicity than the sample with Amritikarana. ConclusionFrom the present study, it is concluded that TB with Amritikarana was found to be relatively safer than TB without Amritikarana at different dose levels in rats and hence suggest for safely use in humans at therapeutic dose level. It proves the role of Amritikarana in the preparation of TB.

Monte Carlo simulations of the dose from imaging with GE eXplore 120 micro-CT using GATE.

Small animals are increasingly used as translational models in preclinical imaging studies involving microCT, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are generally sublethal, studies have shown that low-level radiation can change physiological parameters in mice. In order to rule out any influence of radiation on the outcome of such experiments, or resulting deterministic effects in the subjects, the levels of radiation involved need to be addressed. The aim of this study was to investigate the radiation dose delivered by the GE eXplore 120 microCT non-invasively using Monte Carlo simulations in GATE and to compare results to previously obtained experimental values. Tungsten X-ray spectra were simulated at 70, 80, and 97 kVp using an analytical tool and their half-value layers were simulated for spectra validation against experimentally measured values of the physical X-ray tube. A Monte Carlo model of the microCT system was set up and four protocols that are regularly applied to live animal scanning were implemented. The computed tomography dose index (CTDI) inside a PMMA phantom was derived and multiple field of view acquisitions were simulated using the PMMA phantom, a representative mouse and rat. Simulated half-value layers agreed with experimentally obtained results within a 7% error window. The CTDI ranged from 20 to 56 mGy and closely matched experimental values. Derived organ doses in mice reached 459 mGy in bones and up to 200 mGy in soft tissue organs using the highest energy protocol. Dose levels in rats were lower due to the increased mass of the animal compared to mice. The uncertainty of all dose simulations was below 14%. Monte Carlo simulations proved a valuable tool to investigate the 3D dose distribution in animals from microCT. Small animals, especially mice (due to their small volume), receive large amounts of radiation from the GE eXplore 120 microCT, which might alter physiological parameters in a longitudinal study setup.

Nonaqueous Gel for the Transdermal Delivery of a DTPA Penta-ethyl Ester Prodrug

Diethylenetriamine pentaacetic acid penta-ethyl ester, designated as C2E5, was successfully incorporated into a nonaqueous gel for transdermal delivery. The thermal and rheological properties of a formulation containing 40% C2E5, 20% ethyl cellulose, and 40% Miglyol 840® prepared using the solvent evaporation method demonstrated that the gel had acceptable content uniformity and flow properties. In vitro studies showed that C2E5 was steadily released from the gel at a rate suitable for transdermal delivery. Topical application of the gel at a 200 mg C2E5/kg dose level in rats achieved significantly higher plasma exposures of several active metabolites compared with neat C2E5 oil at the same dose level. The results suggest that transdermal delivery of a chelator prodrug is an effective radionuclide decorporation strategy by delivering chelators to the circulation with a pharmacokinetic profile that is more consistent with the biokinetic profile of transuranic elements in contaminated individuals.

Evaluation of safety profile of black shilajit after 91 days repeated administration in rats

ObjectiveTo evaluate the safety of shilajit by 91 days repeated administration in different dose levels in rats. MethodsIn this study the albino rats were divided into four groups. Group I received vehicle and group II, III and IV received 500, 2 500 and 5 000 mg/kg of shilajit, respectively. Finally animals were sacrificed and subjected to histopathology and iron was estimated by flame atomic absorption spectroscopy and graphite furnace. ResultsThe result showed that there were no significant changes in iron level of treated groups when compared with control except liver (5 000 mg/kg) and histological slides of all organs revealed normal except negligible changes in liver and intestine with the highest dose of shilajit. The weight of all organs was normal when compared with control. ConclusionsThe result suggests that black shilajit, an Ayurvedic formulation, is safe for long term use as a dietary supplement for a number of disorders like iron deficiency anaemia.

Pharmacological profile of intrathecal fadolmidine, a α2-adrenoceptor agonist, in rodent models

The present experiments compared the peripheral and central pharmacological effects of three alpha(2)-adrenoceptor agonists: fadolmidine, clonidine, and dexmedetomidine after single intrathecal bolus injections at analgesic dose level in rats. Effects on mydriasis and cardiovascular functions were studied in anaesthetised rats, the effects on sedation/motor performance, body temperature, and gastrointestinal motility were evaluated in conscious rats, and also the effects on brain biogenic amines were studied. All compounds caused dose-dependent mydriasis, a decrease in blood pressure and heart rate, sedation, hypothermia, and inhibition of gastrointestinal transit, but in contrast to the analgesic effects, dexmedetomidine and clonidine were much more potent than fadolmidine. In accordance with the other systemic effects, dexmedetomidine and clonidine, but not fadolmidine, reduced the turnover of the monoamine neurotransmitters, noradrenaline and serotonin, in brain at the analgesic dose. The difference in the systemic effect profile between fadolmidine and clonidine or dexmedetomidine is most probably explained by differences in their ability to spread from the site of administration at the lumbar level into the periphery and/or the brain and further the concentrations of the compounds in the side of action. These results supports that intrathecally administered fadolmidine could have potential to be used as an analgesic agent with less subraspinal or spinal adverse effects at analgesic doses than dexmedetomidine and clonidine.

Studies on the Metabolic Fate of M17055, a Novel Diuretic (5): Pharmacokinetics and Pharmacodynamics of Unchanged Drug in Rat and Dog After Intravenous Administration of M17055

The pharmacokinetics and pharamacodynamics of M17055, a novel diuretic were studied after a single intravenous administration to rats and dogs, the two species used in the pharmacological and toxicological studies. No gender dependent response to systemic exposure was observed at the high dose level in rats, in agreement with the determined LD(50). A gender difference in urinary excretion of M17055, however, was clearly observed in rats. The slower elimination and the lower total body clearance (CLtot) values of M17055 in dogs reflect the difference of the no-effect level (NOEL) between rats (0.1 mg/kg) and dogs (0.03 mg/kg) well. The diuretic response was well correlated with the urinary M17055 excretion rate by fitting to a sigmoid E(max) model in both rats and dogs. The derived ER(50) value of M17055 in dogs was approximately 10 times less than that reported for furosemide, suggesting that the intrinsic potency of M17055 is equal to or higher than those of other powerful loop diuretics. Although diuretic sensitivity was considered to be lower in dogs than in rats, the higher amount of M17055 reaching the dog kidney is likely to compensate for this. The diuretic response in female rats was predictable by using the pharmacodynamic parameters derived from male rats. These results show that the apparent high diuretic potency and the other pivotal observations for M17055 found in the pharmacological and toxicological studies can be rationalized by the pharmacokinetic and pharmacodynamic properties of the unchanged compound.

Enhancement of SDZ ICT 322-induced cataracts and skin changes in rats following vitamin E- and selenium-deficient diet.

The indole-3-carboxylic acid scopoine ester. SDZ ICT 322, is a selective hydroxytryptamine (5-HT3) antagonist, which after chronic treatment causes posterior subcapsular cataracts and skin changes such as hair loss, hyperaemia, desquamation and hyperkeratosis in rats. The detailed mechanisms underlying these changes are not yet known. In order to evaluate a possible oxidative stress-induced pathomechanism of SDZ ICT 322, the antioxidative defence capacity in rats was modulated by feeding a special vitamin E- and selenium-deficient (VE/SeD) diet. For this purpose 32 male Wistar rats, age 4 weeks, were pretreated for 8 weeks with either a VE/SeD diet or a normal standard diet. Each dietary group was divided into 8 control and 8 SDZ ICT 322-treated animals. SDZ ICT 322 was administered in feed to rats at an adjusted daily dose level of 125 mg/kg for 14 weeks. Plasma levels of SDZ ICT 322 as well as of the N-desmethyl metabolite were similar in rats fed the different diets in weeks 3, 6 and 14. In SDZ ICT 322 treated VE/SeD rats cataracts were observed by week 7, whereas in rats fed normal diet cataracts were first seen in week 14. In the normal dietary group no corneal opacity was found after SDZ ICT 322-treatment; however, a corneal opacity was seen in the deficiency group in parallel with one of the cataract animals in week 7. The incidence and severity of clinical skin signs were greater and their onset was earlier in the deficiency dietary group: onset occurred after 6 weeks compared to 9 weeks on the normal diet. Thiobarbituric acid reactive substances, an indicator mainly of oxidized lipids, were statistically significantly increased in the urine of rats administered SDZ ICT 322 and the VE/SeD diet. Uric acid, which is an endogenous antioxidant was statistically significantly decreased in the urine and plasma of SDZ ICT 322 VE/SeD treated rats. The clinical eye and skin changes occurring early after VE/SeD feeding, the unchanged drug plasma exposure and unchanged drug metabolite formation in combination with the general pro-oxidative activity of the drug suggest an oxidative stress-mediated pathomechanism of SDZ ICT 322 at high dose levels in rats.

Lack of carcinogenicity of pesticide mixtures administered in the diet at acceptable daily intake (ADI) dose levels in rats

Carcinogenic effects of pesticide mixtures were examined with our medium-term carcinogenesis protocols using male F344 rats. In the 8-week liver model, combined dietary administration of 20 pesticides (19 organophosphorus compounds and 1 organochlorine), each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 weeks, mixtures of 40 pesticides (high volume compounds) and 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not enhance carcinogenesis in any organ initiated by 5 different known carcinogens in combination. These results provide support for the safety factor (usually 100) approach presently used for the quantitative hazard evaluation of pesticides.

Comparative Toxicities of o-, m-, and p-Nitrotoluene in 13-Week Feed Studies in F344 Rats and B6C3F1 Mice

Comparative Toxicities of o-, m-, and p-Nitrotoluene in 13-Week Feed Studies in F344 Rats and B6C3F1 Mice. Dunnick, J. K., Elwell, M. R., and Bucher, J. R. (1994). Fundam. Appl. Toxicol. 22, 411-421.Nitrotoluenes are high-production-volume chemicals used in the synthesis of agricultural chemicals and in various dyes. Because of differences in the metabolism of the three isomers and their capabilities to bind to DNA, comparative toxicity studies of o-, m-, and p-nitrotoluene were conducted in F344 rats and B6C3F1 mice. o-, m-, or p-Nitrotoluene was administered in the feed to male and female rats and mice at doses ranging from 625 to 10,000 ppm for 13 weeks. These doses delivered approximately 40 to 700 mg/kg body wt/day for rats and 100 to 1700 mg/kg/day for mice. There were no treatment-related effects on survival in any of the studies. Decreased body weights relative to controls occurred in dosed rats and mice in all studies at the higher dose levels and were most pronounced in rats receiving o-nitrotoluene. Mesotheliomas of the tunica vaginalis were observed in 3 of 10 male rats receiving o-nitrotoluene at 5000 ppm, and mesothelial cell hyperplasia was observed in 2 of 10 male rats receiving o -nitrotoluene at 10,000 ppm. Kidney toxicity was observed in male rats receiving o-, m-, or p-nitrotoluene and included hyaline droplet nephropathy and an associated increase in the renal concentration of α2U-globulin. Evidence of liver toxicity in the male rats receiving o-nitrotoluene included hepatocyte vacuolization, oval cell hyperplasia, and increased serum bile acids, sorbitol dehydrogenase, and alanine aminotransferase. Although there was no histopathologic evidence of hepatic toxicity in male or female rats given the m- or p-isomers or in female rats given the o-isomer, treatment-related hepatic effects were detected in these groups, as measured by an increase in the relative liver weights and by elevations in serum bile acids and liver-specific enzymes. The spleens of treated male and female rats had a mild increase in hematopoiesis, hemosiderin deposition, and/or congestion. These splenic changes were slightly more prominent in rats administered the o- and p-isomers. Administration of o-, m-, or p-nitrotoluene impaired testicular function in the rat, as shown by testicular degeneration and reduction in the density, motility, and number of sperm cells. Administration of each isomer to rats caused increases in the length of the estrus cycle. The only histopathologic evidence for treatment-related toxicity in mice in the 13-week studies occurred in animals receiving the o-nitrotoluene isomer where the chemical caused degeneration and metaplasia of the olfactory epithelium. These comparative toxicity studies of o-, m-, or p -nitrotoluene showed that all three chemicals caused toxicity in the kidney, spleen, liver, and/or reproductive system in rats. In general, toxicity was most severe with the ortho-isomer. In mice, olfactory epithelium degeneration was the only treatment-related lesion induced by o -nitrotoluene. Elevations in liver weights were observed at the higher dose levels in rats and mice treated with any of the three isomers. o -Nitrotoluene was carcinogenic in male rats, as indicated by the occurrence of mesotheliomas at 5000 ppm and mesothelial cell hyperplasia at 10,000 ppm.

Comparative Toxicities of o-, m-, and p-Nitrotoluene in 13-Week Feed Studies in F344 Rats and B6C3F1 Mice

Nitrotoluenes are high-production-volume chemicals used in the synthesis of agricultural chemicals and in various dyes. Because of differences in the metabolism of the three isomers and their capabilities to bind to DNA, comparative toxicity studies of o-, m-, and p-nitrotoluene were conducted in F344 rats and B6C3F1 mice. o-, m-, and p-Nitrotoluene was administered in the feed to male and female rats and mice at doses ranging from 625 to 10,000 ppm for 13 weeks. These doses delivered approximately 40 to 700 mg/kg body wt/day for rats and 100 to 1700 mg/kg/day for mice. There were no treatment-related effects on survival in any of the studies. Decreased body weights relative to controls occurred in dosed rats and mice in all studies at the higher dose levels and were most pronounced in rats receiving o-nitrotoluene. Mesotheliomas of the tunica vaginalis were observed in 3 of 10 male rats receiving o-nitrotoluene at 5000 ppm, and mesothelial cell hyperplasia was observed in 2 of 10 male rats receiving o-nitrotoluene at 10,000 ppm. Kidney toxicity was observed in male rats receiving o-, m-, or p-nitrotoluene and included hyaline droplet nephropathy and an associated increase in the renal concentration of α2U-globulin Evidence of liver toxicity in the male rats receiving o-nitrotoluene included hepatocyte vacuolization, oval cell hyperplasia, and increased serum bile acids, sorbitol dehydrogenase, and alanine aminotransferase. Although there was no histopathologic evidence of hepatic toxicity in male or female rats given the m- or p-isomers or in female rats given the o-isomer, treatment-related hepatic effects were detected in these groups, as measured by an increase in the relative liver weights and by elevations in serumbile acids and liver-specific enzymes. The spleens of treated male and female rats had a mild increase in hematopoiesis, hemosiderin deposition, and/or congestion. These splenic changes were slightly more prominent in rats administered the o- and p- isomers. Administration of o-, m-, or p-nitrotoluene impaired testicular function in the rat, as shown by testicular degeneration and reduction in the density, motility, and number of sperm cells. Administration of each isomer to rats caused increases in the length of the estrus cycle. The only histopathologic evidence for treatment-related toxicity in mice in the 13-week studies occurred in animals receiving the o-nitrotoluene isomer where the chemical caused degeneration and metaplasia of the olfactory epithelium. These comparative toxicity studies of o-, m-, or p-nitrotoluene showed that all three chemicals caused toxicity in the kidney, spleen, liver, and/or reproductive system in rats. In general, toxicity was most severe with the ortho-isomer. In mice, olfactory epithelium degeneration was the only treatment-related lesion induced by o-nitrotoluene. Elevations in liver weights were observed at the higher dose levels in rats and mice treated with any of the three isomers. o-Nitrotoluene was car cinogenic in male rats, as indicated by the occurrence of mesotheliomas at 5000 ppm and mesothelial cell hyperplasia at 10,000 ppm.

Toxicity of monochloroacetic acid administered by gavage to F344 rats and B6C3F1 mice for up to 13 weeks

Groups of 20 rats and 20 mice of each sex were administered monochloroacetic acid (MCAA) once daily, 5 days per week, in water by gavage for up to 13 weeks. Doses used were 0, 30, 60, 90, 120, or 150 mg/kg for rats and 0, 25, 50, 100, 150, or 200 mg/kg for mice. Compound-related deaths occured at the four highest dose levels in rats and at the highest dose level in mice. Mean body weights of treated groups of rats and mice surviving until the end of the study were similar to those of the controls. A dose-related increase in blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, as well as a dose-related increase in the relative liver and kidney weights was observed in rats but not in mice. A dose-related increase in the incidence and severity of cardiomyopathy occured in rats. This lesion may be related to the inhibition of heart mitochondrial aconitase activity. No compound-related lesions were observed in mice. The results of this study indicate that F344 rats are more sensitive than B6C3F1 mice; sexes within the species were equally sensitive. The no-observable-effect level was estimated as 30 mg MCAA/kg body weight for rats and 100 mg MCAA/kg body weight for mice.

Salivary excretion of 5-fluorouracil (5-FU). IV. Dependency of saliva/plasma concentration ratio and salivary clearance on plasma concentration of 5-FU during constant-rate intravenous infusion in rats.

Salivary excretion profiles of 5-fluorouracil (5-FU) were investigated following simultaneous bolus intravenous injection of a loading dose and constant-rate intravenous infusion of a maintenance dose of at one of three dose levels in rats. By stimulating salivation with pilocarpine infused intravenously, mandibular (M) and parotid (Pr) saliva samples were periodically collected separately via cannulas inserted into the ducts. Simultaneously, salivary pH and salivary flow rate were determined. (1) There was a good correlation between plasma concentration and each of the saliva concentrations of 5-FU with regard to the pooled data of the three doses (p less than 0.01). (2) A gland type difference between M and Pr in the saliva/plasma concentration ratio (S/P ratio) of 5-FU was observed. This difference seemed to result from that in salivary pH. These findings were similar to the results following bolus intravenous administration of 5-FU in rats. (3) The fluctuations of the S/P ratio and salivary clearance of 5-FU were smaller than those following the bolus intravenous administration. (4) The S/P ratio and salivary clearance were larger at higher dose and higher plasma concentration of 5-FU. It was confirmed that non-linear kinetics might be involved in the salivary excretion of 5-FU in rats, and it was speculated that 5-FU excreted into primary saliva might be reabsorbed partly through some saturable process.

Studies on the short-term toxicity of theophylline in rats and mice

The purpose of these studies was to evaluate the short-term toxicity of theophylline, a compound present in tea and used in a variety of clinical applications. Fourteen-day repeated-dose toxicity studies were conducted in B6C3F1 mice and F344 rats of both sexes. Theophylline was administered in feed (0, 500, 1000, 2000, 4000, and 8000 ppm) or by gavage in corn oil (12.5-twice daily, 25, 50, 50-twice daily, 100, 200, 200-twice daily, and 400 mg/kg). Dosed-feed exposure to theophylline at concentrations up to 8000 ppm induced no significant toxicity except for dose-related uterine hypoplasia in rats. Palatability problems at that level precluded administration of higher concentrations. In the gavage study, 400 mg/kg was acutely toxic for both species, but mice and rats differed in that this same daily dose administered as two separate doses of 200 mg/kg was acutely toxic in rats but not in mice. No doserelated weight gain depression was evident in mice; weight gain was depressed in the majority of dose levels in rats and was pronounced at the higher levels. Clinical signs in mice were squinting and distended testes in males, and in rats, rapid respiration (all doses), squinting, and hunching. Gross necropsies, organ weights, clinical pathology, and pathology identified no target organs in mice, while histopathologic observations in rats suggested heart and stomach as possible target organs. Histopathologic effects in a number of other tissues, including lung, thymus, bone marrow, spleen, and uterus, were considered to reflect agonal changes in treated rats, possibly related to inanition. The results suggest that both species and sex differences exist with respect to sensitivity to theophylline toxicity, with F344 rats being more sensitive than B6C3F1 mice and male rats being more sensitive than female rats.

Effects of polychlorinated biphenyls at low dose levels in rats.

Clophen® A-50, a commercial polychlorinated biphenyl (PCB) mixture, was administered orally to rats for six weeks at the dose levels of 2, 10, 50, 150, and 250 mg/kg. An accumulation of PCBs was found in the liver, the kidney, and in the adipose tissue of all dosed animals. The highest levels were observed in the fatty tissue, which were 10 and 40 times higher than those found in the liver and kidney, respectively. After six weeks treatment with 2 mg/kg, histopathological alterations were evident in the liver, manifest as centrolobular necroses. At the dose level of 10 mg/kg, increases were found in the liver weight and in serum cholinesterase activity. The serum bilirubin concentration and serum protein content were elevated at 50 mg/kg. The activities of serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) however, were only increased at doses higher than 50 mg/kg. The levels of the serum lipids cholesterol and triglycerides were elevated at the doses of 2 mg and 50 mg/kg respectively. The urinary excretion of δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) was enhanced at the dose levels between 50 and 250 mg/kg, whereas the urinary porphyrin levels remained unchanged. The no-effect level of repeated oral PCB administration in rats was less than 2 mg/kg.