Target Organs Of Rats Research Articles

Evaluation of 28-day repeated oral dose toxicity of SUNACTIVE Zn–P240 in rats

This study was conducted to investigate the potential toxicity of repeated oral dose of SUNACTIVE Zn–P240, a new type of zinc supplement, in Sprague-Dawley rats. SUNACTIVE Zn–P240 was administered once daily by gavage at doses of 0, 500, 1000, and 2000 mg/kg/day for each group over a 28-day period. At 2000 mg/kg/day, there were increases in serum alkaline phosphatase (ALP) and alanine aminotransferase, liver weight, histopathological changes in stomach, liver, and pancreas and decreases in body weight, food consumption, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein (TP), and albumin. At 1000 mg/kg/day, there was an increase in the serum ALP level and there were decreases in the MCV, MCH, and TP. There were no treatment-related adverse effects in the 500 mg/kg/day group. Under the present experimental conditions, the target organs in rats were determined to be the stomach, pancreas, liver, and erythrocyte and the no-observed-adverse-effect level (NOAEL) in rats was considered to be 500 mg/kg/day.

Inhibitory Effect of Filipendula ulmaria on Mammary Carcinogenesis Induced by Local Administration of Methylnitrosourea to Target Organ in Rats.

The meadowsweet (Filipendula ulmaria (L.) Maxim.) may have a cancer prophylactic activity, since its extracts exhibit antioxidant, anti-inflammatory and other effects. We investigated the ability of a meadowsweet decoction to inhibit mammary carcinogenesis induced by intramammary injections of Methylnitrosourea (MNU) to the target organ in rats. The chemical composition of meadowsweet extracts was studied by traditional methods. In animal experiments, adult outbred female rats received single injections of MNU at a dose 1mg directly into the tissue of each mammary gland. After carcinogenic exposure one group (MNU) of rats continued to receive standard feed and tap water throughout life. In another group (MNU+meadowsweet), rats were given daily a decoction of the meadowsweet instead of drinking water and standard feed. Meadowsweet extracts showed a sufficiently high content of flavonoids and tannins and also some individual phenolic compounds. In rats after injections of MNU the overall incidence of tumors was 90% with tumor multiplicity of 3.1. The majority of rats (86%) developed multiple malignant tumors of the mammary gland (most often adenocarcinomas). In rats from the group MNU+meadowsweet, there was a statistically significant decrease of the overall tumor multiplicity-by 1.5 times, and the incidence and multiplicity of breast tumors-by 1.6 and 2.2 times, respectively. Meadowsweet extract can be considered an effective inhibitor of breast carcinogenesis.

Analysis of toxicity biomarkers of fullerene C₆₀ nanoparticles by confocal fluorescent microscopy.

The methods of laser confocal microscopy were employed to study the changes in rat target organs (iliac mucosa and liver) provoked by peroral administration of dispersion of nanosized (31 nm) multimolecular fullerene C60 particles in doses of 0.1, 1.0, and 10 mg/kg body weight over 92 days. The micropreparations were selectively stained with fluorescent dyes to mark the cell nuclei (DAPI), actin microfilaments (fluorescently labeled phalloidin), and the membrane proteins CD106, CD31, and claudins in tight junctions (fluorescently labeled monoclonal antibodies). In rats treated with fullerene in the examined doses, the iliac mucosa demonstrated normal morphology of the villi. There were no signs of inflammation and no alterations in the actin fi laments of cytoskeleton and in enterocytic tight junctions. The count of CD106(+) and CD31(+) cells did not change. The highest examined doses of fullerene (1 and 10 mg/kg body weight) increased population and modified distribution of hepatic CD106(+) cells. They also resulted in accumulation of cytoplasmic granules presumably identified as Kupffer macrophages without any signs of visible inflammation or necrotic areas. This phenomenon can reflect the early stages of toxic reaction being a sensitive bioindicator of the damage produced by administered fullerene C60 in the hepatic tissue.

Evaluation of toxicity to triclosan in rats following 28 days of exposure to aerosol inhalation

The present study was conducted to investigate the potential subchronic toxicity of triclosan (TCS) in rats following 28days of exposure by repeated inhalation. Four groups of six rats of each sex were exposed to TCS-containing aerosols by nose-only inhalation of 0, 0.04, 0.13, or 0.40mg/L for 6h/day, 5days/week over a 28-day period. During the study period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. At 0.40mg/L, rats of both sexes exhibited an increase in the incidence of postdosing salivation and a decrease in body weight. Histopathological alterations were found in the nasal septum and larynx. There were no treatment-related effects in rats of either sex at ⩽0.13mg/L. Under the present experimental conditions, the target organs in rats were determined to be the nasal cavity and larynx. The no-observed-adverse-effect concentration in rats was determined to be 0.13mg/L.

Expression profiles of DNA repair-related genes in rat target organs under subchronic cadmium exposure.

We aimed to evaluate the toxicity of long-term exposure to different cadmium (Cd) doses in rats and expression profiles of DNA repair-related genes. The model rats were exposed to different concentrations of CdCl2 for 3 months, and 5 DNA repair-related genes - hMSH2, MLH1, XRCC1, hOGG1, ERCC1 - were cloned in different tissues, including the liver, kidney, heart, and lung. Accumulated amounts of Cd were detected in the tissues. Gene and protein detections were conducted via fluorescence quantitative real-time polymerase chain reaction and Western blotting, respectively. Methylated sequences of the 5 DNA repair-related gene promoters were used to investigate whether the low expression levels of the genes were related to methylation of the promoter. In the Cd-exposed group, 3 DNA repair genes (i.e., XRCC1, hOGG1, and ERCC1) significantly decreased in the rat liver, kidney, heart, and lung according to the β-actin internal standard (P < 0.01). Western blotting indicated the same trend for the different tissues. Each of the DNA repair genes had special characteristics; for example, hOGG1 gene expression decreased by 75% in the kidney, and XRCC1 gene expression decreased by 5% in the liver and heart when compared to the control group (P < 0.01). A negative correlation between the DNA repair gene expression levels and the cumulative levels of Cd was also suggested by malignancy pathology. The expression levels of 3 DNA repair genes (i.e., ERCC1, XRCC1, and hOGG1) played an important role in the rat response to Cd exposure but not DNA methylated protection.

Time‐dependent biodistribution and excretion of silver nanoparticles in male Wistar rats

Silver nanoparticles (AgNPs) are the most commonly used nanoparticles owing to their antimicrobial properties. The motivation of the present study was (1) to analyze the effect of silver particle size on rat tissue distribution at different time points, (2) to determine the accumulation of AgNPs in potential rat target organs, (3) to analyze the intracellular distribution of AgNPs and (4) to examine the excretion of AgNPs by urine and feces. AgNPs were characterized by dynamic light scattering (DLS), zeta potential measurements, BET surface area measurements, transmission and scanning electron microscopy. AgNPs (20 and 200 nm) were administered intravenously (i.v.) to male Wistar rats at a dose of 5 mg kg(-1) of body weight. Biological material was sampled 24 h, 7 and 28 days after injection. Using inductively coupled plasma-mass spectrometry (ICP-MS) and transmission electron microscopy (TEM) it was observed that AgNPs translocated from the blood to the main organs and the concentration of silver in tissues was significantly higher in rats treated with 20 nm AgNPs as compared with 200 nm AgNPs. The highest concentration of silver was found in the liver after 24 h. After 7 days, a high level of silver was observed in the lungs and spleen. The silver concentration in the kidneys and brain increased during the experiment and reached the highest concentration after 28 days. Moreover, the highest concentration of AgNPs was observed in the urine 1 day after the injection, maintained high for 14 days and then decreased. The fecal level of silver in rats was the highest within 2 days after AgNPs administration and then decreased.

한약제제 KOB03의 랫드에서의 4주 반복 경구투여에 의한 독성 연구

Objectives : To evaluate the toxicity of KOB03, polyherbal medicine for the treatment of allergic rhinitis, we performed the dose-range finding test of KOB03 by oral supplementation for 4 weeks in Sprague-Dawley rats. Methods : The water extract of KOB03 consisting of five different herbs was supplied from GLP company. KOB03 was supplemented by gavage at 0, 500, 2,500 and 5,000 mg/kg/day for 4-week consecutive days. We recorded the clinical signs of toxicity, body weight, organ weights, hematology, gross and histological changes in target organs of rats, and clinical chemistry analysis. Results : KOB03 at all doses was shown no mortality or abnormal clinical signs in rats during at the observation period. Furthermore, there was no difference in body weight and food-take consumption, organ weight, gross pathological findings, and urine analysis among the groups of rats treated with different doses of KOB03. The hematological analysis and clinical blood chemistry data were revealed no toxic effects from KOB03-supplemented rats. Conclusions : The results suggest that KOB03 is a wide margin of safety on dose-range toxicity in rats. The no observable adverse effect level (NOAEL) of the test, KOB03 in rats is no less than 5,000 mg/kg/day.

Analysis of the Impacts of Environmental Pollution of Pesticides on Oxidative Stress Profile in Liver and Kidney: A Case of Raid® in Wistar Rat

The widespread use of pesticides has numerous pathological consequences including agents which generate oxidative stress. Analysis of impacts of pesticides and oxidative stress provide available evidence that suggests changes that play a key role in various conditions which limit the human life span. Ingestion of insecticide Raid® was administered to wistar rats for 30 and 60 days and various target organs of rats were examined for oxidative stress profile. Results showed that all the parameters either in erythrocyte or the organs compared negatively with the control groups (P<.05). The results indicated that catalase, superoxidedimutase (SOD), glutatathione reductase (Gr), and glutathione (GSH) levels significantly decreased in rats treated with insecticide Raid® alone compared with the liver and kidney. Besides, raid-induced oxidative damage caused a significant increase in malondialdehyde (MDA) levels of the liver and kidney tissues. Even more disturbing is the fact that pesticide is typically associated with cellular dysfunction as discussed.

Metabonomic study of plasma after intratracheally instilling titanium dioxide nanoparticles in rats

1H magnetic resonance (1H MR) spectroscopic technique in combination with pattern recognition technique were applied to analyze toxic effects of rats which were intratracheally instilled with titanium dioxide nanoparticles (nano-TiO2) as well as to detect the target organs and biomarkers associated with the toxic effects. Twenty-four SD male rats were divided into 4 groups randomly which were high dose group (40 mg/kg nano-TiO2), moderate dose group (4 mg/kg nano-TiO2), low dose group (0.4 mg/kg nano-TiO2) and control group (0.9% NaCl solution) respectively, there were six rats per group. All rats were exposed to the object by single intratracheally instilling at a volume of 0.1 ml/100 g. After one week observation, 1H MR spectra of plasma were measured and analyzed by principal component analysis. Histopathologic examination for tissues such as heart, lung, liver, and kidney were performed simultaneously. The relative content of lactate [(37.86+/-2.58)x10(-3)], citrate [(2.21+/-0.45)x10(-3)], choline [(7.74+/-0.76)x10(-3)] and creatine [(4.17+/-1.15)x10(-3)] in high dose group were significantly decreased as compared with those [(52.07+/-5.12)x10(-3), (3.01+/-0.21)x10(-3), (9.28+/-0.78)x10(-3), (8.59+/-2.64)x10(-3)] in control group (t values were -6.024, -3.177, -3.374, -4.215 respectively, P<0.05), however the relative content of glucose [(19.41+/-1.72)x10(-3)] was significantly increased compared with that [(14.45+/-2.45)x10(-3)] in control group (t value was 2.802, P<0.05). The relative content of lactate [(44.39+/-5.09)x10(-3)] and creatine [(3.67+/-0.76)x10(-3)] in moderate group was significantly decreased compared with those [(52.07+/-5.12)x10(-3), (8.59+/-2.64)x10(-3)] in control group (t values were -3.254, -4.694 respectively, P<0.05). The relative content of pyruvate [(3.84+/-0.70)x10(-3)] was significantly increased in low dose group as compared with that [(3.13+/-0.46)x10(-3)] in control group (t value was 2.787, P<0.05), however the relative content of creatine [(8.10+/-0.72)x10(-3)] was significantly decreased compared with that [(9.28+/-0.78)x10(-3)] in control group (t value was -2.602, P<0.05). No significant difference was found between other experimental groups and control group. No visible damage was found in histopathologic examination. Lung, liver, kidney and heart were the target organs of rats which were intratracheally instilling titanium dioxide nanoparticles. Lactate, pyruvate, glucose, citrate, choline and creatine can be presumed as the biomarkers when searching the target organs of the toxic effects.

Characterization of liver toxicity in F344/N rats and B6C3F1 mice after exposure to a flame retardant containing lower molecular weight polybrominated diphenyl ethers

Lower molecular weight polybrominated diphenyl ethers (PBDEs), components of flame retardants, are found in the environment and in human and animal tissues. Toxicity studies were conducted in F344/N rats and B6C3F1 mice by administering a flame retardant containing these lower molecular weight PBDEs (BDE-47, BDE-99, BDE-100, and BDE153) by oral gavage 5 days/week for 13 weeks at doses of 0.01, 5, 50, 100 or 500 mg/kg/day. Liver was the primary target organ in rats and mice. Treatment-related increases in liver weights, liver cytochrome P450 (1A1, 1A2, 2B) and UDPGT (rats only) levels, and liver lesions were seen in both rats and mice. Hepatocyte hypertrophy and vacuolization increased in incidence and severity with treatment, and occurred at levels of 50 mg/kg and above in rats, and at 100 mg/kg and above in mice. Liver Cyp 1A1, 1A2, and 2B levels were increased at exposure levels of 50 mg/kg and above in rats and mice. In addition, treatment-related thyroid lesions occurred particularly in rats. The most sensitive parameter for PBDE toxicity was the increase in liver weights which occurred at 5 mg/kg above in rats and 50 mg/kg and above in mice. These results suggest that liver may be a target organ for carcinogenesis processes after long-term administration of PBDEs. A chronic PBDE study is currently being conducted by the National Toxicology Program.

Development of miltefosine as an oral treatment for leishmaniasis

Miltefosine was originally formulated and registered as a topical treatment for cutaneous cancers. For this indication and in subsequent development for leishmaniasis, a large body of non-clinical data has been generated. The gastrointestinal organ is the main site of toxicity, in both animal and in human studies. The testis and retina were identified as target organs in rats, although corresponding changes were not observed in clinical studies in humans. In terms of pharmacokinetics, the terminal elimination half-life is long (84h and 159h in rats and dogs respectively). Miltefosine is widely distributed in body organs and not metabolized by cytochrome P450 enzymes in vitro. The drug is embryotoxic and fetotoxic in rats and rabbits, and teratogenic in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, and contraception is required beyond the end of treatment in women of child-bearing age.

Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys.

A compendium of carcinogenesis bioassay results organized by target organ is presented for 738 chemicals that are carcinogenic in chronic-exposure, long-term bioassays in at least 1 species. This compendium is based primarily on experiments in rats or mice; results in hamsters, monkeys, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites and to determine whether target sites are the same for chemicals positive in more than 1 species. The source of information is the Carcinogenic Potency Database (CPDB). which includes results of 6073 experiments on 1458 chemicals (positive or negative for carcinogenicity) that have been reported in Technical Reports of the National Cancer Institute/National Toxicology Program or in papers in the general published literature. The published CPDB includes detailed analyses of each test and citations. The CPDB is publicly available in several formats (http://potency.berkeley.edu). Chemical carcinogens are reported for 35 different target organs in rats or mice. Target organs in humans are also summarized for 82 agents that have been evaluated as human carcinogens at a particular target site by the International Agency for Research on Cancer (IARC). Comparisons are provided of target organs for mutagens versus nonmutagens and rats versus mice.

Comparison of early onco/suppressor gene expressions in peripheral leukocytes and potential target organs of rats exposed to the carcinogen 1-nitropyrene.

An in-vivo model has been developed to study early expressions of c-myc, Ha-ras oncogenes and p53 suppressor gene as biomarkers of carcinogenic exposure and/or tumorigenesis. In order to validate the in-vivo expression changes as biomarkers, rats were treated with the outdoor air pollutant carcinogen 1-nitropyrene. The gene expression levels were measured after 24 and 48 h in potential target tissues (lung, liver, lymph nodes, kidneys, spleen) and in peripheral blood leukocytes. Another main objective was to prove the applicability of leukocytes as a surrogate tissue, having a similar expression pattern of the selected genes upon carcinogenic exposure. The c-myc oncogene was not suitable as an early biomarker because of the lack or low level of its expression. However, in the case of the other oncogene Ha-ras and the suppressor gene p53, remarkable and early changes were detected in the expression signals. Similar expression patterns could only be detected in leukocytes and the spleen; therefore we continue this validation study by using other types and routes of exposure.

Dose- and sex-related carcinogenesis by N-bis(2-hydroxypropyl)nitrosamine in Wistar rats.

An initiation‐promotion medium‐term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N‐bis(2‐hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control—untreated group; Multi‐organ initiated group (also referred to as DMBDD, based on the initials of the five initiators)—treated sequentially with N‐diethylnitrosamine (DEN, i.p.), N‐methyl‐N‐nitrosourea (MNU, i.p.), N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN, drinking water), N, ďN′‐dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0.2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S‐transferase‐positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN‐exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex‐related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.

Bosentan reduces blood pressure and the target-organ damage induced by a high-fructose diet in rats.

Rats fed a high-fructose diet develop hyperinsulinaemia, hypertriglyceridaemia, hypertension, renal changes similar to those in diabetic rats and left ventricular hypertrophy with deposition of collagen. Bosentan is an antagonist of endothelin receptors. Other authors have demonstrated that bosentan is effective in preventing the increase in blood pressure induced by a high-fructose diet but, until now, the effect of the drug on the target organs has not been investigated. To evaluate whether bosentan is effective, not only in reducing blood pressure, but also in limiting the renal and cardiac changes induced by a high-fructose diet Forty Wistar-Kyoto (WKY) male rats were divided into four groups: groups 1 and 2 received a high-fructose diet, groups 3 and 4 received a standard diet for 1 month. Thereafter, the following treatments were administered: group 1, high-fructose diet plus bosentan 100 mg/kg per day; group 2, high-fructose diet plus placebo; group 3, standard diet plus bosentan 100 mg/kg per day; group 4, standard diet plus placebo. After a further 1 month, all animals were killed. A morphometric analysis was performed by examining 100 glomeruli for each animal. Renal deposits of collagen and fibronectin and cardiac deposits of collagen III were measured by means of immunochemistry. By the end of the study, bosentan had completely reversed the increase in blood pressure induced by a high-fructose diet, without modifying the blood pressure in normotensive rats. Moreover, bosentan reduced glomerular hypertrophy and deposits of collagen and fibronectin in the kidney and cardiac deposits of collagen III. The results of this study demonstrate that bosentan not only normalizes blood pressure, but also protects target organs in rats receiving a high-fructose diet.

Chlorophylls as anticarcinogens (review)

Chlorophylls, chlorins, and other porphyrins have been used clinically for many years, including photodynamic therapy of tumors. More recently, the cancer chemopreventive properties of chlorophylls have come to be recognized. Chlorophylls exhibit anti-mutagenic activity in short-term genotoxicity assays, and protect against various intermediate biomarkers of cancer in vivo. The anticarcinogenic activity of sodium-copper chlorophyllin (CHL), a clinically-used water soluble salt of chlorophyll, has been studied in several species. Collectively, the results from these studies support a chemopreventive role for CHL against aromatic carcinogens (aflatoxins, polycyclic aromatic hydrocarbons, heterocyclic amines) in various target organs of rats, mice, and rainbow trout. In vivo mechanism studies indicate that inhibition is most effective when CHL is administered simultaneously with the carcinogen, thereby allowing direct interaction (molecular complex formation) between CHL and the carcinogen. Studies of post-initiation treatment with CHL have provided conflicting results, with evidence for inhibition or promotion of carcinogenesis. These findings are discussed in terms of the inhibitory and promotional mechanisms of CHL, the relevance of such mechanisms to natural chlorophylls present in the diet, and the current use of CHL as a health supplement.

In vitro and in vivo induction of heat shock (stress) protein (Hsp) gene expression by selected pesticides

The chloroacetamide insecticide alachlor, polyhalogenated cyclic hydrocarbons endrin and chlordane and the organophosphate pesticides chlorpyrifos and fenthion induce oxidative tissue damaging effects including lipid peroxidation and nuclear DNA-single strand breaks. The mechanism involved in the induction of oxidative stress by these xenobiotics is unknown. No information is available regarding whether these pesticides can induce the expression of heat shock (stress) protein (Hsp) genes as a common protective mechanism against tissue damage. The pesticides were administered p.o. individually to female Sprague-Dawley rats in two 0.25 LD 50 doses at 0 h and 21 h. The animals were killed at 24 h, and liver, brain, heart and lung tissues were removed to examine the induction of Hsps by Western and Northern blot analysis. In a separate series of experiments, cultured neuroactive PC-12 cells were treated 24 h with 50, 100 or 200 nM concentrations of these pesticides. Alachlor, endrin, chlorpyrifos and fenthion induced Hsp89α and Hsp89β in hepatic and brain tissues, as well as in cultured PC-12 cells. Chlordane induced some expression of Hsp89α but not Hsp89β in the hepatic and brain tissues of treated rats. Some expression of Hsp89β was observed in lung tissues of endrin and alachlor treated animals. These findings were substantiated by Western blot analysis using Hsp90 antibody. Except chlordane all these pesticides induced enhanced synthesis of Hsp90 in cultured PC-12 cells. The results indicate striking tissue differences in the patterns of the Hsps induced by the pesticides which were used, and demonstrate that these pesticides can induce the expression of Hsp89α and Hsp89β genes in various target organs of rats. The results support the hypothesis that these genes may be mechanistically involved in protecting tissues against oxidative stress induced by structurally diverse pesticides.

Subchronic toxic effects of fusarium moniliforme and fumonisin B1 in rats and mice

Fumonisins are mycotoxins produced by the fungi Fusarium moniliforme, F. proliferatum, and other Fusarium species. Fumonisin B1, the most commonly found fumonisin, causes the fatal diseases equine leukoencephalomalacia and porcine pulmonary edema. Fumonisins are suspected human carcinogens because of the extraordinarily high incidences of esophageal cancer coincidentally found in areas of southern Africa and China where F. moniliforme-contaminated corn is consumed as a dietary staple. The subchronic (up to 90 days) effects of F. moniliforme-contaminated corn, corn cultures of this fungus, and purified fumonisin B1 (FB1) in rats and mice were systematically studied to determine target organs, characterize organ-specified lesions, and obtain dose-response data. The liver is a target organ in both species. Serum chemical findings indicative of hepatocellular injury and morphological findings, including apoptosis, appeared qualitatively similar in both species. The kidney is also a target organ in rats, but not mice. Lesions which include apoptosis and cellular degeneration are predominately found in the outer medella. Results of several investigations showed that the kidney was consistently affected at lower doses than the liver. The "no-observed-effect" level for nephropathy in rats was also consistently lower in males than females, suggesting a sex-related difference in nephrotoxic response to fumonisins. Other findings suggest that toxigenesis may be mediated by disruption of de novo sphingolipid biosynthesis. Hepatic and renal sphingolipid profiles, specifically sphinganine concentration and sphinganine-to-sphingosine ratio, were altered in rats fed FB1 at levels that did not cause serum chemical, organ weight, or histopathological evidence of toxicity.

Chronic toxicity and carcinogenicity studies with the insecticide endosulfan in rats and mice

The insecticide endosulfan was evaluated for chronic toxicity and carcinogenicity in long-term feeding studies in both Sprague-Dawley rats and NMRI mice. Dietary concentrations of the test substance were administered to rats at 0, 3, 7.5, 15 and 75 ppm and to mice at 0, 2, 6 and 18 ppm for 24 months each. In the rat study, only the treatment with the highest dose caused a significant reduction of body weight gains of the males and females at 75 ppm. The increased incidence of enlarged kidneys seen at autopsy at 75 ppm in females, and the slightly increased incidence of progressive glomerulonephrosis and slightly increased incidence of renal aneurysms seen histopathologically in the 75 ppm males, make the kidney the target organ in rats. On the basis of these findings a dietary concentration of 15 ppm is considered to be the no-observed-effect level (NOEL) in rats, equivalent to a daily test substance intake of 0.6 mg/kg body weight in males and 0.7 mg/kg body weight in females. In the mouse study, the treatment with 18 ppm caused a significant increase of mortality in the females and a slight (in the first third of the study, significant) reduction of body weight gain in males. Since there were no other substance-related findings, the dietary concentration of 6 ppm is considered to be the NOEL in mice, equivalent to a daily test substance intake of 0.84 mg/kg body weight in males and 0.97 mg/kg body weight in females. An evaluation of all relevant tumour data gained in both studies revealed no differences between control and treated groups. It was concluded, therefore, that endosulfan has no carcinogenic potential.

Marketed Human Pharmaceuticals Reported to be Tumorigenic in Rodents

The 1994 U.S. Physicians' Desk Reference reports the results of rodent carcinogenicity tests on 241 pharmaceutical agents. Positive results were reported for 101 agents, with a class label implying a carcinogenic hazard also attached to 9 estrogenic, 4 androgenic, and 3 progestogenic agents. Of the positive agents tested in both rats and mice, 39 of 72 were positive in both species, 22 were positive in rats only, and 11 were positive in mice only. There were few (19) unequivocally genotoxic agents, and only one of these was not reported to be tumorigenic to rodents. The liver was a common target organ in rats and mice. In rats, the other most common target organs for tumors were (in decreasing order) the thyroid, testis, mammary, adrenal, and pituitary. In mice, the only other common target organ was the lung.