Obstructive nephropathy induced with DL-potassium hydrogen tartrate in F344 rats

We experienced obstructive nephropathy in F344 rats treated with DL-potassium hydrogen tartrate (PHT) in a 13-week oral repeated dose toxicity study. Six-week-old male and female F344/DuCrj rats were fed a diet containing up to 2.0% PHT for 13 weeks. Microscopical findings including irregular dilation of the distal tubule lumen, foreign body giant cells, inflammatory cell infiltration, and regeneration of renal tubules were observed focally or multifocally in the renal cortex and/or medulla in the 0.5% and higher dosage groups of both sexes. The severity of these lesions increased in a dose-dependent manner. In the urinalysis, an increase in protein and white blood cells or the concentration of tartaric acid was detected in the 0.5% PHT and higher dosage groups of both sexes or males, respectively, though conventional blood biochemical analysis did not indicate failure of renal function. These results indicate that the PHT induces obstructive nephropathy in rats. There were no other treatment-related changes in other organs.     

Evaluation of the Subchronic Toxicity of Dietary Administered Equisetum arvense in F344 Rats

Equisetum arvense, commonly known as the field horsetail, has potential as a new functional food ingredient. However, little information is available on its side effects, and the general toxicity of Equisetum arvense has yet to be examined in detail. In the present study, we evaluated the influence of administration in diet at doses of 0, 0.3, 1 and 3% for 13 weeks in male and female F344 rats. No toxicity was detected with reference to clinical signs, body weight, urinalysis, hematology and serum biochemistry data and organ weights. Microscopic examination revealed no histopathological lesions associated with treatment. In conclusion, the no-observed-adverse-effect level (NOAEL) for Equisetum arvense was determined to be greater than 3% in both sexes of F344 rat (males and females: >1.79 g/kg BW/day and >1.85 g/kg BW/day, respectively) under the conditions of the present study.     

Unilateral degeneration of retina and optic nerve in Fischer-344 rats

Unilateral degeneration of the retina and optic nerve was observed among Fischer-344 (F-344) rats fed a semi-purified synthetic feed. Further studies were conducted using standard cereal-based and synthetic diets. Beginning at 4 weeks of age, all experimental rats (169 F-344 rats) were fed various diets and were examined for morphologic and functional changes in the retina and optic nerve. No ocular lesions were observed in any F-344 rats prior to 21 weeks of age, whether fed a synthetic diet or a standard diet; however, approximately 16% (13/86) of the F-344 rats examined between 57 and 64 weeks of age developed unilateral degeneration of the retina and optic nerve. On the other hand, the F-344 rats fed the synthetic diet developed the degenerative lesions by 30 weeks of age, while the F-344 rats fed the standard diet did not develop lesions over this shorter time period. Degenerative changes of the affected retinas and optic nerves were closely related with functional abnormalities evaluated by electroretinogram and visual evoked potentials. In contrast with the F-344 rats, Long-Evans rats that were fed either the synthetic or standard diet up to the age of 68 weeks (77 rats) did not develop the ocular lesions. There was no apparent relationship of the development of the lesions with dietary modification, toxicity or trauma; thus, these observations appear to indicate that spontaneous unilateral degeneration of the retina and optic nerve occurs in F-344 rats and that these ocular lesions may be accelerated by the feeding of certain semi-purified synthetic diets.     

Occurrence of Spontaneous Tumors in the Central Nervous System (CNS) of F344 and SD Rats

In order to accurately assess the carcinogenicity of chemicals with regard to rare tumors such as rat CNS tumors, sufficient information about spontaneous tumors are very important. This paper presents the data on the type, incidence and detected age of CNS tumors in F344/DuCrlCrlj (a total of 1363 males and 1363 females) and Crl:CD(SD) rats (a total of 1650 males and 1705 females) collected from in-house background data-collection studies and control groups of carcinogenicity studies at our laboratory, together with those previously reported in F344 and SD rats. The present data on F344/DuCrlCrlj rats (F344 rats) and Crl:CD(SD) rats (SD rats) clarified the following. (1) The incidences of all CNS tumors observed in F344 rats were less than 1%. (2) The incidences of malignant astrocytoma and granular cell tumor were higher in male SD rats than in female SD rats. (3) The incidences of astrocytoma and granular cell tumor were higher in SD rats than in F344 rats. (4) Among astrocytoma, oligodendroglioma and granular cell tumor, oligodendroglioma was detected at the youngest age, followed by astrocytoma, and ultimately, granular cell tumor developed in both strains. The incidences observed in our study were almost consistent with those previously reported in F344 and SD rats.     

Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats

Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe₃O₄ nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233–239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes     

Background data of 2-year-old male and female F344 gpt delta rats

Although gpt delta rats, as reporter gene-transgenic rats, were originally developed for in vivo mutation assays, they have also been used to evaluate chemical carcinogenesis and comprehensive toxicity. Therefore, it is necessary to accumulate background data on carcinogenicity and general toxicity in gpt delta rats. Here, we investigated the background data of 110-week-old male and female F344 gpt delta rats and wild-type rats. There was no effect of reporter gene transfection on animal survival rates and body weights during the experiment. The relative weight of male gpt delta rat adrenals was significantly higher than that of wild-type rats, possibly due to the higher incidence of pheochromocytoma. There were no intergenotype differences in the incidence of nonneoplastic lesions in both sexes, including chronic progressive nephropathy and focus of cellular alteration in the liver, which had a higher incidence in both genotypes. Additionally, the significantly higher incidence of adrenal pheochromocytoma in male gpt delta rats than that in wild-type rats was likely incidental because of the lack of differences in the incidences of preneoplastic (male and female) and neoplastic (female) adrenal lesions in both genotypes. Other neoplastic lesions in both sexes showed no intergenotype differences in incidence rates, although large granular lymphocytic leukemia in the spleen and Leydig cell tumors in the testes of males showed higher incidence rates. Overall, there were no effects of reporter gene transfection on the spectrum of spontaneous lesions in F344 gpt delta rats, thus supporting their applicability in evaluating chemical toxicity and carcinogenicity.     

Time-course comparison of pulmonary inflammation induced by intratracheal instillation of four different nickel oxide nanoparticles in male Fischer rats

Occupational exposure to nickel oxide (NiO) is an important cause of respiratory tract cancer. Toxicity is known to be associated with the dissociated component, i.e. nickel (II) ions. To address the relationship between physicochemical properties, including solubility in artificial lysosomal fluid, of NiO and time-course changes in the pulmonary response, we conducted an intratracheal instillation study in male Fischer rats using four different well-characterized NiO products, US3352 (NiO A), NovaWireNi01 (NiO B), I small particle (NiO C), and 637130 (NiO D). The NiOs were suspended in purified water and instilled once intratracheally into male F344 rats (12 weeks old) at 0 (vehicle control), 0.67, 2, and 6 mg/kg body weight. The animals were euthanized on days 3, 28, or 91 after instillation, and blood analysis, bronchoalveolar lavage fluid (BALF) testing, and histopathological examination were performed. The most soluble product, NiO B, caused the most severe systemic toxicity, leading to a high mortality rate, but the response was transient and surviving animals recovered. The second-most-soluble material, NiO D, and the third, NiO A, caused evident pulmonary inflammation, and the responses persisted for at least 91 days with collagen proliferation. In contrast, NiO C induced barely detectable inflammation in the BALF examination, and no marked changes were noted on histopathology. These results indicate that the early phase toxic potential of NiO products, but not the persistence of pulmonary inflammation, is associated with their solubility.     

Carcinogenicity and chronic toxicity in mice and rats exposed by inhalation to para-dichlorobenzene for two years

Carcinogenicity and chronic toxicity of para-dichlorobenzene (p-DCB) were examined by exposing 50 BDF1 mice and 50 F344 rats of both sexes by inhalation to p-DCB vapor at a target concentration of 0 (control), 20, 75 or 300 ppm for 6 hr/day, 5 days/week and 2 years. Incidences of hepatocellular carcinomas, hepatoblastomas and hepatic histiocytic sarcomas in the 300 ppm-exposed male mice, and hepatocellular adenomas and carcinomas and hepatoblastomas in the 300 ppm-exposed female mice were increased. An increase in the incidences of most of those liver tumors was dose-related. No increase in tumor incidence was found in any p-DCB-exposed rat of either sex. Centrilobular hypertrophy of hepatocytes and papillary mineralization and pelvic urothelial hyperplasia of the kidney were noted in the 300 ppm-exposed male rats. Treatment- and age-related increases in incidences of the eosinophilic globules of the respiratory and olfactory epithelia in female rats and incidences of the respiratory metaplasia of the nasal gland epithelium in mice and rats and the olfactory epithelium in mice were noted. The nasal lesion was the most sensitive endpoint of chronic inhalation toxicity. Induction of the mouse hepatocarcinogenicity and lack of the rat nephrocarcinogenicity found in the present study were compared with the mouse liver tumors and the rat renal tumors reported by the NTP gavage study, and discussed in light of the estimated p-DCB uptake into the body through the inhalation and the oral administration.     

锌中毒对雏鸡外周血T-淋巴细胞的影响

200只1日龄艾维菌肉鸡随机分为4组，即对照组（每千克日粮含锌100mg）、锌中毒Ⅰ组（每千克日粮含锌1500mg）、锌中毒Ⅱ组（每千克日粮含锌2000mg）、锌中毒Ⅲ组（每千克日粮含锌2500mg），每组均饲喂日粮7周。以流式细胞术和酸性α-醋酸萘酯醇（ANAE）染色法观测外周血T-淋巴细胞的动态变化。结果，3个锌中毒组7周龄时，外周血T-淋巴细胞ANAE阳性率显著低于对照组（P〈0．05或P〈0．01），同时3个锌中毒组间比较也呈显著差异（P〈0．05或P〈0．01）。与对照组比较，锌中毒Ⅲ组2至7周龄和锌中毒Ⅱ组6、7周龄CD4^＋T淋巴细胞数量减少，锌中毒Ⅱ组、Ⅲ组2至4周龄和锌中毒Ⅰ组、Ⅲ组7周龄CD8^＋T淋巴细胞数量降低，CD4^＋／CD8^＋比值3个锌中毒组2、4周龄升高，6、7周龄降低。由此表明，锌中毒可抑制T-淋巴细胞的生成，降低其在外周血中的数量。     

Ethanol Does Not Promote MeIQx-initiated Rat Colon Carcinogenesis Based on Evidence from Analysis of a Colon Cancer Surrogate Marker

Epidemiological studies suggest that alcohol consumption increases the risk of developing colorectal cancer. However, the data are confounded by numerous cosegregating variables. To cast further light on the relationships between alcohol intake and colon cancer development, 21-day-old male F344/DuCrj rats were fed 200 ppm 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in their diet for 8 weeks and doses of 0, 0.1, 0.3, 1, 3, 10 and 20% of ethanol in their drinking water ad libitum for 16 weeks thereafter. The rats were sacrificed after 24 weeks of experiment, and aberrant crypt foci (ACF), surrogate lesions for colon cancer, were examined under a light microscope at low magnification. Ethanol was found not to affect the ACF formation at any dose compared with the initiated-controls. Furthermore, ethanol did not alter colon epithelial cell proliferation. These data, obtained by analysis of a colon cancer surrogate marker lesion, indicate that ethanol lacks promotion activity for MeIQx-initiated rat colon carcinogenesis.     

锌对雏鸭外周血T-淋巴细胞的影响

15 0只 1日龄天府肉鸭健雏随机分为 3组 ,分别喂给缺锌 (每千克日粮含 Zn 2 2 .9mg)、对照 (每千克日粮含 Zn10 0 mg)和锌中毒 (每 kg日粮含 Zn130 0 mg)日粮 7周或 4周 ,以酸性 - α-醋酸萘酯酶 (ANAE)染色法观测外周血 T-淋巴细胞的动态变化。结果锌缺乏组和锌中毒组雏鸭外周血 T-淋巴细胞的 ANAE阳性率显著低于对照组 (P<0 .0 1) ,表明锌缺乏或锌中毒可抑制 T-淋巴细胞的生成 ,降低其在外周血中的数量。本试验还对锌缺乏和锌中毒引起的外周血 T-淋巴细胞减少的机理进行了探讨     

A 13-week subchronic toxicity study of 2-(l-menthoxy)ethanol in F344 rats

2-(l-Menthoxy)ethanol has been frequently employed as a flavoring agent; however, data regarding 2-(l-menthoxy)ethanol toxicity remain limited. We performed a 13-week subchronic toxicity study of 2-(l-menthoxy)ethanol in male and female F344 rats, with doses of 0, 15, 60, or 250 mg/kg body weight (BW)/day orally administered by gavage using corn oil as the vehicle. No significant toxicological changes in general condition, body weight, or food intake were observed in any groups. The hematological assessment showed decreased hemoglobin, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin and increased platelet count in the male 250 mg/kg group. Serum biochemistry revealed elevated total cholesterol in the 250 mg/kg group of male and female rats, reduced triglyceride in the female 250 mg/kg group, and increased total protein in the male 250 mg/kg group, indicating effects on lipid metabolism and protein synthesis. For organ weights, absolute and relative weights of the liver and adrenal glands were increased in the 250 mg/kg group of both sexes and the male 250 mg/kg group, respectively. Histopathological analysis showed chronic nephropathy in the male 15 mg/kg or higher groups, with increased absolute and relative kidney weights, as well as elevated serum creatinine, in the male 60 and 250 mg/kg groups. However, eosinophilic granules containing α_2u-globulin were identified in proximal tubules, suggesting α_2u-globulin nephropathy specific to male rats and without toxicological significance. These results indicated that the no-observed-adverse-effect level of 2-(l-menthoxy)ethanol was 60 mg/kg BW/day for both sexes.     

The failure of selenium supplementation to prevent copper-induced liver damage in Fischer 344 rats.

This study evaluates the ability of selenium (Se) supplementation to prevent experimental copper (Cu)-induced hepatocellular damage. Weanling male Fischer 344 rats were randomly assigned to groups of 15, 3 groups (A,B,C) were fed Cu-loaded diets (containing 2000 microg/g copper, added as CuSO4) and different levels of Se (added as Na2SeO3 x 5H2O) as follows: A) Cu-loaded/Se adequate diet (0.4 microg/g Se, fed basis); B) Cu-loaded/Se-supplemented diet (2 microg/g Se); and C) Cu-loaded/Se-deficient diet (< 0.2 microg/g). Three additional groups (D,E,F) were fed diets containing adequate levels of Cu (14 microg/g Cu, fed basis) and different levels of Se as follows: D) Cu-adequate/Se-adequate diet; E) Cu-adequate/Se-supplemented diet (2 microg/g Se); and F) Cu-adequate/Se-deficient (< 0.2 microg/g) diet. After 4, 8, and 12 weeks on the experimental diets, liver samples were processed for histology, histochemistry, metal analysis, glutathione peroxidase (GSH-Px) measurement, and quantification of malondialdehyde (MDA). Morphologic changes characteristic of Cu-associated hepatitis, without an increase in hepatic MDA levels, were seen in all Cu-loaded rats in each sampling. Similar changes occurred in rats fed Se-adequate, Se-supplemented and Se-deficient diets. This study demonstrates that Fischer 344 rats fed 2000 microg/g Cu develop morphologic changes due to Cu toxicity without evidence of lipid peroxidation. Furthermore, Se supplementation does not result in protection against Cu-induced liver injury.     

Background Data for General Toxicology Parameters in RccHan:WIST Rats at 8, 10, 19 and 32 Weeks of Age

Recently, RccHan(TM):WIST (Wistar Hannover) rats were introduced to toxicity studies in Japan. The present study was performed to obtain control data for general toxicological parameters as an aid for interpretation of results in toxicity studies using this strain of rats. Four test groups comprising of 25 male and 25 female RccHan(TM):WIST rats were housed for 2, 4, 13 or 26 weeks from 6 weeks of age and observed and examined for clinical observation, body weight, food consumption, urinalysis, hematology, blood chemistry, organ weight, necropsy and/or histopathology. Ophthalmological examination was not conducted in this study, and the data in this report were obtained from an ongoing 104-week background study in RccHan(TM):WIST rats. These data were compared with the historical control data of CD(SD) (Sprague-Dawley) and/or F344 (Fischer) rats. The body weights of RccHan(TM):WIST rats were lower than those of CD(SD) rats and higher than those of F344 rats. The ophthalmological examination revealed a greater incidence of focal corneal opacity. Histopathology revealed focal mineralization of the cornea and Berlin blue-positive pigmentation in the epididymal interstitium as well as hepatocytes. Other than the above, some minor differences were found in urinalysis, hematology, blood chemistry and organ weights as compared with CD(SD) rats.     

腐霉素的安全性及药效研究 Ⅱ.腐霉素的致畸作用

本文研究了腐霉素钠盐对Wistar大鼠的致畸作用。传统致畸试验,以1/5、1/15、1/45及1/135LD_(50)4个剂量的腐霉素进行试验,结果表明,1/5 LD_(50)组孕鼠已出现体重下降和死亡、吸收胎率和死胎率升高(P<0.05)诸现象,但各剂量组未产生明显的致畸作用(P>0.05)。喂养致畸试验,以1/10、1/50及1/100 LD_(50)3个剂量的腐霉素连续混料饲喂大鼠90天,然后交配检查,结果表明各剂量组均未出现任何明显的致畸作用(P>0.05)。腐霉素致畸指数小于10,属非致畸物。     

铜中毒对雏鸡外周血T-淋巴细胞的影响

180只1日龄艾维茵肉鸡健雏随机分为3组，分别饲喂对照（每千克日粮含铜11．97mg）和铜中毒（每千克日粮舍铜650mg，铜中毒Ⅰ组；每千克日粮含铜850mg，铜中毒Ⅱ组）日粮6周，以流式细胞术和酸性-α-醋酸萘酯酶（ANAE）染色的方法观测外周血T-淋巴细胞的动态变化。2个铜中毒组1～6周龄外周血T-淋巴细胞的ANAE阳性率均显著低于对照组（P〈0．05或P〈0．01），同时2个铜中毒组间比较也呈显著差异（P〈0．05或P〈0．01）。与对照组比较，2个铜中毒组2～6周龄CD4^＋T淋巴细胞数量均显著降低（P〈0．05或P〈0．01），CD8^＋T淋巴细胞数量变化不明显（P〉0．05），CD4^＋／CD8^＋比值降低（P〈0．05）。结果表明，铜中毒可抑制T-淋巴细胞的生成，降低其在外周血中的数量。     

Acute Phase Pulmonary Responses to a Single Intratracheal Spray Instillation of Magnetite (Fe3O4) Nanoparticles in Fischer 344 Rats

Iron nanomaterials are of considerable interest for application to nanotechnology-related fields including environmental catalysis, biomedical imaging, drug delivery and hyperthermia, because of their superparamagnetic characteristics and high catalytic abilities. However, information about potential risks of iron nanomaterials is limited. The present study assessed pulmonary responses to a single intratracheal spray instillation of triiron tetraoxide nanoparticles (magnetite) in rats. Ten-week-old male and female Fischer 344 rats (n=5/group) were exposed to a single intratracheal spray instillation of 0 (vehicle), 5.0, 15.0 or 45.0 mg/kg body weight (BW) of magnetite. After 14 days, the rats were sacrificed, and biological consequences were investigated. The lung weights of the 15.0 and 45.0 mg/kg BW male and female groups were significantly higher than those of the control groups. The lungs of treated rats showed enlargement and black patches originating from the color of magnetite. The typical histopathological changes in the lungs of the treated rats included infiltration of macrophages phagocytosing magnetite, inflammatory cell infiltration, granuloma formation and an increase of goblet cells in the bronchial epithelium. The results clearly show that instilled magnetite causes foreign body inflammatory and granulating lesions in the lung. These pulmonary responses occur in a dose-dependent manner in association with the increase in lung weight.     

No Modifying Effect of Antioxidant N-Acetyl-L-Cysteine on Fenofibrate-induced Hepatocarcinogenesis in Rats

To clarify the modifying effect of N-Acetyl-L-Cysteine (NAC), which has antioxidative ability, on hepatocarcinogenesis promoted by fenofibrate (FF), a peroxisome proliferator-activated receptor (PPAR) alpha agonist , male F344/N rats were administered a single intraperitoneal injection of N-diethylnitrosamine (DEN) as an initiator followed by administration of a diet containing 3,000 ppm of FF for 16 weeks. Two-thirds partial hepatectomy was performed 1 week after the FF treatment. Additionally, NAC treatments for 14 weeks from 2 weeks after the FF treatment were performed. Although the expression level of tumor protein p53 (Tp53) mRNA decreased in the DEN+FF+NAC group as compared with that in the DEN+FF group, no significant differences between the DEN+FF and DEN+FF+NAC groups were observed in the number of hepatocellular altered foci and activities of hepatocellular proliferation. In addition, the results of an antioxidant enzyme assay and measurement of the amounts of total glutathione in the liver revealed no significant difference between the DEN+FF and DEN+FF+NAC groups; although no significant differences were observed in many genes between the DEN+FF and DEN+FF+NAC groups, only glutathione peroxidase 2 (Gpx2) mRNA increased in the DEN+FF+NAC group as compared with the DEN+FF group. The results under the present experimental conditions indicate no obvious modifying effect of NAC on liver tumor promotion by FF in rats.     

Carcinogenicity of biphenyl in mice by two years feeding

Carcinogenicity and chronic toxicity of biphenyl was examined in the male and female BDF1 mice fed a diet containing biphenyl at 667, 2,000 or 6,000 ppm for 2 years. There was no difference in survival rate between any biphenyl-containing diet-fed group of either sex and the respective control. Body weights of the males and females fed 6,000 ppm diet were significantly lower than the respective control. Incidences of hepatocellular carcinomas and hepatocellular adenomas in the females fed diets containing biphenyl were significantly increased in a dose-related manner, and exceeded a range of the historical control data in the Japan Bioassay Research Center. Incidences of basophilic cell foci in the liver were increased in the females fed 2,000 and 6,000 ppm diets. There was no increase in tumor or tumor-related lesion in the males fed diets containing biphenyl. Chronic toxicity of biphenyl was characterized by increased incidences of urothelial desquamation in the renal pelvis in males and females and mineralization in the inner stripe of renal outer medulla in females, as well as changes in serum levels of BUN, ALP and some electrolytes in males and females. In conclusion, the 2-year oral administration of biphenyl-containing diets induced pre-neoplastic and neoplastic lesions in the liver of females and non-neoplastic lesions in the kidney of males and females. Causative factors for the biphenyl-induced hepatocarcinogenicity were discussed in light of our published finding of peroxisome proliferation.     

Assessment of Alloxan-Induced Diabetic Rats as a Periodontal Disease Model Using a Selective Cyclooxygenase (COX)-2 Inhibitor

Several recent studies have reported that alloxan-treated rats with long-term hyperglycemia can develop naturally occurring periodontal disease (PD). Our previous studies detected dental caries in the same model. Therefore, these two lesions of different etiologies are expected to occur concurrently. In this study, we evaluated the use of diabetic rats as a PD model by employing a selective COX-2 inhibitor reported to be effective against PD. Six-week-old female F344 rats were divided into 3 groups: intact rats (control), alloxan-induced diabetic rats fed a standard diet (AL) and alloxan-induced diabetic rats fed a diet containing 0.01% etodolac (AL+Et). The animals were euthanized at 26 weeks of age, and their oral tissues were examined histopathologically. Gingivitis, marginal periodontitis and alveolar bone resorption were markedly enhanced along with dental caries in the AL group compared with the control group. However, the COX-2 inhibitor had no effect on periodontal inflammation in the AL+Et group. In addition, in the AL group, periodontitis was notably nonexistent around the normal molars, and gingivitis was scarcely worse than that in the control group. In the diabetic rats, the progression of periodontal inflammation was closely correlated with the severity of adjacent dental caries, and marginal periodontitis was frequently continuous with apical periodontitis. In conclusion, an alloxan-induced diabetic rat is not a model of PD but of dental caries. It is probable that in this model, hyperglycemia may enable crown caries to progress to apical periodontitis, while the associated inflammation may rostrally expand to surrounding periodontal tissue.