Hye-Yeong Lee

Historical control data from 13-week repeated toxicity studies in Crj:CD (SD) rats

Reference ranges of standard experimental parameters are useful for comparisons in toxicology. The aim of this study was to collect data from 13-week repeated toxicity studies in Crl:CD (SD) rats, a strain widely used for toxicity and efficacy research, for establishing domestic reference values. Data on body weight, food consumption; urinalysis, hematological, and blood biochemical parameters; and organ weights were collected from 11 toxicity studies in 220 Crl:CD (SD) rats (110 males and 110 females). The studies had been performed at a single testing facility over the last 5 years and involved animals sourced from a single breeder. The findings were collated as means, standard deviations, percentages, and ranges. Urine volume, uterus weight, eosinophil, and basophil counts, and triglyceride, total bilirubin, and gamma-glutamyl transpeptidase levels showed standard deviations of 30% or more. These historical control data would help to interpret the effects of test substances in routine toxicity and efficacy studies.

Subchronic toxicity study of Coptidis Rhizoma in rats

ETHNOPHARMACOLOGICAL RELEVANCE Coptidis Rhizoma (CR) is a medical herb from the family Ranunculacease that has been used to treat gastroenteritis, dysentery, diabetes mellitus, and severe skin diseases. AIM OF THE STUDY To evaluate the no-observed-adverse-effect level (NOAEL) and the toxicity of CR, following repeat oral administration to rats for 13 weeks. MATERIALS AND METHODS CR was administered by oral gavage to groups of rats (n=10/group, each sex) at dose levels of 0 (control), 25, 74, 222, 667 or 2000 mg/kg/day 5 times per week for 13 weeks. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, urinalysis, vaginal cytology and sperm morphology, organ weights, gross and histopathological findings were compared between control and CR groups. RESULTS Urinalysis showed a significant increase in N-acety1-β-glucosaminidase in males in the 2000 mg/kg/day group (P<0.01). However, no mortality or remarkable clinical signs were observed during this 13-week study. No adverse effects on body weight, food consumption, hematology, serum chemistry, organ weights, gross lesion, histopathology, vaginal cytology, sperm motility, or deformity were observed in the males or female rats treated with CR. CONCLUSIONS On the basis of these results, the NOAEL of CR is determined to be 667 mg/kg/day for males and 2000 mg/kg/day for females.

Subchronic oral toxicity of evodia fruit powder in rats.

ETHNOPHARMACOLOGICAL RELEVANCE Evodia, a fruit from Evodia rutaecarpa, has been used in oriental medicine, and since its various pharmaceutical actions, including anti-cancer activity, have become known, evodia has been widely used as a dietary supplement. However, information regarding its toxicity is limited. MATERIALS AND METHODS Evodia fruit from Evodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang (0, 25, 74, 222, 667, and 2000 mg/kg) was administered orally five times per week for 13 weeks. Clinical signs, body weight, food consumption, hematology, serum chemistry, urinalysis, vaginal cytology, sperm morphology, organ weight, and gross and histopathological findings were evaluated. RESULTS Urinary ketone body excretion was detected in males at 667 and 2000 mg/kg and in females at 2000 mg/kg. An increase in absolute/relative liver weight was observed in both sexes at 2000 mg/kg. Although levels of serum alanine aminotransferase, glucose, total cholesterol, and triglycerides were significantly reduced in males and/or females at 200 and/or 667 and 2000 mg/kg, all values were within normal ranges and were considered non-adverse. In addition, no treatment-related differences in body weight, food consumption, hematology, vaginal cytology, sperm morphology, or gross and histopathological examination were detected. CONCLUSIONS The subchronic no-observable-adverse-effect level for evodia fruit powder following oral administration in rats is greater than 2000 mg/kg.

Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats

Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes.

Subchronic toxicity of Acorus gramineus rhizoma in rats

ETHNOPHARMACOLOGICAL RELEVANCE Acorus gramineus rhizoma (AGR) is the dry rhizome of Acorus gramineus Solander from the family Araceae that has been used as sedative, analgesic, diuretic, digestive and antifungal agent. AIM OF THE STUDY To evaluate the no-observed-adverse-effect level (NOAEL) and the toxicity of AGR, following repeated oral administration to rats for 13 weeks. MATERIALS AND METHODS AGR was administered by oral gavage to groups of rats (10 per group, each sex) at doses of 0 (control), 25, 74, 222, 667, or 2,000mg/kg/day, 5 times per week for 13 weeks. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, urinalysis, vaginal cytology, sperm motility, sperm morphology, organ weights, gross and histopathological findings were compared between control and AGR groups. RESULTS No mortality or remarkable clinical signs were observed during this 13-week study. No adverse effects on body weight, food consumption, urinalysis, hematology, serum chemistry, organ weights, gross lesion, histopathology, vaginal cytology, sperm motility or deformity were observed in any of the male or female rats treated with AGR. CONCLUSIONS On the basis of these results, the NOAEL of AGR is determined to be 2,000mg/kg/day for male and female rats.

Sub-acute toxicity study in female ICR mice following repetitive intramuscular injection of cervical cancer vaccines.

Objectives The sub-acute toxic effects following repetitive intramuscular injection of two cervical cancer vaccines newly developed against human papillomaviruse (HPV)16/58/18 and HPV16 were investigated in female ICR (CrljOri: CD1) mice, and the no-observedadverse- effect-level (NOAEL) of the cervical cancer vaccines was estimated. Methods Female ICR mice (n=15 in each group) were exposed to a 1:1 mixture of two cervical cancer vaccines by repetitive intramuscular injection (once a week, 5 times) for 5 weeks. Mortality, body weight, organ weight, hematological/biochemical parameters, and histopathological effects were examined at different concentrations (0, 1×108, 5×108, and 2.5×109 copies/animal) of the cervical cancer vaccines. Results The cervical cancer vaccines did not show toxic responses for body weight, absolute/ relative organ weight, hematological/biochemical parameters, or histopathological parameters. Conclusions Female ICR mice exposed to vaccines for cervical cancer did not show any toxic response. We suggest that a NOAEL of the vaccine following repetitive intramuscular injection for 5 weeks is >2.5×109 copies/animal.