In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.
Animals ; Chemistry, Clinical ; Hematology ; Japan ; Jurisprudence ; No-Observed-Adverse-Effect Level ; Organ Size ; Rats ; Urinalysis

In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.
Animals ; Chemistry, Clinical ; Hematology ; Japan ; Jurisprudence ; No-Observed-Adverse-Effect Level ; Organ Size ; Rats ; Urinalysis

OBJECTIVE: First-in-human dose estimation is an essential approach for successful clinical trials for drug development. In this study, we systematically compared first-in-human dose and human pharmacokinetic parameter estimation approaches. METHODS: First-in-human dose estimation approaches divided into similar drug comparison approaches, regulatory guidance based approaches, and pharmacokinetic based approaches. Human clearance, volume of distribution and bioavailability were classified for human pharmacokinetic parameter estimation approaches. RESULTS: Similar drug comparison approaches is simple and appropriate me-too drug. Regulatory guidance based approaches is recommended from US Food and Drug Administration (FDA) and European Medicines Agency (EMA) regarding no-observed-adverse-effect level (NOAEL) or minimum anticipated biological effect level (MABEL). Pharmacokinetic based approaches are 8 approaches for human clearance estimation, 5 approaches for human volume of distribution, and 4 approaches for human bioavailability. CONCLUSION: This study introduced and compared all methods for first-in-human dose estimation. It would be useful practically to estimate first-in-human dose for drug development.
Biological Availability ; Humans ; No-Observed-Adverse-Effect Level ; Pharmacokinetics ; United States Food and Drug Administration

Calomel is a common traditional Chinese medicine (TCM) containing mercury in clinical external application. Although the toxicity of calomel has attracted concern, there is no unified standard yet in clinical external application. Risk assessment is used for evaluating the potential health effects of hazardous substances. The purpose of this article was to evaluate the health risk of calomel in clinical external application on the basis of toxicity data, to ensure safe and rational application of TCM containing calomel. The toxicity data of transdermal administration of calomel or mercurous chloride were collected by searching the literature. The daily maximum exposure dosage of calomel in clinical external application was estimated by following the four procedures of risk assessment, and Margin of Safety (MOS) as an evaluation indicator was then calculated to evaluate the safety of calomel on clinical application. It has been reported that the adult in single transdermal administration of calomel at 1. 5 g was lethal. Based on the LOAEL of calomel for long-term transdermal exposure (1 month) in rats was 0.096 g · kg(-1) · d(-1), the NOAEL of calomel for patients (about 60 kg) by external application within 2 weeks was estimated to be 1.46 mg · kg(-1) · d(-1). When MOS value equals to 1, the daily maximum exposure of calomel in clinical external application within 2 weeks was calculated to be 1.1 g. The results suggest that daily single dose of calomel in clinical external application should be lower than 1.5 g for adults, and more attention should be paid to changes in hepatic and renal function of patients when repeated dose more than 1.1 g within 2 weeks. The approach of risk assessment could be helpful in rational application of TCM containing mercury.
Animals ; Humans ; Medicine, Chinese Traditional ; Mercury Compounds ; toxicity ; No-Observed-Adverse-Effect Level ; Rats ; Risk Assessment

Renal toxicity by melamine in combination with cyanuric acid (1:1) was investigated. Male rats were orally administered melamine plus cyanuric acid (5, 50 or 400 mg/kg each) for 3 days. In contrast to a negligible effect by melamine alone (50 mg/kg, a no-observed-adverse-effect-level: NOAEL), co-administration with cyanuric acid markedly increased the concentrations of blood urea nitrogen and creatinine, as well as kidney weight. A high dose (400 mg/kg) of melamine plus cyanuric acid induced more severe kidney toxicity. The increased blood parameters for kidney toxicity and organ weight lasted longer than 4 days. Combined treatment with melamine and cyanuric acid (50-400 mg/kg each) resulted in many gold-brown crystals and toxic lesions in renal tubules, which were not observed in animals treated with melamine alone (50 mg/kg). These results indicate that only a 3-day exposure to melamine in combination with cyanuric acid causes severe renal damage, even at a NOAEL for melamine found in a 13-week toxicity study. Therefore, it is suggested that the tolerable daily intake or regulatory/management levels of melamine need to be re-considered for cases of co-exposure with cyanuric acid.
Animals ; Blood Urea Nitrogen ; Creatinine ; Humans ; Kidney ; Male ; No-Observed-Adverse-Effect Level ; Organ Size ; Rats ; Triazines

The purpose of this study was to investigate the NOAEL of the nickel ion and provide with basic data for the biological evaluation of those medical devices containing nickel. Five groups SD rats were repeatedly exposed during 14 d respectively to nickel at first stage doses of 4.9, 3.7, 2.5 mg/(kg.d), and the second stage doses of 1.2, 0.25 mg/(kg.d) by the intravenous route. The results showed that the NOAEL of nickel ion is 0.25 mg/(kg.d) for SD rats, and the result was verified by subchronic systemic toxicity test of nickel alloy. The threshold of toxicological concern (TTC) of nickel is 150 μg/d (based on application of 100-fold uncertainty factor and a body weight of 60 kg)deduced by these data.
Animals ; Equipment and Supplies/adverse effects* ; Nickel/toxicity* ; No-Observed-Adverse-Effect Level ; Rats ; Rats, Sprague-Dawley ; Risk Assessment

UG0712 is a new ginsenoside extract processed from ginseng leaves. A subchronic toxicity study of UG0712 was conducted in male and female SD rats. Rats were treated with UG0712 at doses of 100, 400 and 1,600 mg/kg/day for 13 weeks, and observed followed by 4-week recovery period at a highest dose. No-treatment-related effects were observed regarding the mortality, ophthalmic examination, urinalysis and histopathology. Although the changes in clinical sign, body weight, organ weight, hematology, and serum biochemistry were observed, they were temporal and pharmacological effects. Based on the present experiment conditions, the no observed adverse effect level was considered to be more than 1,600 mg/kg/day in both sexes of rats.
Animals ; Biochemistry ; Body Weight ; Female ; Hematology ; Humans ; Male ; Mortality ; No-Observed-Adverse-Effect Level ; Organ Size ; Panax* ; Rats* ; Urinalysis

OBJECTIVETo study the oral chronic toxicity of 97% isopropyl thioxanthone (97% ITX) in rats, determine the no-observed adverse effect levels (NOAEL).

METHODSFour groups of rats were fed with foodstuff containing 97% ITX in the dosage of 1000.0, 250.0, 62.5 mg/kg respectively for 2 years. The general behavior, body weight, food availability ect. were observed during the experiment. At the end of the experiment, blood and urine samples were collected for routine and biochemical assays. The internal organs were taken for calculating their organ coefficients and histopathological examinations.

RESULTSDuring the experimental period, no obvious abnormality were found in the experimental animals. The body weight and the total food availability rate in the high dosage group of male were lower than that of control (P < 0.05). Hematology examination showed that the quantity of Hb and RBC in high dosage groups of both the male and female and Hb in the male middle group were all lower than the control group (P < 0.01 or P < 0.05). Analysis of correlation indicated that r = -0.433, P < 0.01 in male, r = -0.337, P < 0.01 in female of Hb; r = -0.266, P < 0.05 in male, r = -0.317, P < 0.01 in female of RBC. There were obviously negative correlation. Serum biochemistry examination showed the concentration of CHO in the high and middle dosage treated rats of male and female were higher than that of the control (P < 0.01 or P < 0.05). Analysis of correlation indicated that r = 0.497, P < 0.01 in male, r = 0.417, P < 0.01 in female. No abnormality were found in urine examination. The organ weight and organ coefficient such as liver, were higher than control group (P < 0.01). The result of histopathological examinations displayed that the renal tubule Cast and the tubulointerstitial nephritis in the treated groups were higher than that of control group (P < 0.01).

CONCLUSION97% ITX could obviously interfere with the animals' physical condition, and reduce the number of RBC and the concentration of Hb in the blood, interact metabolism of lipoid and induce the concentration of CHO in the serum. The livers of the treated rats are compensatory enlarged. And kidneys of the poisoning animals are damaged. The 2 years oral NOAEL of 97% ITX in rats are more than 4.63 mg/kg for female rats, and larger than 4.06 mg/kg for male rats.

Administration, Oral ; Animals ; Female ; Male ; No-Observed-Adverse-Effect Level ; Rats ; Rats, Wistar ; Toxicity Tests, Chronic ; Xanthones ; toxicity

OBJECTIVETo study genetic damage of mice caused by the volatile organic compounds (VOC) of decoration materials.

METHODSFifty-five hotel guest rooms newly decorated within 6 months and 18 hotel guest rooms not decorated within 3 years were selected to determine the concentrations of 6 main VOC (benzene, methylbenzene, dimethylbenzene, ethyl acetate, butyl acetate, formaldehyde) in the air. Mice were exposed to VOC with the concentrations of 5, 10, 20, 40 times respectively as high as those present in the newly decorated rooms in an exposure cabinet for 15 days. DNA damage of peripheral lymphocytes of the mice was determined by single cell gel electrophoresis (SCGE) and bone marrow micronucleus test.

RESULTSThe concentrations of benzene, methylbenzene, dimethylbenzene, ethyl acetate, butyl acetate and formaldehyde in the rooms newly decorated within 6 months (6.50, 3.00, 6.70, 41.33, 1.70 and 0.14 mg/m(3) respectively) were significantly higher than those in rooms not decorated within 3 years (0.08, 0.94, 1.38, 0.25, 0.25, 0.01 mg/m(3), P < 0.01). DNA damage rates of peripheral lymphocytes in the concentrations of 10, 20, 40 times of exposure groups were significantly higher than those in the control groups (P < 0.05 or P < 0.01), and the frequencies of micronucleus in the mice exposed to 40 times of concentration was significantly higher than that in control group.

CONCLUSIONHigh concentrations of the volatile organic chemical compounds may cause genetic damage in mice. SCGE test is more sensitive than micronucleus test.

Air Pollutants ; toxicity ; Air Pollution, Indoor ; adverse effects ; Animals ; DNA Damage ; drug effects ; Mice ; Micronucleus Tests ; No-Observed-Adverse-Effect Level ; Organic Chemicals ; toxicity ; Paint ; adverse effects

OBJECTIVE: To explore the general reproductive toxicity in mice exposed to low-level ozone. METHODS: Low-level (0.09 approximately 0.18 mg/m3) ozone was created by 15 W ultraviolet light. The mice in 3 experimental groups and a control group were fed in low-level ozone environment or normal environment, respectively, and then the mating experiment was conducted. The pregnancy rate and the weight variations of the female mice were observed. The weight of the live fetuses was observed, and the appearance, bone and internal organs were checked for malformation. RESULTS: There were no significant differences in any indexes between the experimental groups and the control group. CONCLUSION Low-level ozone created by 15 W ultraviolet light may not have reproductive toxicity in mice.
Animals ; Dose-Response Relationship, Drug ; Female ; Fertility ; drug effects ; Inhalation Exposure ; adverse effects ; Male ; Mice ; No-Observed-Adverse-Effect Level ; Ozone ; toxicity ; Random Allocation ; Reproduction ; drug effects ; Ultraviolet Rays