Kazunori Yamazaki

Embryotoxic effects of ethylene glycol monomethyl ether in mice

An embryotoxicity study on ethylene glycol monomethyl ether (EGM) was carried out in ICR mice. They were given EGM daily at 6 dose levels (31.25, 62.5, 125, 250, 500 or 1000 mg/kg body wt) by gastric intubation on days 7 through 14 of gestation. On day 18 of gestation all fetuses were examined. Marked and dose-related embryotoxic effects were observed. Skeletal and gross anomalies, reduced fetal weight and fetal death were all observed at lower dosages of EGM, while marked leucopenia of the dams occurred at the highest dose.

Carcinogenicity studies of 1,4-dioxane administered in drinking-water to rats and mice for 2 years

The carcinogenicity of 1,4-dioxane was examined by giving groups of 50 F344/DuCrj rats and 50 Crj:BDF(1) mice of each sex 1,4-dioxane in the drinking-water for 2 years. The concentrations of 1,4-dioxane were 0 (control), 200, 1000 and 5000 ppm (wt./wt.) for rats and 0, 500, 2000 and 8000 ppm for mice. The highest dose levels did not exceed the maximum tolerated dose. In the rat, there was significant induction of nasal squamous cell carcinomas in females and hepatocellular adenomas and carcinomas in males and females, peritoneal mesotheliomas in males, and mammary gland adenomas in females. In the mouse, there was significant induction of hepatocellular tumors in males and females. Two nasal tumors occurring in the 8000 ppm-dosed groups were spontaneously rare and, thus, were attributed to 1,4-dioxane exposure. The present studies provided clear evidence of carcinogenicity in rats and mice. Lifetime cancer risk of humans exposed to 1,4-dioxane through drinking-water was quantitatively estimated with a non-threshold approach by application of a linearized multistage model to dose-carcinogenic response relationships, in addition to a threshold approach for estimation of the tolerable daily intake using no-observed- or lowest-observed-adverse-effect levels of the carcinogenic responses and uncertainty factors.

An Exposure System for Combined Administration of an Organic Solvent to Rodents by Inhalation and Water-Drinking and its Operational Performance

An Exposure System for Combined Administration of an Organic Solvent to Rodents by Inhalation and Water‐Drinking and its Operational Performance: Hirokazu Kano, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health Association—In order to obtain bioassay data for carcinogenicity and chronic toxicity of an organic solvent being absorbed into the body through multiple media by inhalation and ingestion, an exposure system for combined inhalation and oral exposures of rats to the organic solvent was constructed. Operational performance of the system was examined by monitoring air and water concentrations of chloroform or 1,4‐dioxane in both an inhalation exposure chamber and an automatic watering system, while groups of 50 male rats each were exposed to chloroform or 1,4‐dioxane by inhalation for 6 h/d, 5 d/wk and 104 wk and by water drinking for 24 h/d and 7 d/wk throughout the 104 wk. Day‐to‐day and time‐to‐time variations in concentrations in the exposure chamber were maintained at less than 0.8% C.V. and 4.8% C.V., respectively, in the case of chloroform, and less than 1.2% and 8.1 %, respectively, in the case of 1,4‐dioxane. The mean 6‐h averaged concentrations deviated by less than 0.4% from the respective target concentrations for all sets of the combined exposures. The watering system which was composed of a drinking valve, in‐between piping, a container and a solenoid drainage valve was used for giving ad libitum drinking water containing 1000 ppm chloroform or 1,4‐dioxane to rats. Mean water concentrations of chloroform and 1,4‐dioxane were attenuated by 3‐8% and by 1% in the container after 1 ‐weeks supply, respectively. It was concluded that this exposure system can give accurate and reproducible air and water concentrations of chloroform and 1,4‐dioxane for long‐term combined inhalation and oral exposure.

Carcinogenicity and chronic toxicity in mice and rats administered vinyl acetate monomer in drinking water.

Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water: Yumi Umeda, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health Association—Carcinogenicity and chronic toxicity of vinyl acetate monomer (VA) were examined in male and female Crj:BDF1 mice and F344/DuCrj Rats. Groups of 50 mice and 50 rats of each sex were orally administered VA in drinking water containing 0, 400, 2,000 or 10,000 ppm (g/g) VA for 104 wk. Squamous cell tumors were clearly evident in the upper digestive tract of treated mice and rats, and in the larynx of treated mice of both sexes. In mice, squamous cell carcinomas and papillomas were observed in the oral cavity, esophagus, forestomach and larynx of the 10,000 ppm group, together with basal cell hyperplasia, squamous cell hyperplasia and epithelial dysplasia. In rats, incidences of squamous cell carcinomas and papillomas were increased in the oral cavity of the 10,000 ppm group of both sexes, and an esophagus squamous cell carcinoma was observed in a 10,000 ppm female. Pre‐neoplastic hyperplasias were also noted. Mapping of the neoplastic and pre‐neoplastic lesions in the oral cavity of the 10,000 ppm group revealed that both the lesions occurred predominantly at Level V in mice and at Level VI in rats. A lower confidence limit of a benchmark dose (BMDL10) of 477 mg/kg/d was obtained from a dose‐response relationship between combined incidence of squamous cell carcinomas and papillomas in the oral cavity of mice and rats and the estimated daily VA intakes per body weight, and compared with literature values.

Systemic and myelotoxic effects of single administration of 2,3,7,8-tetrabromodibenzo-p-dioxin in rats

ObjectiveSystemic and myelotoxic effects of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) were examined by the single administration of TBDD by gavage to rats.MethodsFifteen Wistar rats of both sexes per group received 0, 10, 30, 100 or 300 μg TBDD/kg body weight. Rats surviving to the scheduled necropsy on Days 2, 7 and 36 after TBDD administration were examined for growth rate, organ weight, hematology, histopathology and adipose tissue levels of TBDD.ResultsThree 300 μg/kg-dosed females died on Days 21, 23 and 27, and exhibited a marked decrease in body weight, severe thymic atrophy, decreased bone marrow hematopoiesis and hemorrhage in the subarachnoid space of brain and spinal cord. TBDD-dosed surviving rats exhibited growth retardation, decreased bone marrow hematopoiesis, decreases in red blood cell counts, hemoglobin concentrations, and hematocrit values, an increase in reticulocytes and decreases in platelet counts, white blood cell counts and eosinophils. These signs suggested TBDD myelotoxicity. Splenic extramedullary hematopoiesis was increased in both sexes given TBDD, whereas atrophy of the splenic white pulp occurred only in TBDD-dosed females. Marked decreases in body weights and the size and weight of the thymus, severe thymic atrophy and death in TBDD-dosed females suggested a wasting syndrome. The adipose tissue level of TBDD culminated on Day 7 and decreased to 20–30% of the Day 7 level on Day 36.ConclusionsThe TBDD-induced effects were characterized by a wasting syndrome and myelotoxicity that appeared at the dose levels of 30 μg/kg and higher and caused death in 300 μg/kg-dosed females.

Oral Carcinogenicity and Toxicity of 2-Amino-4-chlorophenol in Rats

Oral Carcinogenicity and Toxicity of 2‐Amino‐4‐chlorophenol in Rats: Kazunori Yamazaki, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health Association