Benzene-induced hematopoietic neoplasms including myeloid leukemia in Trp53-deficient C57BL/6 and C3H/He mice.

This research focused on three major questions regarding benzene-induced hematopoietic neoplasms (HPNs). First, why are HPNs induced equivocally and at only threshold level with low-dose benzene exposure despite the significant genotoxicity of benzene even at low doses both in experiments and in epidemiology? Second, why is there no linear increase in incidence at high-dose exposure despite a lower acute toxicity (LD(50) > 1000 mg/kg body weight; WHO, 2003, Benzene in drinking-water. Background document for development of WHO Guidelines for Drinking-Water Quality)? Third, why are particular acute myeloid leukemias (AMLs) not commonly observed in mice, although AMLs are frequently observed in human cases of occupational exposure to benzene? In this study, we hypothesized that the threshold-like equivocal induction of HPNs at low-dose benzene exposure is based on DNA repair potential in wild-type mice and that the limited increase in HPNs at a high-dose exposure is due to excessive apoptosis in wild-type mice. To determine whether Trp53 deficiency satisfies the above hypotheses by eliminating or reducing DNA repair and by allowing cells to escape apoptosis, we evaluated the incidence of benzene-induced HPNs in Trp53-deficient C57BL/6 mice with specific regard to AMLs. We also used C3H/He mice, AML prone, with Trp53 deficiency to explore whether a higher incidence of AMLs on benzene exposure might explain the above human-murine differences. As a result, heterozygous Trp53-deficient mice of both strains showed a nonthreshold response of the incidence of HPNs at the lower dose, whereas both strains showed an increasing HPN incidence up to 100% with increasing benzene exposure dose, including AMLs, that developed 38% of heterozygous Trp53-deficient C3H/He mice compared to only 9% of wild-type mice exposed to the high dose. The detection of AMLs in heterozygous Trp53-deficient mice, even in the C57BL/6 strain, implies that benzene may be a potent inducer of AMLs also in mice with some strain differences.

[Gymnema sylvestre leaf extract: a 52-week dietary toxicity study in Wistar rats].

A 52-week study of oral-repeated-dose toxicity for the extraction powder of Gymnema sylvestre (GS), Indian-native genus, Metaplexis japonica, was conducted in both genders of Wistar rats. The rats were administered a graded dose of GS at 0.01, 0.10 and 1.00% of basal powder diet, along with a group fed solely with the basal powder diet without GS, for 52 weeks. General conditions were recorded daily. Body weights and food consumptions were recorded weekly up to 12 weeks, and thereafter at longer intervals. At 26 weeks, for an intermediate examination, and 52 weeks, for the final examination, animals were subjected to hematology, serum chemistry, and pathological examination. None of the animals died in the period up to 52 weeks. No exposure-related changes in body-weight, in the food consumption, in the hematological examinations, or in the serum biochemical examinations were recognized. No histopathological alterations were seen. Thus, it was concluded that there was no toxic effect in rats treated with GS at up to 1.00% in the diet for 52 weeks. The no-observable-effect level from this study is 1.00% GS, i.e., 504 mg/kg/day for male and 563 mg/kg/day for female as mean daily intake, for 52 weeks.

[Twenty-eight day repeated dose oral toxicity test of synergist of a pyrethroid insecticide, 2,3,3,3,2',3',3',3'-Octachlorodipropyl ether (S-421) in rats].

2,3,3,3,2',3',3',3'-Octachlorodipropyl ether (Abbreviation; S-421) is originally developed as synergist of a pyrethroid insecticide. In recent years, S-421 is used widely at home, for a mosquito-repellent incense, electric mosquito-repellent, an insect-killing spray, a vacuum cleaner paper pack, etc. as well. On the other hand, S-421 has been detected in vacuum cleaner dust samples as well as human milk samples in Japan indicating that our living environment is already contaminated by this compound. Long term toxicity studies including a carcinogenesis study have been performed and NOEL of chronic toxicity has been settled. However, it is clear that S-421 is used in close proximity so that acute or subacute exposure at relatively higher dose levels than chronic NOEL values are easily assumed, such as use of a spray in an ill-ventilated room, etc. This study, 28 day repeated oral dose toxicity study of S-421 was performed to monitor the outcome of acute and subacute exposure assuming possible exposure accidents mentioned above. The protocol is as follows; Groups of 10 rats of each sex(5 week-old), were treated with intragastric administration of S-421 with a dose of 0 (olive oil, control), 10, 40, 160 or 640 mg/kg body weight. For recovery test, 14 day after the last treatment, the control and 640 mg/kg groups were examined, respectively. All animals of all groups in both sexes survived. In the 640 mg/kg groups of the both sexes, all animals were set to drowsiness from about 5 hours after administration, however, they recovered by the next morning. In the hematology examination, Hb, MCH, MCHC, WBC values were significantly decreased and MCV value was significant increased in the 640 mg/kg group of both sexes. In the serum biochemistry, items increased in the 640 mg/kg groups of both sexes returned to normal level after 14 days recovery period. Absolute and relative liver weight increase seen in the 160 mg/kg and above also returned to control level after recovery. Histopathologically, slight hepatocellular swelling was observed in the 160 mg/kg groups and severe hepatocellular swelling with vacuolization and slight necrosis was seen in the 640 mg/kg group. In conclusion, the no-observed-effect levels (NOEL) of S-421 under these conditions was judged to be 40 mg/kg/day.

[Kooroo color: 90-day dietary toxicity study in F344 rats].

A subchronic toxicity study on kooroo color was conducted using F344 rats of both genders. Kooroo color is an extract of yam root, Dioscorea matudai Hayata, of which the major components are known to be flavonoid pigments. Use of kooroo as a food color is permitted by the Food Sanitation Law in Japan, but the chronic toxicity has not been evaluated in the literature. Rats were fed the product of kooroo color (PKC) at doses of 0.5%, 1.50%, and 5.0% in basal powder diet, while control groups received PKC-free basal diet, for ninety days. A vehicle control given propylene glycol (PG) alone, at the same dosage that the 5.0% group received, was included, because PKC used in this study contained ca. 80 percent PG, used as an extractant during the manufacturing processes. Daily observation of general behavior, and weekly measurement of body weight as well as food consumption were performed. Hematological, serum biochemical and anatomopathological examinations were conducted at the end of administration. No abnormalities ascribable to the treatment with PKC or PG were noted in any examination in this study. Hence, dietary intake of 5.0% of PKC, i.e., 2,993 mg/kg/day for males, and 3,376 mg/kg/day for females, as a mean daily intake for 90 days, had no observable adverse effect in F344 rats. Therefore, kooroo color has no significant general toxicity, and its toxicity, if any, is of a very low order.