ビスフェノールAの内分泌かく乱作用のヒトヘの健康影響評価

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Bisphenol A has been identified as an endocrine disrupter, showing estrogenic activities. Several research groups have reported that the estrogenic activities were evoked at the dose levels of the μg/kg order in rodents. However, these low dose effects could not be reproduced at other laboratories. Regarding the low dose effects of endocrine disrupters including bisphenol A, the US National Toxicology Program and the International Program on Chemical Safety held professional meetings in succession and stated the necessity of further research for scientific assessment of the human health risk. In this article, the properties of endocrine disrupting toxicities of bisphenol A are reviewed, and the reported experimental dose levels are compared to the assumed human exposure levels. The almost relative estrogenic activities in vitro of bisphenol A are about 3 or 4 orders of magnitude less than estradiol or diethylstilbestrol. The responses are induced at a range of concentration between 100^<-7> and 10^<-5>M. The uterotropical effects in immature or ovariectomized rodents were reported to be above approximately 10 mg/kg/day. A decrease of daily sperm production in adult SD rats was detected at more than 20 μg/kg. But the extent of the effect was almost the same up to 200 mg/kg, indicating no dose-dependent effects. Other male reproductive organ toxicities in rodents after birth were reported at doses of more than 10 mg/kg/day. Many studies on the developmental toxicity by parental low dose exposure have recently been conducted. The most sensitive endpoint was an increased prostate weight in the next generation by 2 μg/kg/day of bisphenol A treatment between pregnancy period day 11 and 17, which was reported by vom Saal et al. (1998). The effect was reproduced in a 50 μg/kg/day of bisphenol A treatment study reported by Gupta(2000), and also supported by molecular-pathological researches and neurobehavioral examinations at the sub mg/kg order of dose treatment. In more expanded dose range studies and multi generational studies, however, no reproductive organ toxicities were detected at doses of less than 50 mg/kg/day. In rats, almost all absorbed bisphenol A in the body is conjugated with glucuronic acid. About 10 to 30 % of total absorption is excreted to urine, and the rest is excreted to faeces by biliary excretion. The bioavailability via oral exposure is about one order lower than that via subcutaneous or intravenous injection, but elimination half life via oral exposure is about one order longer (between 20 and 40 hours) owing to enterohepatic circulation. Information about the metabolism information of bisphenol A in human is limited, but the major metabolite is considered to be glucuronide. The total intake of bisphenol A in the general population is estimated from the several reports, in which total intake via food contamination or elimination levels in human urine were reported. The ordinary intake is thought to be roughly 0.1 μg/kg/day, and even the maximum level is considered to be lower than 1 μg/kg/day. It is noteworthy that the temporary high dose intake of a few μg/kg/day is possible as the worst case scenario. Comparing to these human exposure levels with the representation of low dose effects by bisphenol A, the margin of safety is relatively small. However, because these low dose effects were not reproducible and the toxicological meaning in humans is obscure, it is difficult to use these low dose incidences for quantitative risk assessment. Recently, the Scientific Committee on Food in the European Commission reassessed the food risk of bisphenol A, and set the provisional tolerable daily intake (TDI) as 10 μg/kg/day. The provisional TDI was calculated from the no adverse effect level as 50 mg/kg/day derived from a three generation study of rats, which detected no low dose reproductive toxicity. But the uncertainty factor for unresolved low dose effects by the limited database was used for the TDI derivation. Further investigation and research is necessary to resolve the uncertainties about the low dose and significance of the reported effects for human.
日本食品化学学会の論文
2003-05-23

ビスフェノールAの内分泌かく乱作用のヒトヘの健康影響評価

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