Does rapid metabolism ensure negligible risk from bisphenol A?
Does rapid metabolism ensure negligible risk from bisphenol A?
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DOI：
10.1289/ehp.0901010
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发表时间：
2009-11
影响因子：
10.4
通讯作者：
Rice DC
中科院分区：
文献类型：
--
作者：
Ginsberg G;Rice DC
许多监管机构正在评估双酚A（BPA）的风险，因为双酚A（BPA）的暴露范围很广，并且低剂量时存在潜在毒性。我们评估了BPA在人类中比在大鼠中清除更快的证据，与BPA风险评估有关。欧洲食品安全局（EFSA）根据药代动力学证据得出结论，啮齿动物毒性数据与人类风险评估没有直接关系。此外，EFSA认为，由于孕妇的BPA葡萄糖醛酸化或新生儿的硫酸化，快速代谢将导致围产期的暴露可忽略不计。这些论点没有考虑子宫内BPA葡萄糖醛酸苷通过β-葡萄糖醛酸苷酶的解结合，β-葡萄糖醛酸苷酶是一种在胎盘和各种其他组织中存在高浓度的酶。此外，芳基硫酸酯酶C，它重新激活内源性硫酸化雌激素，在生命早期发展，因此可能在新生儿中解偶联BPA硫酸盐。生物监测研究和实验室实验记录了大鼠和人类母体、胎盘和胎儿组织中的游离BPA，表明人类BPA暴露不可忽略。这些检测的模式与胎盘中的去结合一致，导致胎儿暴露。EFSA设定的每日耐受摄入量（0.05 mg/kg/天）远高于一些动物研究报告的效应水平。这种潜在风险不应基于不确定的药代动力学参数而被排除。相反，风险评估人员需要破译BPA的剂量反应，并将其应用于人类的综合药代动力学模型，解释代谢物的解偶联。
Bisphenol A (BPA) risks are being evaluated by many regulatory bodies because exposure is widespread and the potential exists for toxicity at low doses. We evaluated evidence that BPA is cleared more rapidly in humans than in rats in relation to BPA risk assessment. The European Food Safety Authority (EFSA) relied on pharmacokinetic evidence to conclude that rodent toxicity data are not directly relevant to human risk assessment. Further, the EFSA argues that rapid metabolism will result in negligible exposure during the perinatal period because of BPA glucuronidation in pregnant women or sulfation in newborns. These arguments fail to consider the deconjugation of BPA glucuronide in utero by β-glucuronidase, an enzyme that is present in high concentrations in placenta and various other tissues. Further, arylsulfatase C, which reactivates endogenous sulfated estrogens, develops early in life and so may deconjugate BPA sulfate in newborns. Biomonitoring studies and laboratory experiments document free BPA in rat and human maternal, placental, and fetal tissues, indicating that human BPA exposure is not negligible. The pattern of these detections is consistent with deconjugation in the placenta, resulting in fetal exposure. The tolerable daily intake set by the EFSA (0.05 mg/kg/day) is well above effect levels reported in some animal studies. This potential risk should not be dismissed on the basis of an uncertain pharmacokinetic argument. Rather, risk assessors need to decipher the BPA dose response and apply it to humans with comprehensive pharmacokinetic models that account for metabolite deconjugation.