Department of Occupational and Environmental Health, School of Public Health, Université de Montréal, Montreal, Canada; Université de Montréal Public Health Research Institute (IRSPUM), Montreal, Canada; Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Agency for Toxic Substances and Disease Registry, Atlanta, GA, USA.
Environ Int. 2018 Feb;111:260-267. doi: 10.1016/j.envint.2017.12.019. Epub 2018 Jan 8.
Multiple agencies have developed health-based toxicity values for exposure to perfluorooctanoic acid (PFOA). Although PFOA exposure occurs in utero and through breastfeeding, current health-based toxicity values have not been derived using fetal or child dosimetry. Therefore, current values may underestimate the potential risks to fetuses and nursing infants.
Using fetal and child dosimetry, we aimed to calculate PFOA maternal human equivalent doses (HEDs), corresponding to a developmental mouse study lowest observed adverse effect level (LOAEL, 1mg/kg/day). Further, we investigated the impact of breastfeeding duration and PFOA half-life on the estimated HEDs.
First, a pharmacokinetic model of pregnancy and lactation in mice was used to estimate plasma PFOA levels in pups following a maternal exposure to 1mg PFOA/kg/day for gestational days 1-17. Four plasma PFOA concentration metrics were estimated in pups: i) average prenatal; ii) average postnatal; iii) average overall (prenatal and postnatal); and iv) maximum. Then, Monte Carlo simulations were performed using a pharmacokinetic model of pregnancy and lactation in humans to generate distributions of maternal HEDs that would result in fetal/child plasma levels equivalent to those estimated in pups using the mouse model. Median (HED) and 1st percentile (HED) of calculated HEDs were calculated.
Estimated PFOA maternal HEDs ranged from 3.0×10 to 1.1×10mg/kg/day and HEDs ranged from 4.7×10 to 2.1×10mg/kg/day. All calculated HEDs were lower than the HED based on adult dosimetry derived by the Environmental Protection Agency (EPA) (5.3×10mg/kg/day).
Our results suggest that fetal/child dosimetry should be considered when deriving health-based toxicity values for potential developmental toxicants.
多个机构已经制定了基于健康的毒理学值，以评估接触全氟辛酸（PFOA）的毒性。尽管 PFOA 的暴露发生在子宫内和通过母乳喂养期间，但目前的基于健康的毒理学值并未使用胎儿或儿童剂量学来推导。因此，目前的数值可能低估了对胎儿和哺乳期婴儿的潜在风险。
我们使用胎儿和儿童剂量学来计算 PFOA 的母体人类等效剂量（HED），相当于发育毒理学研究中的最低观察到不良效应水平（LOAEL，1mg/kg/天）。此外，我们还研究了哺乳期持续时间和 PFOA 半衰期对估计 HED 的影响。
首先，我们使用小鼠妊娠和哺乳期的药代动力学模型来估计母体在妊娠第 1 天至第 17 天每天暴露于 1mg PFOA/kg 后，幼仔的血浆 PFOA 水平。在幼仔中估计了四个血浆 PFOA 浓度指标：i）平均产前；ii）平均产后；iii）总平均值（产前和产后）；和 iv）最大值。然后，我们使用人类妊娠和哺乳期的药代动力学模型进行蒙特卡罗模拟，以生成会导致胎儿/儿童血浆水平与使用小鼠模型估计的幼仔血浆水平相当的母体 HED 分布。计算出的 HED 的中位数（HED）和第 1 百分位数（HED）。
估计的 PFOA 母体 HED 范围为 3.0×10 至 1.1×10mg/kg/天，HED 范围为 4.7×10 至 2.1×10mg/kg/天。所有计算出的 HED 均低于环境保护署（EPA）基于成人剂量学推导的 HED（5.3×10mg/kg/天）。
我们的研究结果表明，在推导潜在发育毒性物质的基于健康的毒理学值时，应考虑胎儿/儿童剂量学。
