Globally, biomonitoring data demonstrate virtually all humans carry residues of multiple per- and polyfluoroalkyl substances (PFAS). Despite pervasive co-exposure, limited mixtures-based in vivo PFAS toxicity research has been conducted. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are commonly detected PFAS in human and environmental samples and both produce adverse effects in laboratory animal studies, including maternal and offspring effects when orally administered during pregnancy and lactation. To evaluate the effects of combined exposure to PFOA and PFOS, we orally exposed pregnant Sprague-Dawley rats from gestation day 8 (GD8) to postnatal day 2 (PND2) to PFOA (10–250 mg/kg/d) or PFOS (0.1–5 mg/kg/d) individually to characterize effects and dose response curve parameters, followed by a variable-ratio mixture experiment with a constant dose of PFOS (2 mg/kg/d) mixed with increasing doses of PFOA (3–80 mg/kg/d). The mixture study design was intended to: 1) shift the PFOA dose response curves for endpoints shared with PFOS, 2) allow comparison of dose addition (DA) and response addition (RA) model predictions, 3) conduct relative potency factor (RPF) analysis for multiple endpoints, and 4) avoid overt maternal toxicity. Maternal serum and liver concentrations of PFOA and PFOS were consistent between the individual chemical and mixture experiments. Combined exposure with PFOS significantly shifted the PFOA dose response curves towards effects at lower doses compared to PFOA-only exposure for multiple endpoints and these effects were well predicted by dose addition. For endpoints amenable to mixture model analyses, DA produced equivalent or better estimates of observed data than RA. All endpoints evaluated were accurately predicted by RPF and DA approaches except for maternal gestational weight gain, which produced less-than-additive results in the mixture. Data support the hypothesis of cumulative effects on shared endpoints from PFOA and PFOS co-exposure and dose additive approaches for predictive estimates of mixture effects.

在全球范围内，生物监测数据表明几乎所有人类都携带多种全氟烷基物质和多氟烷基物质 (PFAS) 残留物。尽管共同暴露现象普遍存在，但基于混合物的体内PFAS 毒性研究仍然有限。全氟辛酸 (PFOA) 和全氟辛烷磺酸 (PFOS) 是人类和环境样本中常见的 PFAS，它们都会在实验动物研究中产生不良影响，包括在怀孕和哺乳期间口服给药时对母体和后代的影响。为了评估联合暴露于 PFOA 和 PFOS 的影响，我们将妊娠 Sprague-Dawley 大鼠从妊娠第 8 天 (GD8) 到出生后第 2 天 (PND2) 经口暴露于 PFOA (10–250 mg/kg/d) 或 PFOS (0.1 –5 mg/kg/d) 分别表征效果和剂量响应曲线参数，然后进行可变比例混合实验，将恒定剂量的 PFOS (2 mg/kg/d) 与递增剂量的 PFOA (3-80毫克/公斤/天）。混合物研究设计的目的是：1) 改变与 PFOS 共享终点的 PFOA 剂量反应曲线，2) 比较剂量添加 (DA) 和反应添加 (RA) 模型预测，3) 进行相对效力因子 (RPF)多终点分析，4) 避免明显的母体毒性。在各个化学实验和混合物实验中，PFOA 和 PFOS 的母体血清和肝脏浓度是一致的。与仅暴露于多个终点的 PFOA 相比，与 PFOS 联合暴露显着地将 PFOA 剂量反应曲线转向较低剂量的效应，并且通过剂量添加可以很好地预测这些效应。对于适合混合模型分析的终点，DA 产生了与 RA 相同或更好的观测数据估计。 所有评估的终点均通过 RPF 和 DA 方法准确预测，但母亲妊娠体重增加除外，这在混合物中产生的结果低于相加结果。数据支持 PFOA 和 PFOS 共同暴露对共同终点的累积效应假设，以及用于预测估计混合物效应的剂量添加方法。