Verner Marc-André, Ayotte Pierre, Muckle Gina, Charbonneau Michel, Haddad Sami
Département des sciences biologiques, Centre Toxen, Université du Québec à Montréal, and Centre de recherche du Hospitalier Universitaire de Québec, Montréal, Québec, Canada.
Environ Health Perspect. 2009 Mar;117(3):481-7. doi: 10.1289/ehp.0800047. Epub 2008 Nov 10.
It has been suggested that pre- and postnatal exposure to persistent organic pollutants (POPs) can promote several adverse effects in children, such as altered neurodevelopment. Epidemiologic studies to date have relied on the analysis of biological samples drawn pre- or post-natally for exposure assessment, an approach that might not capture some key events in the toxicokinetics of POPs.
We aimed to build a generic physiologically based pharmacokinetic (PBPK) modeling framework for neutral POPs to assess infant toxicokinetic profiles and to validate the model using data on POP levels measured in mothers and infants from a Northern Québec Inuit population.
The PBPK model developed herein was based upon a previously published model to which an infant submodel was added. Using the model and maternal blood levels at the time of delivery, exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT), hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), 2,2',3,4,4',5'-hexachlorobiphenyl (PCB-138), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), and 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB-180) in mothers was estimated to subsequently simulate infant blood, breast milk, and cord blood POP concentration. Simulations were then compared with corresponding measured levels through Spearman correlation analyses.
Predictions were highly correlated with measured concentrations for PCB-153, PCB-180, PCB-138, HCB, and p,p'-DDE (r = 0.83-0.96). Weaker correlations were observed for p,p'-DDT and beta-HCH for which levels were near the limits of detection.
This is the first study to validate a PBPK model of POPs in infants on an individual basis. This approach will reduce sampling efforts and enable the use of individualized POP toxicokinetic profiles in the epidemiologic studies of POP adverse effects on child development.
有研究表明，产前和产后接触持久性有机污染物（POPs）会对儿童产生多种不良影响，如神经发育改变。迄今为止的流行病学研究依赖于分析产前或产后采集的生物样本以评估接触情况，这种方法可能无法捕捉到POPs毒代动力学中的一些关键事件。
我们旨在构建一个通用的基于生理的中性POPs药代动力学（PBPK）建模框架，以评估婴儿的毒代动力学特征，并使用来自魁北克北部因纽特人群母亲和婴儿的POPs水平数据验证该模型。
本文开发的PBPK模型基于之前发表的模型，并添加了婴儿子模型。利用该模型和分娩时母亲的血液水平，估计母亲对1,1-二氯-2,2-双（对氯苯基）乙烯（p,p'-DDE）、1,1,1-三氯-2,2-双（对氯苯基）乙烷（p,p'-DDT）、六氯苯（HCB）、β-六氯环己烷（β-HCH）、2,2',3,4,4',5'-六氯联苯（PCB-138）、2,2',4,4',5,5'-六氯联苯（PCB-153）和2,2',3,4,4',5,5'-七氯联苯（PCB-180）的接触情况，随后模拟婴儿血液、母乳和脐带血中的POPs浓度。然后通过Spearman相关分析将模拟结果与相应的测量水平进行比较。
对于PCB-153、PCB-180、PCB-138、HCB和p,p'-DDE，预测值与测量浓度高度相关（r = 0.83 - 0.96）。对于p,p'-DDT和β-HCH，相关性较弱，其水平接近检测限。
这是第一项在个体基础上验证婴儿POPs的PBPK模型的研究。这种方法将减少采样工作量，并能够在POPs对儿童发育不良影响的流行病学研究中使用个性化的POPs毒代动力学特征。
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