Kodavanti P R, Ward T R
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Environ Health Perspect. 1998 Aug;106(8):479-86. doi: 10.1289/ehp.98106479.
Polychlorinated biphenyls (PCBs) are persistent contaminants that exist as complex mixtures in the environment. One problem faced by risk assessors is that the possible interactive effects of specific PCB congeners and related chemicals found in environmental and biological samples have not been systematically investigated. Some PCBs perturb Ca2+ homeostasis and cause protein kinase C (PKC) translocation in neuronal cell cultures and in brain homogenate preparations at concentrations where no cytotoxicity is observed, and these systems are necessary for the growth and normal functioning of neurons. The changes in second messenger systems appear to be associated with the extent of noncoplanarity of the PCB molecule. We studied the interactive effects of selected PCB congeners, a PCB metabolite, and a dioxin on PKC translocation, as determined by [3H]phorbol ester binding in cerebellar granule cells. The binary combinations included coplanar and noncoplanar PCB congeners or PCB congeners with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/PCB metabolite. In addition, we tested the interactive effects of several PCB congeners (three or more) found in environmental samples such as human milk and blood, contaminated fish, and brain samples from PCB-treated animals. The results indicated that 1) the coplanar congener [3,3',4, 4'-tetrachlorobiphenyl (TeCB)] did not alter the in vitro activity of the noncoplanar (2,2',5,5'-TeCB) or coplanar [4, 4'-dichlorobiphenyl (DCB)] congeners; 2) binary mixtures of active PCB congeners (2,2',4,4'-TeCB and 2,2'-DCB; 2,2'-DCB and 3,5-DCB; 2,2',3,5',6-PeCB and 2,2',4,4',5-PeCB) interact in a dose-additive manner; 3) TCDD did not alter the activity of either coplanar (3,3', 4,4'-TeCB) or noncoplanar (2,2',5,5'-TeCB) congeners; 4) the interaction between the parent PCB congener and hydroxy metabolite of PCB is additive; 5) PCB congener mixtures at the ratios found in environmental samples are biologically active; and 6) there was no indication of synergism in any of the combinations studied. These results suggest that the biological effects of binary mixtures of PCB congeners fit a dose-additive model, indicating that there is a specific site of action for these PCB congeners which is independent of the aryl hydrocarbon receptor. Environmental mixtures contain mostly noncoplanar PCB congeners, and because they appear to be biologically active, the potential human health risk by this group of chemicals should be considered in the risk assessment of PCBs.
多氯联苯（PCBs）是持久性污染物，在环境中以复杂混合物的形式存在。风险评估人员面临的一个问题是，尚未系统地研究环境和生物样品中特定多氯联苯同系物与相关化学物质可能的相互作用。在神经元细胞培养物和脑匀浆制剂中，某些多氯联苯在未观察到细胞毒性的浓度下会扰乱Ca2+稳态并导致蛋白激酶C（PKC）易位，而这些系统对于神经元的生长和正常功能是必需的。第二信使系统的变化似乎与多氯联苯分子的非共面程度有关。我们研究了选定的多氯联苯同系物、一种多氯联苯代谢物和一种二噁英对PKC易位的相互作用，这是通过在小脑颗粒细胞中[3H]佛波酯结合来确定的。二元组合包括共面和非共面的多氯联苯同系物或与2,3,7,8 - 四氯二苯并 - p - 二噁英（TCDD）/多氯联苯代谢物的多氯联苯同系物。此外，我们测试了在环境样品如人乳、血液、受污染的鱼类以及多氯联苯处理动物的脑样品中发现的几种多氯联苯同系物（三种或更多）的相互作用。结果表明：1）共面同系物[3,3',4,4'-四氯联苯（TeCB）]不会改变非共面（2,2',5,5'-TeCB）或共面[4,4'-二氯联苯（DCB）]同系物的体外活性；2）活性多氯联苯同系物（2,2',4,4'-TeCB和2,2'-DCB；2,2'-DCB和3,5-DCB；2,2',3,5',6-五氯联苯和2,2',4,4',5-五氯联苯）的二元混合物以剂量相加的方式相互作用；3）TCDD不会改变共面（3,3',4,4'-TeCB）或非共面（2,2',5,5'-TeCB）同系物的活性；4）母体多氯联苯同系物与多氯联苯的羟基代谢物之间的相互作用是相加的；5）环境样品中发现的比例的多氯联苯同系物混合物具有生物活性；6）在所研究的任何组合中均未显示出协同作用的迹象。这些结果表明，多氯联苯同系物二元混合物的生物学效应符合剂量相加模型，表明这些多氯联苯同系物存在一个独立于芳烃受体的特定作用位点。环境混合物中大多是非共面的多氯联苯同系物，并且由于它们似乎具有生物活性，在多氯联苯的风险评估中应考虑这组化学物质对人类健康的潜在风险。
