Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on cytochrome P450 1A1 and 1B1 gene expression in blood. (November 2016) - Wimmerová, Soňa
Abstract: Background: In the risk assessment of PCDDs, PCDFs, and dioxin-like (DL) PCBs, regulatory authorities support the use of the toxic equivalency factor (TEF)-scheme derived from a heterogeneous data set of the relative effect potency (REPs) estimates. Objectives: We sought to determine REPs for dioxin-like compounds (DLCs) using expression of cytochrome P450 ( CYP ) 1A1 and 1B1 mRNA in human peripheral blood mononuclear cells representing two different pathways. Methods: We used a sex and age adjusted regression-based approach comparing the strength of association between each DLC and the cytochrome P450 ( CYP ) 1A1 and 1B1 mRNA expression in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. Results: We calculated REPs based on CYP1A1 expression for 4 PCDDs, 8 PCDFs, and 1 PCB congener, and based on CYP1B1 expression for 5 PCDFs and 11 PCB congeners. REPs from CYP1A1 correlated with REPs previously derived from thyroid volume ( ρ = 0.85; p < 0.001) and serum FT4 ( ρ = 0.77; p = 0.009). The 13 log REPs from CYP1A1 correlated with log WHO-TEFs ( r = 0.63; p = 0.015) and 11 log PCB REPs with PCB consensus toxicity factors (CTFs) for compounds with WHO-TEFs ( r = 0.80; p = 0.003). The complete set of derived 56 log REPs correlated with the log CTFs ( r = 0.77; p = 0.001) and log WHO-TEFs ( r = 0.81; p < 0.001). Conclusions: REPs calculated from thyroid and cytochrome P450 endpoints realistically reflect human exposure scenarios because they are based on human chronic and low-dose exposures. While the CYP 1A1 seems more suitable for toxicity evaluation of PCDD/Fs, the CYP 1B1 is more apt for PCDFs and PCBs and reflects different pathways. Highlights: TEFs for assessment of health risks from dioxin-like compounds are regularly updated. Besides TEFs based on animal studies, we derived REPs based on human health outcomes. We used thyroid and cytochrome P450 ( CYP ) 1A1 and 1B1 gene expression endpoints in PBMC of exposed adults. REPs from CYP1A1 correlated with REPs derived from thyroid volume and serum FT4 outcomes. REPs based on chronic, low-dose exposure sustain validity of dioxin TEFs and reflect most human exposure scenarios.