title: Analysis of the CYP1A1 mRNA dose-response in human keratinocytes indicates that relative potencies of dioxins, furans, and PCBs are species and congener specific.
abstract: Reports indicate that toxic equivalency factors (TEFs) based primarily on rodent data do not accurately predict in vitro human responsiveness to certain dioxin-like chemicals (DLCs). To investigate this in cells responsive to dioxins and relevant to chloracne, normal human epidermal keratinocytes were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and several DLCs, each with a TEF value of 0.1, representing three classes of congeners. We estimated half maximal effective concentration (EC50)-based donor-specific relative potency (REP) values for cytochrome P450 1A1 (CYP1A1) messenger RNA (mRNA) induction for TCDD, 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,6,7,8-hexachlorodibenzofuran (HxCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126). We also determined EC50-based population-level REP values (n = 4) for CYP1A1 mRNA induction for TCDD, HxCDF, and PCB 126. Furthermore, an alternative factor, the relative threshold factor (RTF) based on the low end (threshold) of the dose-response curve, was calculated. Our results demonstrated that HxCDF had a population-based REP value of 0.98, 9.8-fold higher than its assigned TEF value of 0.1. Conversely, PCB 126 had an REP value of 0.0027 and an RTF of 0.0022, 37-fold and 45-fold less than its assigned TEF of 0.1, respectively. The REP values for HxCDD and TCDF were 0.24 and 0.10, respectively, similar to their assigned value of 0.1. Therefore, although the DLCs tested in the current study all possessed the same assigned TEF value of 0.1, congener-specific differences in REPs and RTFs were observed for human keratinocytes. These congener-specific discrepancies are likely because of differences in interspecies factors that have yet to be defined.
authors.affiliation: Department of Biological Sciences and W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee 38152-3560, USA. csutter@memphis.edu
authors.forename: Carrie H
authors.initials: CH
authors.lastname: Sutter
authors.forename: Sridevi
authors.initials: S
authors.lastname: Bodreddigari
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Sutter
authors.forename: Erik A
authors.initials: EA
authors.lastname: Carlson
authors.forename: Jay B
authors.initials: JB
authors.lastname: Silkworth
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity
chemical_list: D001572:Benzofurans; D004147:Dioxins; D004785:Environmental Pollutants; D012333:RNA, Messenger; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; C023035:3,4,5,3',4'-pentachlorobiphenyl
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