Differential relative effect potencies of some dioxin-like compounds in human peripheral blood lymphocytes and murine splenic cells.
Human risk assessment for dioxin-like compounds is typically based on the concentration measured in blood serum multiplied by their assigned toxic equivalency factor (TEF). Consequently, the actual value of the TEF is very important for accurate human risk assessment. In this study we investigated the effect potencies of three polychlorinated dibenzo-p-dioxins (PCDDs), six polychlorinated dibenzofurans (PCDFs) and 10 polychlorinated biphenyls (PCBs) relative to the reference congener 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) in in vitro exposed primary human peripheral blood lymphocytes (PBLs) and mouse splenic cells. REPs were determined based on cytochrome P450 (CYP) 1A1, 1B1 and aryl hydrocarbon receptor repressor (AhRR) gene expression as well as CYP1A1 activity in human PBLs and Cyp1a1 gene expression in murine splenic cells. Estimated median human REPs for 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (1234678-HpCDD), 2,3,4,7,8,-pentachlorodibenzofuran (23478-PeCDF), 1,2,3,4,7,8-hexachlorodibenzofuran (123478-HxCDF) and 1,2,3,4,7,8,9-heptachlorodibenzofuran (1234789-HpCDF) were with 0.1, 1.1, 1 and 0.09, respectively, significantly higher compared to those estimated for mouse with REPs of 0.05, 0.45, 0.09 and 0.04, respectively. Opposite to these results, the estimated median human REP of 3,3',4,4',5-pentachlorobiphenyl (PCB 126), was with 0.001 30-fold lower compared to the mouse REP of 0.03. Furthermore, human REPs for 1234678-HpCDD, 23478-PeCDF, 123478-HxCDF, 1234789-HpCDF and PCB 126 were all outside the ± half log uncertainty range that is taken into account in the WHO-assigned TEFs. Together, these data show congener- and species-specific differences in REPs for some, but not all dioxin-like congeners tested. This suggests that, more emphasis should be placed on human-tissue derived REPs in the establishment of a TEF for human risk assessment.
Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands. Electronic address: k.i.vanede@uu.nl.
Karin I
KI
van Ede
Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands. Electronic address: konrad_gaisch@yahoo.co.uk.
Konrad P J
KP
Gaisch
Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands. Electronic address: m.vandenberg@uu.nl.
Martin
M
van den Berg
Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, 3584 CM Utrecht, The Netherlands. Electronic address: m.vanduursen@uu.nl.
Majorie B M
MB
van Duursen
D000328:Adult; D000368:Aged; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D001572:Benzofurans / Q000633:toxicity; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D000072338:Dibenzofurans, Polychlorinated; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D013045:Species Specificity; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism; D018675:Toxicity Tests; D055815:Young Adult
D001189:Aryl Hydrocarbon Hydroxylases; D051792:Basic Helix-Loop-Helix Proteins; D001572:Benzofurans; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D000072338:Dibenzofurans, Polychlorinated; D004147:Dioxins; D004785:Environmental Pollutants; D011078:Polychlorinated Biphenyls; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C484722:Ahr protein, mouse; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse
Dibenzodioxins; Dibenzofurans; Lymphocytes; PCBs; REPs; Risk assessment