Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8-pentachlorodibenzofuran.
The concentration dose response for aryl hydrocarbon receptor (AHR)-mediated CYP1A1 and CYP1A2 messenger RNA (mRNA) induction and enzyme activity was determined in primary cultures of rat and human hepatocytes for 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 2,3,7,8-tetrachlorodibenzofuran. Eleven different congener concentrations from 0.00001 to 100 nM were used, thus spanning seven orders of magnitude. The Hill model was used to obtain values of EC(x) and maximal response from the individual data sets. No-observed effect concentration values were derived using several statistical methods including Dunnett's test, the Welch-Aspin test, and step-down bilinear regression. Thresholds were estimated using baseline projection methods and a "hockey stick" fitting method. Human hepatocytes were less responsive and less sensitive with respect to CYP1A1 activity and mRNA induction than rats. On the other hand, the human CYP1A2 response was more robust than the response in rats but generally less sensitive. These data allow an evaluation of relative species sensitivities for developing interspecies toxicodynamic adjustment factors, for assessing AHR activation thresholds, and for evaluating relative congener potencies. Overall, these data support the position that humans are less sensitive than rats to these AHR-dependent end points and support the use of a data-derived adjustment factor of 1.0 or less for extrapolating between rats and humans.
Budinsky
Robert A
RA
The Dow Chemical Company, Midland, Michigan 48674, USA. rbudinsky@dow.com
LeCluyse
Edward L
EL
Ferguson
Stephen S
SS
Rowlands
J Craig
JC
Simon
Ted
T
D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018570:Risk Assessment; D013045:Species Specificity
D001572:Benzofurans; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C038890:2,3,4,7,8-pentachlorodibenzofuran; C014211:2,3,7,8-tetrachlorodibenzofuran