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ToxSci Advance Access originally published online on July 27, 2005
Toxicological Sciences 2005 87(2):508-519; doi:10.1093/toxsci/kfi261
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Comparison of TCDD and PCB CYP1A Induction Sensitivities in Fresh Hepatocytes from Human Donors, Sprague-Dawley Rats, and Rhesus Monkeys and HepG2 Cells

Jay B. Silkworth*,1, Aruna Koganti{dagger}, Kati Illouz*, Antonio Possolo*, Ming Zhao* and Stephen B. Hamilton{ddagger}

* General Electric Company, Global Research Center, One Research Circle, Niskayuna, New York 12309; {dagger} In Vitro Technologies, Inc., Baltimore, Maryland 21227; and {ddagger} General Electric Company, Fairfield, Connecticut 06431

Received July 4, 2005; accepted July 13, 2005

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals induce cytochrome P450 1A (CYP1A) gene expression and, at sufficient exposures, cause toxicity. Human health risks from such exposures are typically estimated from animal studies. We tested whether animal models predict human sensitivity by characterizing CYP1A gene expression in cultures of fresh hepatocytes from human donors, rats, and rhesus monkeys and HepG2 human hepatoma cells. We exposed the cells to three aryl hydrocarbon receptor (AhR) ligands of current environmental interest and measured 7-ethoxyresorufin-O-deethylase (EROD) activity and concentrations of CYP1A1 and CYP1A2 mRNA. We found that human cells are about 10–1000 times less sensitive to TCDD, 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and Aroclor 1254 than rat and monkey cells, that relative potencies among these chemicals are different across species, and that gene expression thresholds exist for these chemicals. Newly calculated rat–human interspecies relative potency factors for PCB 126 were more than 100 times lower than the current rodent-derived value. We propose that human-derived values be used to improve the accuracy of estimates of human health risks.

Key Words: polychlorinated biphenyls; PCB; TCDD; dioxin; dioxin equivalents; TEQ; relative potency factors; human hepatocytes; HepG2 cells; cytochrome P450 1A; CYP1A1; CYP1A2; risk assessment.


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