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.

Chronic exposure of Sprague-Dawley (SD) rats to either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or Aroclor 1254 results in female-selective induction of hepatic tumors. The relative potency of dioxins and polychlorinated biphenyl mixtures, such as Aroclor 1254, is often estimated using the internationally endorsed toxic equivalency (TEQ) approach. Comparing the genome wide changes in gene expression in both genders following exposure to TEQ doses of these chemicals should identify critical sets of early response genes while further defining the concept of the TEQ of halogenated aromatic hydrocarbons. Aroclor 1254 at 0.6, 6.0, and 60 mg/kg body weight and TEQ doses of TCDD (0.3 and 3.0 mug/kg), calculated to match the top two Aroclor 1254 doses, were orally administered to SD rats for three consecutive days. Day 4 gene expression in hepatic tissue was determined using microarrays. A linear mixed-effects statistical model was developed to analyze the data in relation to treatment, gender, and gender * treatment (G*T) interactions. The genes most changed included 54 genes with and 51 genes without a significant model G*T term. The known aryl hydrocarbon receptor (AHR) battery genes (Cyp1a1, Cyp1a2, Cyp1b1, Aldh3a1), and novel genes, responded in a TEQ dose-dependent manner in both genders. However, an important observation was the apparent disruption of sexually dimorphic basal gene expression, particularly for female rats. Because many of these genes are involved in steroid metabolism, exposure to either TCDD or Aroclor 1254 could disrupt proliferative signals more in female rats as a possible consequence of altered estrogen metabolism. This study extends the findings of previous rodent bioassays by identifying groups of genes, other than the well-characterized AHR response genes, whose disruption may be important in the tumorigenic mechanism in this rat strain.