The National Toxicology Program (NTP) carcinogenicity study will provide the experimental data needed to address the uncertainty regarding the use of Toxic Equivalency Factors (TEFs) to predict the carcinogenic potency of dioxin-like halogenated aromatic hydrocarbons (HAHs) in female Sprague-Dawley rats. The primary hypothesis of this proposal is that the target tissue dose dependent induction of hepatic cytochrome P-450 1A1 (CYP1A1), CYP1A2, and/or CYP1B1 by HAHs is related to the relative carcinogenic potencies of dioxin-like compounds, individually and in defined mixtures. Thus, similar studies of the target tissue dose dependent induction of CYP1A1, 1A2, and 1B1 in rat and human liver slices exposed in vitro to these HAHs in dynamic organ culture will provide for a better means to extrapolate experimental data from lab animals to humans. The proposed studies will utilize frozen liver tissue from the NTP cancer study and fresh precision-cut rat and human liver slices maintained in dynamic organ culture under conditions which will generate similar tissue levels of the HAHs to that obtained in the chronic NTP cancer study. The proposed studies will address the following specific experimental aims: 1. Assess the target tissue dose dependent induction of hepatic CYP1A1, CYP1A2, and CYP1B1 in female Sprague-Dawley rats following 52 weeks of exposure to the NTP test compounds, individually and in defined mixtures (all 7 exposure protocols). 2. Assess the uptake of the NTP test compounds from culture medium into precision cut rat and human liver slices maintained in dynamic organ culture. 3. Determine the target tissue dose-response relationships for the induction of CYP1A1, CYP1A2, and CYP1B1 in precision-cut rat and human liver slices exposed to the NTP test compounds, individually and in defined mixtures. The biochemical responses in aim one will be compared with NTP data on the target tissue dose and the carcinogenic potency of the HAHs in each of the 7 exposure protocols to address the primary hypothesis of this application. Biochemical and tissue dose data from in vitro rat liver slice studies in aim 2 and 3 will be compared with similar data obtained following in vivo exposure (aim 1) to further validate this in vitro model. Finally, the target tissue dose-response relationships for the induction of CYP1A1, CYP1A2, and CYP1B1 for these selected HAHs will be compared in rat and human liver slices to ultimately validate the use of TEFs for human cancer risk assessment.
| Ovando, Bladimir J; Ellison, Corie A; Vezina, Chad M et al. (2010) Toxicogenomic analysis of exposure to TCDD, PCB126 and PCB153: identification of genomic biomarkers of exposure to AhR ligands. BMC Genomics 11:583 |
| Ovando, Bladimir J; Vezina, Chad M; McGarrigle, Barbara P et al. (2006) Hepatic gene downregulation following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 94:428-38 |
| Vezina, Chad M; Walker, Nigel J; Olson, James R (2004) Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression. Environ Health Perspect 112:1636-44 |
