SAR of Nongenotoxic Carcinogens

By far the most extensively stodied mechanism of epigenetic carcinogens is receptor-mediated cell proUfoation. Xenobiotic ligand-induced activation of sevaal 

Structure can be observed by the loss of dioxin-like activities of PCBs with ring substitution(s) at one or more of the ortho (2,2 6,6 -) position(s) which can lead to distortion from planar structure. Subsequent AhR binding data indicated that polychlorinated dibenzofuran congeners have binding activity similar to that of their dibenzo-p-dioxin counterparts (Woo and Lai 2003). 

These SAR considerations have been captured in EPA s OncoLogic Cancer Expert System for predicting carcinogenic potential of chemicals completed in 1999-2000 (Woo and Lai 2005 Woo et al. 1995). In 2006, the NTP completed the cancer bioassay of a number of new congeners of polychlorinated dibenzofurans and PCBs. The results of these studies are summarized in the table below and compared to the OncoLogic predictions. As can be seen from the table, the mechanism-based SAR approach of the OncoLogic system allowed the system to accurately predict the carcinogenic activities. 

NTPTR Chemical Agent NTP Bioassay Result in Female Rats OncoLogic Prediction  

The human relevance of PPARa-mediated rodent hapatocarcmogenesis has been a subject of intensive debate for more than a decade. Whoeas the relevancy cannot be totally disregarded, considering the totality of the evidence, most regulatory agencies are supportive of the conclusion that this mechanism is not relevant to humans (lARC 1994 Klaunig et al. 2003 Lai 2004). Nevertheless, the SAR features mentioned above can be effectively used to interpret rodent cancer data and assess the significance of human cancer risk. 

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