The Toxic Equivalency Factor (TEF) approach is a methodology that assigns relative toxicity values to structurally related chemicals in comparison to a reference chemical. For the polychlorinated dibenzo-p-dioxins (PCDDs), the reference is the most potent congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we critically review the literature on the effects of a weak PCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD), and describe the uncertainties of assigning its TEF. PCDDs, including OCDD, are less potent in human cell models compared to the rat models from which the TEF are estimated. This lack of concordance is even more pronounced with the weaker congeners such as OCDD. Furthermore, OCDD is also likely to compete with TCDD for binding to cytochrome P4501A2 (CYP1A2), effectively decreasing the hepatic tissue/fat ratio of TCDD. Overall, the predictive value of TEFs would be improved by incorporating into this number the relative sensitivity of human cell responses compared to rodent responses, by determining the toxicological effects of altering the tissue distribution of dioxin-like compounds through competition for CYP-binding sites, and by understanding the mechanism of cancer causation of any dioxin and whether this mechanism is conserved in humans and at equivalent doses.