Activation, Long term AHR receptor driven direct and indirect gene expression changes leads to N/A, Hepatotoxicity, Hepatopathy, including a constellation of observable effects

It is not exactly known just how sustained AHR activation leads to hepatotoxicity. Nonetheless, the constellation of different histopathological alterations included in toxic hepatopathy are highly associated with tumor formation (Simon et al. 2009).

Figure 4: Indirect key event relationships. Sustained AHR activation was identified as the MIE and determined as the product of fractional AHR activation measured by CYP1A1 induction and time in weeks. The frequency of histopathology and tumors observed in rats in the NTP bioassays was plotted against sustained AHR activation. A) Relationships between the MIE and aspects of KE2 (hepatopathy and hyperplasia; all response shown as filled circles). B) Relationships between the MIE and the two tumor types representing the adverse outcome (AO) (responses shown as an X). The Hill coefficients, BMD21 and TDV21 values are shown in the table below. The values shown as open circles in the two plots in B show tumor responses in animals in the stop-exposure group that were exposed to the maximum DLC concentration for 31 weeks (see text for discussion). In each plot in B, three values, one each for TCDD, 4-PeCDF and PCB-126, are shown for the stop-exposure experiments and only two are not obscured by the other responses. The numerical ESA50 values are the half-maximal level of sustained AHR activation similar to an EC50 and described in the text.

The quantitative KER linking the sustained AHR activation to Hepatotoxicity/Hepatopathy is shown in Fig. 4 at the left. Indirect key event relationships. Sustained AHR activation was identified as the MIE and determined as the product of fractional AHR activation measured by CYP1A1 induction and time in weeks. The frequency of histopathology and tumors observed in rats in the NTP bioassays was plotted against sustained AHR activation. A) Relationships between the MIE and aspects of Hepatotoxicity/Hepatopathy and Cellular Proliferation / Hyperplasia; all response shown as filled circles). B) Relationships between the MIE and the two tumor types representing the adverse outcome (AO) (responses shown as an X). The Hill coefficients, BMD21 and TDV21 values are shown in the table below. The values shown as open circles in the two plots in B show tumor responses in animals in the stop-exposure group that were exposed to the maximum DLC concentration for 31 weeks. In each plot in B, three values, one each for TCDD, 4-PeCDF and PCB-126, are shown for the stop-exposure experiments and only two are not obscured by the other responses. The numerical ESA50 values are the half-maximal level of sustained AHR activation similar to an EC50 and described in the text.Using methods described in Simon et al. (2014), the transitional dose values of the sustained AHR activation index based on a 21% response level are shown in the table below Here, the transitional dose value is the projection from the 21% response level to the background response level using the slope of the dose-response at this same 21% response level (Sand et al., 2006; Simon et al., 2014). While not definitive thresholds, transitional dose values based on the 21% response level can be used as an approximation of a threshold. As noted, toxic hepatopathy includes a constellation of effects and the transitional dose value has the lowest value of the three effects representing the Hepatotoxicity/Hepatopathy and the Cellular Proliferation / Hyperplasia.

Hill Model parameters and Transitional Dose Values (TDV) for Hepatotoxicity/Hepatopathy, Cellular Proliferation / Hyperplasia and the occurrence of Hepatocellular and Bile Duct Tumors based on the Quantitative Measure of the MIE or Sustained AHR Activation in ppb-weeks

ESA50 (Fig. 4) is similar to an EC50 - it is the effective level of sustained AHR activation necessary to achieve a 50% response. As described, the level of sustained AHR activation can be calculated by multiplying the fractional level of AHR activation measured by CYP1A1 induction by the number of weeks of dosing. Bile duct hyperplasia occurs at a higher level of sustained AHR activation and oval cell hyperplasia at an even higher level (Fig. 5A, middle and bottom plots). The dose-response for oval cell hyperplasia is much steeper than the other two histopathological effects that comprise KE#3. Although speculative, this higher level of sustained AHR activation needed for bile duct hyperplasia may be the reason why Kociba et al. (1978) failed to observe bile duct tumors whereas they were observed in NTP (2006a). Possibly, the distinction between the two studies may be that dosage regimen (diet vs. gavage) or changes in the Sprague-Dawley strain over time. In the rats used in Kociba et al. (1978), the degree of sustained AHR activation needed for promotion of bile duct tumors may not have been achieved.

The relationship between Hepatoxicity/Hepatopathy and downstream KEs of Cellular Proliferation / Hyperplasia and Hepatocellular and Bile Duct Tumors does not appear to occur in humans; however, a comprehensive assessment of this KER in humans has not been conducted in a fashion appropriate for this AOP.