AOPs Including This Stressor
Events Including This Stressor
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The promiscuous nature of the AHR with its ability to bind to a large number of endogenous and exogenous ligands, make the task of constructing an AOP a challenge. For example, many structurally diverse chemicals can bind to and activate the AHR, including dioxin-like chemicals (DLCs), polyaromatic hydrocarbons (PAHs), indole-3-carbinol as found in broccoli and Brussels sprouts, natural flavonoids such as quercetin, galangin and genistein, and endogenous ligands such as indirubicin, equilenin, metabolites of arachidonic acid, heme, tryptophan, and UV photoproducts of tryptophan such as 6-formylindolo[3,2-b]carbazole (FICZ)   
It is believed, although not proven, that the endogenous and natural ligands ingested in the diet participate in normal homeostatic control of development and physiology through episodic and short-lived AHR activation. Developmental pathologies in AHR knockout rodents and toxicity associated with sustained AHR activation provide evidence that the AHR has a normal and necessary role.   Weak agonists also include benzimidazoles such as omeprazole used pharmaceutically as a proton pump inhibitor and antihelminthics such as thiabendazole. Other weak agonists include primaquine, vinclozolin, YH439, phenylthiourea, curcumin and Oltipraz.  Therefore, a necessary task for this AOP is to differentiate between AHR ligands that act as rodent liver tumour promoters and those that do not. It may be that ligands resistant to metabolic clearance (e.g., TCDD), or sufficiently high doses of rapidly cleared ligands are able to create the sustained AHR activation required to bring about tumour promotion.
Chemical properties for a selection of AHR ligands are provided in Table 3 along with EC50, which itself is a measure of potency and one of the determinants of sustained AHR activation. These representative ligands demonstrate the diversity in chemical properties modelling pharmacokinetics and bioavailability as well as sources, including anthropogenic chemicals, dietary constituents, and endogenous substances formed in vivo. The determinants of sustained AHR activation include:
- AHR binding potency, usually measured by an EC50 or ED50 value;
- AHR binding efficacy or intrinsic activity measured by the maximal response;
- pharmacokinetic determinants including,
- Speed and extent of metabolism/elimination of a particular ligand;
- Delivery to the target tissue; and,
- Magnitude and duration of exposure.
Not all AHR ligands will produce sustained activation. Some ligands may stabilize the AHR, thus keeping it activated for longer times.  DLCs are highly hydrophobic and lipid soluble with half-lives in humans up to seven years or more.  Hence, a single high-dose exposure to a highly persistent compound such as TCDD can lead to sustained AHR activation sufficient to trigger some of the early responses.  In rodents, some of these high-dose responses may lead to the occurrence of KEs.  Exposure to lower doses over a long time may also produce sustained activation but may not culminate in increased tumour incidence.  Endogenous ligands have very different chemical characteristics than halogenated dibenzo-p-dioxins, dibenzofurans, and dioxin-like PCBs. The endogenous ligand FICZ is a more potent AHR agonist than TCDD but is rapidly metabolized by CYP1A1 in a negative feedback loop. As noted, control of AHR activation by endogenous ligands probably plays a role in development.   Ideally, a table similar to Table 3 could be assembled with data on a range of diverse chemicals with results from common assays providing measures of potency, efficacy and metabolism. This information set may be of some utility in predicting the likelihood of a particular chemical to produce sustained AHR activation (the MIE). However, the use of structural alerts or QSAR considerations to predict the occurrence of the MIE remains an area of interest and may become more feasible in the future.
Characterization of Exposure
Generally, AHR ligands are relatively large molecules with hydrophobic nature. Hence, these compounds have low volatility and are poorly absorbed through the skin. Therefore, the assumed route of exposure for this AOP is oral. The primary source of dioxin exposure in humans is animal-based food products, and the dioxin levels in foods have been declining over time.     The dose of PCDD/Fs from dietary exposure can be expressed as TCDD toxic equivalents or TEQ.  Worldwide, this exposure has been estimated at less than 1 pg TEQ/kg/d.   Exposures may be somewhat higher in populations consuming relatively more fish and shellfish.  Exposure to the remaining universe of exogenous and endogenous AHR ligands is not nearly as well characterised as is exposure to DLCs. A sampling of this universe consists of food products, substances in commercial and consumer products, phytoestrogens, prostaglandins, catechins in green tea, bilirubin and biliverdin, tryptophan, and its metabolites.                    Substantial AHR-activity has been reported in human serum and likely reflects many endogenous and naturally occurring AHR ligands from the diet.  The high level of background TEQ may serve as a ModF for the tumour promotion response to sustained AHR activation initiated by sufficient dosages of chlorinated dibenzo-p-dioxins, dibenzofurans and dioxin-like PCBs.
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