Jon Doering, Ph.D., National Research Council Postdoctoral Toxicologist, US EPA Mid-Continent Ecology Division, Duluth, MN, USA, doering.jonathan[at]epa.gov
Prof. Markus Hecker, Ph.D. University of Saskatchewan, Saskatoon, Saskatchewan, Canada, (markus.hecker[at]usask.ca
Dan Villeneuve, Ph.D., US EPA Mid-Continent Ecology Division, Duluth, MN, USA (villeneuve.dan[at]epa.gov)
Prof. Xiaowei Zhang, Ph.D., Nanjing University, School of the Environment, Nanjing, China (Zhangxw[at]nju.edu.cn)
Point of Contact
- Markus Hecker
- Jon Doering
- Dan Villeneuve
|Author status||OECD status||OECD project||SAAOP status|
|Open for comment. Do not cite||EAGMST Under Review||1.27||Included in OECD Work Plan|
This AOP was last modified on May 15, 2017 12:05
|Activation, AhR||June 12, 2017 15:14|
|dimerization, AHR/ARNT||September 16, 2017 10:14|
|Altered, Cardiovascular development/function||September 16, 2017 10:14|
|Increase, COX-2 expression||September 16, 2017 10:14|
|Increased, Mortality||May 15, 2017 11:34|
|Decreased, Population trajectory||April 18, 2017 16:19|
|Activation, AhR leads to dimerization, AHR/ARNT||June 08, 2017 11:32|
|dimerization, AHR/ARNT leads to Increase, COX-2 expression||May 09, 2017 16:30|
|Increase, COX-2 expression leads to Altered, Cardiovascular development/function||May 15, 2017 11:44|
|Altered, Cardiovascular development/function leads to Increased, Mortality||April 18, 2017 15:45|
|Activation, AhR leads to Increased, Mortality||May 17, 2017 16:28|
|Increased, Mortality leads to Decreased, Population trajectory||November 29, 2016 20:10|
|2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)||February 09, 2017 14:32|
|Polycyclic aromatic hydrocarbons (PAHs)||February 09, 2017 15:43|
This adverse outcome pathway details the linkage between activation of the aryl hydrocarbon receptor (AhR) and early life stage mortality in fishes. Fishes represent the most sensitive taxa to adverse effects resulting from activation of the AhR. Embryos are more sensitive than juvenile or adult fishes based on endpoints that could be of significance to population trends. This AOP can be initiated by a range of planar aromatic hydrocarbons, but is best known as the target of dioxin-like compounds (DLCs). These planar compounds are able to bind to the AhR causing heterodimerization with the aryl hydrocarbon nuclear translocator (ARNT) and interaction with dioxin-responsive elements on the DNA causing an up-regulation in dioxin responsive genes. One dioxin-responsive gene is cyclooxygenase 2 (COX-2) which has roles in development of the cardiovascular system. Up-regulation in expression of COX-2 causes alteration in cardiovascular development and function which results in reduced heart pumping efficiency, reduced blood flow, and eventual cardiac collapse and death. Initial development of this AOP draws heavily on evidence collected from zebrafish (Danio rerio) through mechanistic investigations by use of targeted knockdown of AhR, ARNT, or COX-2 and through use of selective agonists and antagonists of COX-2. Comparable apical manifestations of activation of the AhR have been recorded across freshwater and marine teleost and non-teleost fishes, as well as birds. Therefore, this AOP might be broadly applicable across oviparous vertebrate taxa. Despite conservation in the AOP aross taxa, great differences in sensitivity to perturbation exist both among and within taxonomic groups. Therefore, this AOP has utility in support of application toward the mechanistic understanding of adverse effects of chemicals that act as agonists of the AhR, particularly with regard to cross-chemical, cross-species, and cross-taxa extrapolation.
- The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor in the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family of proteins (Okey 2007). The AhR is a highly conserved and ancient protein with homologs having been identified in most major animal groups, apart from the most ancient lineages, such as sponges (Porifera) (Hahn et al 2002).
- Investigations of invertebrates possessing early homologs of the AhR suggest that the AhR evolutionarily functioned in regulation of the cell cycle, cellular proliferation and differentiation, and cell-to-cell communications (Hahn et al 2002). However, critical functions in angiogenesis, regulation of the immune system, neuronal processes, metabolism, development of the heart and other organ systems, and detoxification have emerged sometime in early vertebrate evolution (Duncan et al 1998; Lahvis and Bradfield 1998; Emmons et al 1999).
- Activation of the AhR by anthropogenic pollutants that act as agonists can result in a range of adverse biological effects. These effects can include hepatotoxicity, histological lesions, hemopoiesis, suppression of immune responses and healing, impaired reproductive and endocrine processes, teratogenesis, carcinogenesis, wasting syndrome, and mortality (Kleeman et al 1988; Spitsbergen et al 1986; Walter et al 2000; Giesy et al 2002; Spitsbergen et al 1988a; 1988b).
- Despite the AhR being a highly conserved protein, differences in relative sensitivity to adverse effects both among and within vertebrate taxa are greater than 1000-fold (Cohen-Barnhouse et al 2011; Doering et al 2013; Hengstler et al 1999; Korkalainen et al 2001).
- Differences in binding affinity and transactivation of the AhR have been implicated as a key mechanism contributing to differences in sensitivity to agonists of the AhR among species and taxa. However, the precise mechanisms are not fully understood for all taxa.
- High-throughput, next-generation ‘OMICs’ technologies have identified hundreds to thousands of different genes that are regulated, either directly or indirectly, by the AhR (Brinkmann et al 2016; Doering et al 2016; Huang et al 2014; Li et al 2013; Whitehead et al 2010). These genes include Phase I and Phase II biotransformation enzymes, such as cytochrome P450 1A (CYP1A). Expressions and activities of CYP1A are routinely used as biomarkers of exposure to anthropogenic pollutants that act as agonists of the AhR (Whyte et al 2008).
- Exposure to mixtures of agonists of the AhR during the 1950’s, 1960’s, and 1970’s has been implicated in early life stage mortality of Lake Ontario lake trout (Salvelinus namaycush) leading to population collapse (Cook et al 2003). However, populations of mummichog (Fundulus heteroclitus) and Atlantic tomcod (Microgadus tomcod) exposed to lethal concentrations of agonists of the AhR have evolved tolerance through several mechanisms which has protected against population collapse (Nacci et al 2010; Wirgin et al 2011).
Summary of the AOP
|Polycyclic aromatic hydrocarbons (PAHs)||Strong|
Molecular Initiating Event
|Activation, AhR||Activation, AhR|
|dimerization, AHR/ARNT||dimerization, AHR/ARNT|
|Increase, COX-2 expression||Increase, COX-2 expression|
|Altered, Cardiovascular development/function||Altered, Cardiovascular development/function|
|Increased, Mortality||Increased, Mortality|
|Decreased, Population trajectory||Decreased, Population trajectory|
Relationships Between Two Key Events (Including MIEs and AOs)
|Activation, AhR leads to dimerization, AHR/ARNT||Directly leads to||Strong||Weak|
|dimerization, AHR/ARNT leads to Increase, COX-2 expression||Directly leads to||Strong||Moderate|
|Increase, COX-2 expression leads to Altered, Cardiovascular development/function||Directly leads to||Moderate||Moderate|
|Altered, Cardiovascular development/function leads to Increased, Mortality||Directly leads to||Strong||Moderate|
|Activation, AhR leads to Increased, Mortality||Indirectly leads to||Strong||Strong|
|Increased, Mortality leads to Decreased, Population trajectory||Directly leads to||Moderate||Weak|
Life Stage Applicability
|Atlantic killifish||Fundulus heteroclitus||Moderate||NCBI|
|rainbow trout||Oncorhynchus mykiss||Moderate||NCBI|
|fathead minnow||Pimephales promelas||Moderate||NCBI|
|channel catfish||Ictalurus punctatus||Moderate||NCBI|
|Salvelinus namaycush||Salvelinus namaycush||Moderate||NCBI|
|Salvelinus fontinalis||Salvelinus fontinalis||Moderate||NCBI|
|Carassius carassius||Carassius carassius||Moderate||NCBI|
|Pagrus major||Pagrus major||Moderate||NCBI|
|Acipenser fulvescens||Acipenser fulvescens||Moderate||NCBI|
|Coregonus artedi||Coregonus artedi||Moderate||NCBI|
|Catostomus commersonii||Catostomus commersonii||Moderate||NCBI|
|Esox lucius||Esox lucius||Moderate||NCBI|
|Scaphirhynchus albus||Scaphirhynchus albus||Moderate||NCBI|
|Scaphirhynchus platorynchus||Scaphirhynchus platorynchus||Moderate||NCBI|
|Xenopus laevis laevis||Xenopus laevis laevis||Weak||NCBI|
|Gallus gallus||Gallus gallus||Strong||NCBI|
|Acipenser transmontanus||Acipenser transmontanus||Moderate||NCBI|
|Salmo salar||Salmo salar||Moderate||NCBI|
Graphical RepresentationClick to download graphical representation template
Overall Assessment of the AOP
Consider the following criteria (may include references to KE Relationship pages): 1. concordance of dose-response relationships; 2. temporal concordance among the key events and adverse effect; 3. strength, consistency, and specificity of association of adverse effect and initiating event; 4. biological plausibility, coherence, and consistency of the experimental evidence; 5. alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP. It should be noted that alternative mechanisms of action, if supported, require a separate AOP; 6. uncertainties, inconsistencies and data gaps.
Domain of Applicability
Sex: This AOP is only applicable to early life stages prior to sexual differentiation.
Life stages: This AOP is only applicable starting from embryonic development. In zebrafish, this critical window extends from fertilization to approximately 24 hours post fertilization (hpf) (Belair et al 2001; Goldstone & Stegeman 2008).
Taxonomic: The specific characteristics of altered cardiovascular development and function vary to some degree among taxonomic groups of vertebrates. However, reduction in myocyte proliferation and heart pumping efficiency is common to all investigated vertebrates (Antkiewicz et al 2005; Jones & Kennedy 2009; Thackaberry et al 2005).
This AOP is applicable to:
- All teleost and non-teleost fishes that have been investigated as embryos so far (Buckler et al 2015; Doering et al 2013; Elonen et al 1998; Johnson et al 1998; Park et al 2014; Tillitt et al 2016; Toomey et al 2001; Walker et al 1991; Yamauchi et al 2006; Zabel et al 1995).
- All birds (Canga et al 1993; Cohen-Barnhouse et al 2011; Fujisawa et al 2014; Heid et al 2001; Ivnitski et al 2001; Walker & Catron 2000). However, some details of the AOP might be different in birds as cyclooxygenase-2 (COX-2) is believed to be up-regulated through non-genomic mechanisms in these taxa based on investigations in chicken (Gallus gallus) (Fujisawa et al 2014).
- Amphibians and reptiles have insufficient mechanistic and early life stage mortality information to demonstrate applicability at this time. However, amphibians and reptiles express AhRs that are activated by agonists in a manner consistent with other vertebrates and express AhRs during embryonic development (Lavine et al 2005; Shoots et al 2015; Ohi et al 2003; Oka et al 2016). However, altered cardiovascular development and function and early life stage mortality have not been observed at any investigated concentration of DLC in amphibians studied to date (Jung et al 1997). This tolerance is believed to result from AhRs of amphibians having very low affinity for agonists (Lavine et al 2005; Shoots et al 2015). Therefore, it is acknowledged that this AOP is likely to be applicable to reptiles. However, it might not be applicable to amphibians due to their extreme tolerance to activation of the AhR.
- Cartilaginous fishes (Chondrichthyes) have insufficient mechanistic and early life stage mortality information to demonstrate applicability at this time. However, sharks and rays are known to express AhRs that are structurally comparable to AhRs of teleost fishes (Hahn 2002). Sharks and rays have also been shown to respond to exposure to agonists of the AhR through responses that are comparable to teleost fishes, specifically through induction of CYP1A (Hahn et al 1998). Therefore, it is acknowledged that this AOP is likely to be applicable to Chondrichthyes.
This AOP is not applicable to:
- Mammals because the cause of mortality of the young is primarily a result of wasting syndrome and not necessarily altered cardiovascular development and function (Kopf & Walker 2009). Further, studies of CYP1A1 and CYP1A2 null mice (Mus musculus) demonstrate that wasting syndrome and mortality are mediated by CYP1A1 in mammals (Uno et al 2004).
- Invertebrates because AhRs of invertebrates have less diverse functionalities relative to vertebrates, AhRs of invertebrates are not known to bind agonists that represent anthropogenic pollutants, and no critical adverse effects are known in invertebrates as a result of activation of the AhR (Hahn 2002; Hahn et al 1994).
- Jawless fishes, such as lamprey (Petromyzontiformes) and hagfish (Myxiniformes), because of a lack of measurable AhR-mediated responses (Hahn et al 1998). Although additional information is necessary for this taxa, it is currently acknowledged that this AOP is likely not applicable to jawless fishes.
Essentiality of the Key Events
Support for essentiality for key events in the AOP was provided by a series of knockdown and targeted agonist and antagonist experiments. These investigations were conducted mainly with zebrafish as the model species and TCDD as the model agonist of the AhR.
Rationale for essentiality calls:
- AhR, activation: [Strong] Knockdown of AhR prevents TCDD induced alteration in cardiovascular development and function (Clark et al 2010; Hanno et al 2010; Karchner et al 1999; Prasch et al 2003; Van Tiem & Di Giulio 2011).
- AhR/ARNT, dimerization: [Strong] Knockdown of ARNT prevents TCDD induced alteration in cardiovascular development and function (Antkiewicz et al 2006; Prasch et al 2004). Depletion of ARNT lessens or prevents TCDD induced alteration in cardiovascular development and function (Prasch et al 2004).
- COX-2, increase: [Strong] Knockdown of COX-2 and selective antagonists of COX-2 prevent TCDD induced alteration in cardiovascular development and function (Dong et al 2010; Teraoka et al 2008; 2014). COX-2 inducers that are not agonists of the AhR cause altered cardiovascular development and function that is consistent with activation of the AhR (Huang et al 2007). Knockdown of and selective antagonists of thromboxane A synthase 1 (CYP5A), which is down-stream of COX-2 in the prostaglandin synthesis pathway, prevents TCDD induced alteration in cardiovascular development and function (Teraoka et al 2008). Exposure to the substrate for COX-2, arachidonic acid, causes an up-regulation in COX-2 and altered cardiovascular development and function that is consistent with exposure to TCDD (Dong et al 2010).
- Cardiovascular development and function, altered: [Strong] Isosmotic rearing solution prevents yolk sac edema, but has no effect on TCDD induced alteration in cardiovascular development and function or mortality (Hill et al 2004). This indicates that mortality is not caused by yolk sac edema. Knockdown of cytochrome P450 1A (CYP1A) or injection with antioxidants decreases oxidative stress but has no effect on TCDD induced alteration in cardiovascular development and function or mortality (Carney et al 2004; Scott et al 2011). This is suggestive that mortality is not caused by oxidative stress. Exposure to agonists of the AhR post-heart development lessens or prevents alteration in cardiovascular development, decreased blood flow, and cardiac failure (Carney et al 2004; Lanham et al 2012). Exposure to agonists of the AhR post-heart development dramatically reduces mortality (Carney et al 2004; Lanham et al 2012). This suggests that mortality is caused by circulatory failure as a result of cardiovascular teratogenenesis.
Weight of Evidence Summary
- In general, the biological plausibility and coherence linking activation of the AhR through early life stage mortality from COX-2 induced alteration in cardiovascular development and function is very strong.
- The AhR is known to have critical roles in development of the heart and therefore dysregulation of these roles would be expected to result in altered cardiac development.
- The prostaglandin synthesis pathway, of which COX-2 is a rate limiting step, is known to have roles in development of the heart (Delgado et al 2004; Gullestad & Aukrust 2005; Hocherl et al 2002; Huang et al 2007; Wong et al 1998; Dong et al 2010; Huang et al 2007; Teraoka et al 2008; 2014).
- A properly functioning circulatory system is widely acknowledged to be crucial for survival of vertebrates (Kardong 2006). General dysfunction of the heart or associated vasculature is widely documented to have the potential to result in mortality through cardiac failure, regardless of the mechanism of dysfunction.
Concordance of dose-response relationships:
- There is significant evidence showing concordance of dose-response for incidence and severity of alteration in cardiovascular development and function and subsequently mortality across at least 16 different species of fish (Buckler et al 2015; Elonen et al 1998; Huang et al 2012; Johnson et al 1998; Park et al 2014; Tillitt et al 2016; Toomey et al 2001; Walker et al 1991; Yamauchi et al 2006; Zabel et al 1995) and 8 different species of birds (Cohen-Barnhouse et al 2011; Brunstrom 1990; Brunstrom & Andersson 1988; Hoffman et al 1996; 1998; Powell et al 1998) for several PCDDs, PCDFs, planar PCBs, and PAHs. Concordance of dose-response has not been observed in amphibians studied to date because no elevated mortality or altered cardiovascular development and function was observed at any tested concentration of agonist (Jung et al 1997).
- Less is known regarding concordance of dose-response relationships for COX-2. In Japanese medaka (Oryzias latipes), abundance of transcript of COX-2 is significantly greater than controls at concentrations of TCDD of 0.2 ppb and greater (Dong et al 2010). Likewise, incidence of cardiovascular development and heart area were both significantly different than controls at concentrations of TCDD of 0.2 ppb and greater (Dong et al 2010).
Temporal concordance among the key events and adverse effect:
- Alterations in cardiovascular development or function is first observable in zebrafish around 48 hours post fertilization (hpf), while mortality does not begin to occur until around 86 hpf (Goldstone & Stegeman 2006).
- AhR transcript and protein is first detectable in zebrafish around 24 hpf (Tanguay et al 1999).
- COX-2 transcript is first detectable in zebrafish around 6 hpf (Teraoka et al 2008). Expression of COX-2 was investigated in zebrafish exposed to TCDD at 55 and 72 hpf (Teraoka et al 2014). At 55 hpf there was a trend towards up-regulation of COX-2 (~ 1.5-fold), while at 72 hpf there was a significant up-regulation of COX-2 (~ 4.5-fold) (Teraoka et al 2014).
- Therefore, there is a general temporal concordance in this AOP.
- However, there is some uncertainty in the early manifestations of altered cardiovascular development and up-regulation of COX-2. It is possible that the first manifestations of altered cardiovascular development result from mechanisms other than COX-2. For example, sex determining region Y-box-9b (Sox9b) is first expressed in zebrafish at around 24 hpf and has been known to cause some altered cardiovascular phenotypes (Hofsteen et al 2013; Li et al 2002). However, no studies have yet investigated temporal concordance of regulation of Sox9b by the AhR prior to 72 hpf (Hofsteen et al 2013). It is also possible that temporal concordance of early increases in COX-2 is obscured by the relatively little fold-changes observed for COX-2. Additional investigations into up-regulation of COX-2 by activation of the AhR across developmental stages is warranted.
- There are no known AhR-mediated effects that occur at concentrations below those that cause alteration in cardiovascular development and function that result in early life stage mortality in fishes, amphibians, reptiles, or birds.
- There are no studies in which COX-2 and altered cardiovascular development or function were co-investigated in which altered cardiovascular development or function occurred without an up-regulation in COX-2.
- In TCDD exposure groups, some individuals do not manifest alterations in cardiovascular development or function (Dong et al 2010). TCDD exposed individuals of Japanese medaka that did not manifest alterations in cardiovascular development or function had expression of COX-2 that was not statistically different than controls, while individuals that did manifest alterations in cardiovascular development or function had increased expression of COX-2 (Dong et al 2010).
- There is also consistency in the TCDD-induced alterations in cardiovascular phenotype between distantly related oviparous taxa, namely fish and birds (Teraoka et al 2008; Fujisawa et al 2014). Likewise, COX-2 is known to be up-regulated in both these taxa (Teraoka et al 2008; Fujisawa et al 2014). Cardiovascular development and function and COX-2 have not been investigated in amphibians or reptiles.
Uncertainties, inconsistencies, and data gaps:
- There are several other pathways by which activation of the AhR could result in altered cardiovascular development and function in developing embryos. These include, but are not limited to, down-regulation in Sox9b, BMP-4, and genes in the cell cycle gene cluster (Hofsteen et al 2013; Jonsson et al 2007), oxidative stress (Goldstone & Stegeman 2008), and AhR cross-talk with hypoxia inducible factor 1α (HIF1α) (Goldstone & Stegeman 2008).
- However, investigations of knockdown and null strains for Sox9b in zebrafish do not result in the complete phenotype of altered cardiovascular development recorded in embryos following exposure to planar aromatic hydrocarbons (Hofsteen et al 2013). Injection of TCDD exposed embryos with Sox9b mRNA was able to prevent the Sox9b phenotype of cardiovascular development, however it did not prevent altered cardiovascular development altogether (Hofsteen et al 2013). Further, altered cardiovascular development as a result of down-regulation in Sox9b is not severe enough to cause complete cardiac failure and early life stage mortality in zebrafish (Hofsteen et al 2013).
- Oxidative stress as a result of induction in CYP1A has commonly been proposed as the mechanism of altered cardiovascular development and function and CYP1A follows dose- and temporal concordance with mortality across numerous investigations in fishes and birds (Goldstone & Stegeman 2008). Early studies of CYP1A knockdown in zebrafish demonstrated protection against alteration in cardiovascular development and function induced by exposure to TCDD (Teraoka et al 2003). However, more recent investigations have observed no protection (Carney et al 2006). This inconsistency has been proposed to result from the earlier studies only recording alteration in cardiovascular development and function at early stages when adverse effects are difficult to accurately observe (Carney et al 2006). In birds, COX-2 inhibitors have no effect on expression of CYP1A but protect against TCDD induced alteration in cardiovascular development and function suggesting that CYP1A is not involved in toxicities (Fujisawa et al 2014).
- For cross-species and cross-taxa extrapolation, there is uncertainty in whether COX-2 is up-regulated by AhR through genomic or non-genomic mechanisms. Specifically, there is no detailed analysis regarding how widespread COX-2 genes which contain DREs in the promoter region are among species and among taxa and whether non-genomic or genomic mechanisms of up-regulation in COX-2 are more ubiquitous.
- All mechanistic investigations into mechanisms of AhR-mediated alteration in cardiovascular development and function have been conducted in zebrafish, Japanese medaka, and chicken. Therefore, no mechanistic information is available to conclude cross-species extrapolation outside of a shared phenotype of altered cardiovascular development and function. There is no information about AhR-mediated alteration in cardiovascular development or function or up-regulation of COX-2 in early fishes (Petromyzontiformes; Myxiniformes; Chondrichthyes), amphibians, or reptiles.
- Despite these uncertainties, the strong, quantitative link between activation of the AhR and early life stage mortality means that elucidating the precise series of key events is less critical. Therefore, the evidence suggesting COX-2 as a primary mechanism might be all that is necessary, although multiple mechanisms acting together is the most likely true mechanism.
- There is a strong quantitative understanding between quantitative structure-activity relationship (QSAR) or binding affinity for the AhR and potency among PCDDs, PCDFs, and planar PCBs (Van den Berg et al 1998; 2006). Specifically, these studies have demonstrated that congeners with greater binding affinity have greater potency (Van den Berg et al 1998; 2006). This has partially contributed to the successful development of the toxic equivalency factor (TEF) methodology in risk assessment (Van den Berg et al 1998; 2006).
- There is also a strong quantitative understanding of differences in binding affinity of the AhR among species of birds and differences in sensitivity to early life stage mortality (Karchner et al 2006; Farmahin et al 2012; 2013; Manning et al 2013). Specifically, these studies demonstrate that species of birds with AhRs with greater affinity for DLCs have greater sensitivity than species with AhRs with lesser affinity for DLCs (Karchner et al 2006). These differences in sensitivity range by more than 40-fold for TCDD (Cohen-Barnhouse et al 2011). However, a quantitative understanding between differences in binding affinity of the AhR among species and differences in sensitivity to early life stage mortality is not yet available for other taxa (Doering et al 2013).
- There is some quantitative understanding between up-regulation of COX-2 and incidence of and severity of cardiac deformities for medakafish exposed to TCDD (Dong et al 2010). This quantitative understanding includes a strong linear relationship (R2 = 0.88) between abundance of COX-2 transcript and heart area (Dong et al 2010). However, this information is not available with regards to multiple investigations, species, taxonomic groups, or chemicals.
- There is strong quantitative understanding between incidence of and severity of cardiovascular deformities and mortality. However, numerous different cardiovascular endpoints are investigated among studies making side-by-side comparisons difficult.
Considerations for Potential Applications of the AOP (optional)
There are great differences in sensitivity to agonists of the AhR among species and among taxa and great differences in potency among agonists of the AhR. Therefore, this AOP has utility towards the mechanistic understanding of adverse effects of agonists of the AhR with regard to cross-chemical, cross-species, and cross-taxa extrapolations. This is particularly true regarding ongoing development of a quantitative AOP.
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