Event: 856

Key Event Title


Formation, Hepatocellular and Bile duct tumors

Short name


Formation, Hepatocellular and Bile duct tumors

Biological Context


Level of Biological Organization

Organ term


Organ term
hepatobiliary system

Key Event Components


Process Object Action
hepatocellular carcinoma increased
Bile Duct Neoplasms increased

Key Event Overview

AOPs Including This Key Event


AOP Name Role of event in AOP
Sustained AhR Activation leading to Rodent Liver Tumours AdverseOutcome



Taxonomic Applicability


Term Scientific Term Evidence Link
rodentia rodentia NCBI

Life Stages


Sex Applicability


Key Event Description


If AHR activation is sustained for a period of more than 30 weeks or 30% of a rat's lifespan, hepatocellular adenomas/carcinomas and cholangiocarcinomas develop.. These two tumors are also part of the organ-level response and are the adverse outcome. Adenomas may arise from altered hepatic foci that are derived from hepato- cytes or hepatoblasts whereas hepatocellular carcinomas and cholangiocarcinomas likely arise from initiated stem cells. How- ever, the actual cellular origin of the various liver tumor types is not known with certainty and involvement of both liver stem cells and hepatocyte-like cells have been observed in hepatocellular adenomas (Libbrecht et al., 2001; Libbrecht, 2006).

How It Is Measured or Detected


Histopathological examination is a necessary part of lifetime cancer bioassays. This type of examination is used to detect tumors.

Domain of Applicability


Overall, empirical evidence supporting the applicability of this AOP to humans is absent. Only a single KE has been observed in humans with respect to the binding and activation of the AHR by DLCs with accompanying hepatic CYP1A induction (Abraham et al., 2002; Budinsky et al., 2010; Coenraads et al., 1999; Lambert et al., 2006; Tang et al., 2008). For perspective purposes regarding an unequivocal dioxin effect occurring in highly exposed human subjects, high levels of AHR activation in humans alter the growth and differentiation of keratinocytes and produce chloracne (Forrester et al., 2014; Geusau et al., 2001; Ju et al., 2011; Moses and Prioleau, 1985; Saurat and Sorg, 2010; Saurat et al., 2012; Sorg, 2014; Sutter et al., 2009, 2010, 2011). In contrast, the epidemiological evidence for TCDD- associated liver cancer in humans is negative or equivocal (Akintobi et al., 2007; Bertazzi et al., 1989; Du et al., 2006; Geusau et al., 2005; Hankinson, 2009; Loertscher et al., 2001). Trichlorophenol workers exposed to TCDD show no increase in liver or biliary cancer (Collins et al., 2009; McBride et al., 2009). The occurrence of chloracne indicates high levels of exposure to DLCs and significant AHR activation; even in such cases, no evidence of liver injury or cancer has been reported (Ghezzi et al., 1982; Mocarelli et al., 1986, 1991; Pocchiari et al., 1979; Reggiani, 1980). In other trichlorophenol workers, transient changes in liver enzyme levels were reported in alcohol consumers only (Calvert et al., 1992).

The unique Yusho and Yucheng rice oil poisonings are confounded by exposures to a mixture of complex PCBs, polychlorinated dibenzofurans, and mixtures of quarterphenyl, and terphenyl compounds. Clearly, these compounds possess dioxin- like properties and the mixture was sufficiently potent to induce a chloracne-like condition in some individuals (Lambert et al., 2006). An increase in mortality from cirrhosis and chronic liver disease has been observed among the victims of the Yusho poisoning incident, whereas liver cancer was not elevated (Onozuka et al., 2009). The rate of mortality from chronic liver disease was increased in men only among the victims of the similar Yucheng poisoning incident without excess liver cancer in either sex (Tsai et al., 2007).

In contrast to humans, rodents are highly susceptible to the hepatotoxic, proliferative, and carcinogenic effects of TCDD (Hailey et al., 2005; Goodman and Sauer, 1992; Kociba et al., 1978). To summarize, the sustained AHR activation rodent liver tumor promotion AOP appears to be a pathway that very likely requires exceedance of a threshold for sustained AHR activation for liver cancers to occur in rodents (e.g. Fig. 4). In humans, increases in liver cancer have not been observed even in highly exposed populations, and no population level data in humans are available showing an increased liver cancer response, even in individuals with chloracne and obvious high exposure to DLCs. However, as is often the case for evaluations of chemicals which lead to tumor formation in laboratory animals, for regulatory purposes, assumptions are made that potential risks to human health can be estimated from animal studies. In many cases where there is sparse data, a default linear no-threshold extrapolation method is used. However, in applying this AOP for such an assessment, the extensive body of scientific evidence clearly indicates that liver tumor promotion by DLCs only occurs after a threshold level of sustained AHR activation is exceeded. These thresholds also become apparent in Figs. 3B and 4. Therefore, a quantitative application to derive an exposure guidance value for humans to address the potential for tumor promotion by DLCs should be based on a threshold mode of action (e.g., Simon et al., 2009).

To the extent humans have been inadvertently, accidentally, or intentionally exposed to TCDD, no evidence of increased liver cancer or even liver injury have been observed, consistent with rats being more sensitive than humans. Given that tumorigenic responses in rodents only occur when AHR activation is sustained for a period approximating 30% of the life- span, and the steep slopes corresponding to responses elicited when this apparent threshold of AHR activation is exceeded, risk assessments for humans using this AOP should employ a threshold model.

As noted above, binding to the AHR is insufficient to infer activity leading to the adverse outcome of liver tumors. Moreover, there is considerable scientific debate as to whether the rat liver tumori- genic responses induced by TCDD are relevant endpoints for human health. WHO indicates that cancer may not be the most sensitive response in either humans or animals and EPA's latest assessment is based on non-cancer effects in humans (sperm deficits among young males exposed between the ages of 1e9 and increased TSH levels in 72-hour neonates born of Seveso mothers with elevated serum TCDD concentrations). Nonetheless, the utility of the AOP is the identification and ordering of effects, demonstration of dose-response concordance and illustrating that rodent liver tumor promotion by sustained AHR is a threshold phenomenon.

Regulatory Significance of the Adverse Outcome


For many years, EPA used a cancer slope factor of 1.5 E+05 per mg/kg/d based on the Kociba et al. (1978) bioassay. Today, the toxicity critierion for TCDD and other persistent AHR ligands is based on purported reproductive and developmental effects in humans.



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