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Event Title

Hepatocellular and Bile duct tumors, Formation

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Sustained AhR Activation leading to Rodent Liver Tumours AO

Taxonomic Applicability

Name Scientific Name Evidence Links

Affected Organs

Synonym Scientific Name Evidence Links
liver and biliary system hepatobiliary system Ontobee

Level of Biological Organization

Biological Organization

How this Key Event works

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.

Evidence Supporting Taxonomic 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 Examples Using This 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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Akintobi, A.M., Villano, C.M., White, L.A., 2007. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure of normal human dermal fibroblasts results in AhR-dependent and -independent changes in gene expression. Toxicol. Appl. Pharmacol. 220, 9-17.

Bertazzi, P.A., Zocchetti, C., Pesatori, A.C., Guercilena, S., Sanarico, M., Radice, L., 1989. Ten-year mortality study of the population involved in the Seveso inci- dent in 1976. Am. J. Epidemiol. 129, 1187-1200.

Budinsky, R.A., LeCluyse, E.L., Ferguson, S.S., Rowlands, J.C., Simon, T., 2010. Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8- tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8- pentachlorodibenzofuran. Toxicol. Sci. 118, 224-235.

Calvert, G.M., Hornung, R.W., Sweeney, M.H., Fingerhut, M.A., Halperin, W.E., 1992. Hepatic and gastrointestinal effects in an occupational cohort exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. JAMA 267, 2209-2214.

Coenraads, P.J., Olie, K., Tang, N.J., 1999. Blood lipid concentrations of dioxins and dibenzofurans causing chloracne. Br. J. Dermatol. 141, 694-697.

Collins, J.J., Bodner, K., Aylward, L.L., Wilken, M., Bodnar, C.M., 2009a. Mortality rates among trichlorophenol workers with exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin. Am. J. Epidemiol. 170, 501-506.

Collins, J.J., Bodner, K., Aylward, L.L., Wilken, M., Swaen, G., Budinsky, R., Rowlands, C., Bodnar, C.M., 2009b. Mortality rates among workers exposed to dioxins in the manufacture of pentachlorophenol. J. Occup. Environ. Med. 51, 1212-1219. .

Du, L., Neis, M.M., Ladd, P.A., Keeney, D.S., 2006. Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classic aryl hydrocarbon receptor ligands. J. Pharmacol. Exp. Ther. 319, 1162-1171.

Forrester, A.R., Elias, M.S., Woodward, E.L., Graham, M., Williams, F.M., Reynolds, N.J., 2014. Induction of a chloracne phenotype in an epidermal equivalent model by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on aryl hydrocarbon receptor activation and is not reproduced by aryl hydro- carbon receptor knock down. J. Dermatol. Sci. 73, 10-22.

Geusau, A., Abraham, K., Geissler, K., Sator, M.O., Stingl, G., Tschachler, E., 2001. Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects. Environ. Heal. Perspect. 109, 865-869.

Geusau, A., Khorchide, M., Mildner, M., Pammer, J., Eckhart, L., Tschachler, E., 2005. 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs differentiation of normal human epidermal keratinocytes in a skin equivalent model. J. Invest. Dermatol. 124, 275-277.

Ghezzi, I., Cannatelli, P., Assennato, G., Merlo, F., Mocarelli, P., Brambilla, P., Sicurello, F., 1982. Potential 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure of Seveso decontamination workers: a controlled prospective study. Scand. J. Work. Environ. Heal. 8 (Suppl. 1), 176-179.

Goodman, D.G., Sauer, R.M., 1992. Hepatotoxicity and carcinogenicity in female Sprague-Dawley rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): a pathology working group reevaluation. Regul. Toxicol. Pharmacol. 15, 245-252.

Hailey, J.R., Walker, N.J., Sells, D.M., Brix, A.E., Jokinen, M.P., Nyska, A., 2005. Clas- sification of proliferative hepatocellular lesions in harlan sprague-dawley rats chronically exposed to dioxin-like compounds. Toxicol. Pathol. 33, 165-174.

Hankinson, O., 2009. Repression of aryl hydrocarbon receptor transcriptional ac- tivity by epidermal growth factor. Mol. Interv. 9, 116-118.

Ju, Q., Fimmel, S., Hinz, N., Stahlmann, R., Xia, L., Zouboulis, C.C., 2011. 2,3,7,8- Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro. Exp. Dermatol. 20, 320-325.

Kociba, R.J., Keyes, D.G., Beyer, J.E., Carreon, R.M., Wade, C.E., Dittenber, D.A., Kalnins, R.P., Frauson, L.E., Park, C.N., Barnard, S.D., Hummel, R.A., Humiston, C.G., 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46, 279-303.

Lambert, G.H., Needham, L.L., Turner, W., Lai, T.J., Patterson, D.G.J., Guo, Y.L., 2006. Induced CYP1A2 activity as a phenotypic biomarker in humans highly exposed to certain PCBs/PCDFs. Environ. Sci. Technol. 40, 6176-6180.

Libbrecht, L., 2006. Hepatic progenitor cells in human liver tumor development. World. J. Gastroenterol. 12, 6261-6265.

Libbrecht, L., De Vos, R., Cassiman, D., Desmet, V., Aerts, R., Roskams, T., 2001. He- patic progenitor cells in hepatocellular adenomas. Am. J. Surg. Pathol. 25, 1388-1396.

Loertscher, J.A., Sattler, C.A., Allen-Hoffmann, B.L., 2001. 2,3,7,8-Tetrachlorodibenzo- p-dioxin alters the differentiation pattern of human keratinocytes in organo- typic culture. Toxicol. Appl. Pharmacol. 175, 121-129.

McBride, D.I., Collins, J.J., Humphry, N.F., Herbison, P., Bodner, K.M., Aylward, L.L., Burns, C.J., Wilken, M., 2009. Mortality in workers exposed to 2,3,7,8- tetrachlorodibenzo-p-dioxin at a trichlorophenol plant in New Zealand. J. Occup. Environ. Med. 51, 1049-1056.

Mocarelli, P., Marocchi, A., Brambilla, P., Gerthoux, P., Young, D.S., Mantel, N., 1986. Clinical laboratory manifestations of exposure to dioxin in children. A six-year study of the effects of an environmental disaster near Seveso, Italy. JAMA 256, 2687-2695.

Mocarelli, P., Needham, L.L., Marocchi, A., Patterson, D.G.J., Brambilla, P., Gerthoux, P.M., Meazza, L., Carreri, V., 1991. Serum concentrations of 2,3,7,8- tetrachlorodibenzo-p-dioxin and test results from selected residents of Sev- eso, Italy. J. Toxicol. Environ. Heal. 32, 357-366.

Moses, M., Prioleau, P.G., 1985. Cutaneous histologic findings in chemical workers with and without chloracne with past exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin. J. Am. Acad. Dermatol. 12, 497-506.

Onozuka, D., Yoshimura, T., Kaneko, S., Furue, M., 2009. Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a 40-year follow-up study of Yusho patients. Am. J. Epidemiol. 169, 86-95.

Pocchiari, F., Silano, V., Zampieri, A., 1979. Human health effects from accidental release of tetrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy. Ann. N. Y. Acad. Sci. 320, 311-320.

Reggiani, G., 1980. Acute human exposure to TCDD in Seveso, Italy. J. Toxicol. Environ. Heal. 6, 27-43.

Saurat, J.H., Sorg, O., 2010. Chloracne, a misnomer and its implications. Dermatology 221, 23-26.

Saurat, J.H., Kaya, G., Saxer-Sekulic, N., Pardo, B., Becker, M., Fontao, L., Mottu, F., Carraux, P., Pham, X.C., Barde, C., Fontao, F., Zennegg, M., Schmid, P., Schaad, O., Descombes, P., Sorg, O., 2012. The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. Toxicol. Sci. 125, 310-317.

Simon, T., Aylward, L.L., Kirman, C.R., Rowlands, J.C., Budinsky, R.A., 2009. Estimates of cancer potency of 2,3,7,8-tetrachlorodibenzo(p)dioxin using linear and nonlinear dose-response modeling and toxicokinetics. Toxicol. Sci. 112, 490-506.

Sorg, O., 2014. AhR signalling and dioxin toxicity. Toxicol. Lett. 230, 225-233.

Sutter, C.H., Bodreddigari, S., Campion, C., Wible, R.S., Sutter, T.R., 2011. 2,3,7,8- Tetrachlorodibenzo-p-dioxin increases the expression of genes in the human epidermal differentiation complex and accelerates epidermal barrier formation. Toxicol. Sci. 124, 128-137.

Sutter, C.H., Bodreddigari, S., Sutter, T.R., Carlson, E.A., Silkworth, J.B., 2010. Analysis of the CYP1A1 mRNA dose response in human keratinocytes indicates that relative potencies of dioxins, furans, and PCBs are species and congener specific. Toxicol. Sci. 118, 704-715.

Sutter, C.H., Yin, H., Li, Y., Mammen, J.S., Bodreddigari, S., Stevens, G., Cole, J.A., Sutter, T.R., 2009. EGF receptor signaling blocks aryl hydrocarbon receptor- mediated transcription and cell differentiation in human epidermal keratino- cytes. Proc. Natl. Acad. Sci. U. S. A. 106, 4266-4271.

Tang, N.J., Liu, J., Coenraads, P.J., Dong, L., Zhao, L.J., Ma, S.W., Chen, X., Zhang, C.M., Ma, X.M., Wei, W.G., Zhang, P., Bai, Z.P., 2008. Expression of AhR, CYP1A1, GSTA1, c-fos and TGF-alpha in skin lesions from dioxin-exposed humans with chlor- acne. Toxicol. Lett. 177, 182-187.

Tsai, P.-C., Ko, Y.-C., Huang, W., Liu, H.-S., Guo, Y.L., 2007. Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. Sci. Total. Environ. 374, 216-222.