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Event: 856

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Formation, Hepatocellular and Bile duct tumors

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Formation, Hepatocellular and Bile duct tumors

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
hepatobiliary system

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
hepatocellular carcinoma increased
Bile Duct Neoplasms increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Sustained AhR Activation leading to Rodent Liver Tumours AdverseOutcome Allie Always (send email) Open for citation & comment EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rodentia rodentia NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

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

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

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.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Abraham, K., Geusau, A., Tosun, Y., Helge, H., Bauer, S., Brockmoller, J., 2002. Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: insights into the measurement of hepatic cytochrome P450 1A2 induction. Clin. Pharmacol. Ther. 72, 163-174.

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.