AOP-Wiki

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<div id="title">
<h2>AOP ID and Title:</h2>
<div class="title">AOP 1: Uncharacterized liver damage leading to hepatocellular carcinoma</div>
<strong>Short Title: Liver damage and hepatocellular carcinoma</strong>
</div>
<h2>Graphical Representation</h2>
<img src="https://test.aopwiki.org/system/dragonfly/production/2016/12/02/8x1ydxsev1_1_4_dioxane.jpg" height="500" width="700" alt=""/>
<div id="authors">
<h2>Authors</h2>
<p>Available for adoption
</p>
</div>
<div id="status">
<h2>Status</h2>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Author status</th>
<th scope="col">OECD status</th>
<th scope="col">OECD project</th>
<th scope="col">SAAOP status</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Not under active development</td>
<td></td>
<td></td>
<td>Archived</td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="abstract">
<h2>Abstract</h2>
<p>1,4-Dioxane (also called dioxane) is a semi-volatile, colorless liquid with a faint sweet odor, produced in large amounts (1-10 million pounds in 1994, 1998, and 2002) in the United States.[1] For many years, it was primarily used as a stabilizer for 1,1,1-trichloroethane transport and storage, but that use is being phased out. It is also used as a solvent in the manufacture of household products such as detergents, soaps, lotions, shampoos, and cosmetics, in a variety of food manufacturing and food packaging processes, and is also used as a solvent in the manufacture of lacquers, paints, varnishes, waxes, resins, etc. 1,4-dioxane is water soluble and readily leaches into groundwater; thus,it has a high potential for entering the environment. Dioxane has affected groundwater supplies in many areas.
</p><p>1,4-Dioxane has been classified by IARC as a Group 2N carcinogen, meaning that it is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals.[2] The United States Environmental Protection Agency classifies dioxane as a probable human carcinogen.[3] The compound has an LD50 of 5170 mg/kg.[4]
</p><p>1,4-dioxane is absorbed rapidly following inhalation or oral exposure, with much less absorption occurring through skin contact. Toxicology data for exposure to 1,4-dioxane in humans is limited to a few inhalation exposure studies; no human data is available for oral or dermal exposures. The inhalation studies show that breathing 1,4-dioxane vapor for short periods of time causes irritation to the eyes, nose and throat, and that exposure to large amounts of 1,4-dioxane may cause kidney and liver damage. Accidental exposure of workers to high concentrations (unspecified) of 1,4-dioxane (via inhalation and dermal contact) have resulted in several deaths and the symptoms associated with those deaths suggest adverse nervous system effects and kidney toxicity. Studies in humans found no conclusive evidence for a causal link between occupational exposure to dioxane and increased risk for cancer; however, only two studies were available and these were limited by small cohort size and a small number of reported cancer cases.[5,6]
</p><p>All exposure routes have been studied and described in animals. The majority of these studies have been subchronic and chronic studies of exposure to 1,4-dioxane administered in drinking water where oral exposure induced squamous cell carcinomas in the nasal turbinates and hepatocellular carcinomas in rats of both sexes, and increased the incidence of hepatocellular carcinomas in mice of both sexes. Liver and kidney toxicity were the primary noncancer health effects of subchronic and chronic oral exposure to 1,4-dioxane in animals.
</p><p>There are only two subchronic inhalation studies and two chronic inhalation studies in animals. Inhalation exposure induced hepatocellular carcinomas in rats of both sexes. Liver and nasal toxicity are the primary noncancer health effects associated with inhalation exposure.
</p><p>An oral reference dose (RfD) has been established at 0.03 mg/kg-day, with an overall confidence of medium. The oral cancer slope factor (CSF) is 0.10 (mg/kg-day)-1. The inhalation reference concentration (RfC) is 0.03 mg/m3, also with an overall confidence of medium. The IUR is 5 x 10-6 (g/m3 -1.
</p>
</div>
~~<div id="background">~~
~~</div>~~
<div id="aop_summary">
<h2>Summary of the AOP</h2>
<h3>Events</h3>
<h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sequence</th>
<th scope="col">Type</th>
<th scope="col">Event ID</th>
<th scope="col">Title</th>
<th scope="col">Short name</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>MIE</td>
<td>294</td>
<td><a href="/events/294">N/A, Unknown</a></td>
<td>N/A, Unknown</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td>2</td>
<td>KE</td>
<td>142</td>
<td><a href="/events/142">Hyperplasia, Hyperplasia</a></td>
<td>Hyperplasia, Hyperplasia</td>
</tr>
<tr>
<td>3</td>
<td>KE</td>
<td>57</td>
<td><a href="/events/57">Proliferation, Cell proliferation in the absence of cytotoxicity</a></td>
<td>Proliferation, Cell proliferation in the absence of cytotoxicity</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td>4</td>
<td>AO</td>
<td>334</td>
<td><a href="/events/334">Promotion, Hepatocelluar carcinoma</a></td>
<td>Promotion, Hepatocelluar carcinoma</td>
</tr>
</tbody>
</table>
</div>
<h3>Key Event Relationships</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Upstream Event</th>
<th scope="col">Relationship Type</th>
<th scope="col">Downstream Event</th>
<th scope="col">Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/relationships/324">N/A, Unknown</a></td>
<td>adjacent</td>
<td>Proliferation, Cell proliferation in the absence of cytotoxicity</td>
<td>Moderate</td>
<td></td>
</tr>
<tr>
<td><a href="/relationships/69">Proliferation, Cell proliferation in the absence of cytotoxicity</a></td>
<td>adjacent</td>
<td>Hyperplasia, Hyperplasia</td>
<td>Moderate</td>
<td></td>
</tr>
<tr>
<td><a href="/relationships/158">Hyperplasia, Hyperplasia</a></td>
<td>adjacent</td>
<td>Promotion, Hepatocelluar carcinoma</td>
<td>High</td>
<td></td>
</tr>
<tr>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="overall_assessment">
<h2>Overall Assessment of the AOP</h2>
<p><em>
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.
</em>
</p>
<h3>Domain of Applicability</h3>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>rats</td>
<td>Rattus norvegicus</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="considerations_for_potential_applicaitons">
</div>
<div id="references">
<h2>References</h2>
<p><br />
1. U.S. EPA (U.S. Environmental Protection Agency). (2002). Toxic Substances Control Act (TSCA) Inventory Update Database. Available online at <a rel="nofollow" target="_blank" class="external free" href="http://www.epa.gov/iur/">http://www.epa.gov/iur/</a> (accessed February 22, 2010).
</p><p>2. “Eleventh Report on Carcinogens” (<a rel="nofollow" target="_blank" class="external free" href="http://ntp.niehs.nih.gov/ntp/roc/toc11.htm">http://ntp.niehs.nih.gov/ntp/roc/toc11.htm</a>). United States Department of Health and Human Services’ National Toxicology Program. Retrieved 2 February 2006.
</p><p>3. U.S. EPA (U.S. Environmental Protection Agency). (2005). Guidelines for carcinogen risk assessment [EPA Report]. (EPA/630/P-03/001F). Washington, DC: Risk Assessment Forum. <a rel="nofollow" target="_blank" class="external free" href="http://www.epa.gov/cancerguidelines/">http://www.epa.gov/cancerguidelines/</a>
</p><p>4. Surprenant, KS. (2002). Dioxane. In Ullmann's Encyclopedia of Industrial Chemistry (6th ed.). Weinheim, Germany: Wiley-VCH Verlag. <a rel="nofollow" target="_blank" class="external free" href="http://dx.doi.org/10.1002/14356007.a08_545">http://dx.doi.org/10.1002/14356007.a08_545</a>
</p><p>5. Buffler, PA; Wood, SM; Suarez, L; Kilian, DJ. (1978). Mortality follow-up of workers exposed to 1,4-dioxane. J Occup Environ Med 20: 255-259.
</p><p>6. Thiess, AM; Tress, E; Fleig, I. (1976). Arbeitsmedizinische Untersuchungsergebnisse von Dioxan-exponierten Mitarbeitern [Industrial-medical investigation results in the case of workers exposed to dioxane]. Arbeitsmedizin, Sozialmedizin, Umweltmedizin 11: 35-46.
</p>
</div>
<div id="appendicies">
<h2>Appendix 1</h2>
<h3>List of MIEs in this AOP</h3>
<h4><a href="/events/294">Event: 294: N/A, Unknown</a></h4>
<h5>Short Name: N/A, Unknown</h5>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/33">Aop:33 - Kidney toxicity induced by activation of 5HT2C</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/1">Aop:1 - Uncharacterized liver damage leading to hepatocellular carcinoma</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Molecular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>eukaryotic cell</td></tr>
</tbody>
</table>
</div>
<h3>List of Key Events in the AOP</h3>
<h4><a href="/events/142">Event: 142: Hyperplasia, Hyperplasia</a></h4>
<h5>Short Name: Hyperplasia, Hyperplasia</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>hyperplasia</td>
<td></td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/1">Aop:1 - Uncharacterized liver damage leading to hepatocellular carcinoma</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Tissue</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>liver</td></tr>
</tbody>
</table>
</div>
<h4><a href="/events/57">Event: 57: Proliferation, Cell proliferation in the absence of cytotoxicity</a></h4>
<h5>Short Name: Proliferation, Cell proliferation in the absence of cytotoxicity</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>cell proliferation</td>
<td></td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/1">Aop:1 - Uncharacterized liver damage leading to hepatocellular carcinoma</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>eukaryotic cell</td></tr>
</tbody>
</table>
</div>
<h3>List of Adverse Outcomes in this AOP</h3>
<h4><a href="/events/334">Event: 334: Promotion, Hepatocelluar carcinoma</a></h4>
<h5>Short Name: Promotion, Hepatocelluar carcinoma</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>hepatocellular carcinoma</td>
<td></td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/1">Aop:1 - Uncharacterized liver damage leading to hepatocellular carcinoma</a></td>
<td>AdverseOutcome</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Individual</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>liver</td></tr>
</tbody>
</table>
</div>
<h2>Appendix 2</h2>
<h2>List of Key Event Relationships in the AOP</h2>
<div id="evidence_supporting_links">
<h3>List of Adjacent Key Event Relationships</h3>
<div>
<h4><a href="/relationships/324">Relationship: 324: N/A, Unknown leads to Proliferation, Cell proliferation in the absence of cytotoxicity</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/1">Uncharacterized liver damage leading to hepatocellular carcinoma</a></td>
<td>adjacent</td>
<td>Moderate</td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<h4><a href="/relationships/69">Relationship: 69: Proliferation, Cell proliferation in the absence of cytotoxicity leads to Hyperplasia, Hyperplasia</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/1">Uncharacterized liver damage leading to hepatocellular carcinoma</a></td>
<td>adjacent</td>
<td>Moderate</td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<h4><a href="/relationships/158">Relationship: 158: Hyperplasia, Hyperplasia leads to Promotion, Hepatocelluar carcinoma</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/1">Uncharacterized liver damage leading to hepatocellular carcinoma</a></td>
<td>adjacent</td>
<td>High</td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
</div>
</div>
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