D006965 MESH hyperplasia D006528 MESH hepatocellular carcinoma GO:0008283 GO cell proliferation 1 WIKI increased 10116 NCBI rats Hyperplasia, Hyperplasia Tissue UBERON:0002107 UBERON liver AOPWiki 2016-11-29T18:41:23 2017-09-16T10:14:15 Promotion, Hepatocelluar carcinoma Individual UBERON:0002107 UBERON liver AOPWiki 2016-11-29T18:41:24 2017-09-16T10:14:15 Proliferation, Cell proliferation in the absence of cytotoxicity Cellular CL:0000255 CL eukaryotic cell AOPWiki 2016-11-29T18:41:22 2017-09-16T10:14:15 N/A, Unknown Molecular CL:0000255 CL eukaryotic cell AOPWiki 2016-11-29T18:41:23 2017-09-16T10:14:15 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc67c1f8> AOPWiki 2016-11-29T18:41:33 2016-12-03T16:37:56 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430024d510> AOPWiki 2016-11-29T18:41:33 2016-12-03T16:37:54 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308a3a400> AOPWiki 2016-11-29T18:41:33 2016-12-03T16:37:55 Liver damage and hepatocellular carcinoma Evgeniia Kazymova <p>Available for adoption </p> BY-SA 1.0 <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> adjacent Not Specified Moderate adjacent Not Specified Moderate adjacent Not Specified High Moderate <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> <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> AOPWiki 2016-11-29T18:41:15 2023-09-25T16:26:43