This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 1


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Uncharacterized liver damage leading to hepatocellular carcinoma

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Liver damage and hepatocellular carcinoma
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v1.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Available for adoption

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Evgeniia Kazymova   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Stephen Edwards
  • Evgeniia Kazymova


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Hyperplasia, Hyperplasia September 16, 2017 10:14
Promotion, Hepatocelluar carcinoma September 16, 2017 10:14
Proliferation, Cell proliferation in the absence of cytotoxicity September 16, 2017 10:14
N/A, Unknown September 16, 2017 10:14
N/A, Unknown leads to Proliferation, Cell proliferation in the absence of cytotoxicity December 03, 2016 16:37
Proliferation, Cell proliferation in the absence of cytotoxicity leads to Hyperplasia, Hyperplasia December 03, 2016 16:37
Hyperplasia, Hyperplasia leads to Promotion, Hepatocelluar carcinoma December 03, 2016 16:37


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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.

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]

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]

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.

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.

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.

AOP Development Strategy


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 294 N/A, Unknown N/A, Unknown
KE 142 Hyperplasia, Hyperplasia Hyperplasia, Hyperplasia
KE 57 Proliferation, Cell proliferation in the absence of cytotoxicity Proliferation, Cell proliferation in the absence of cytotoxicity
AO 334 Promotion, Hepatocelluar carcinoma Promotion, Hepatocelluar carcinoma

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help
Term Scientific Term Evidence Link
rats Rattus norvegicus Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

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.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help


List of the literature that was cited for this AOP. More help

1. U.S. EPA (U.S. Environmental Protection Agency). (2002). Toxic Substances Control Act (TSCA) Inventory Update Database. Available online at (accessed February 22, 2010).

2. “Eleventh Report on Carcinogens” ( United States Department of Health and Human Services’ National Toxicology Program. Retrieved 2 February 2006.

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.

4. Surprenant, KS. (2002). Dioxane. In Ullmann's Encyclopedia of Industrial Chemistry (6th ed.). Weinheim, Germany: Wiley-VCH Verlag.

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.

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.