Aop: 31

Title

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

Oxidation of iron in hemoglobin leading to hematotoxicity

Short name
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Hemoglobin oxidation leading to hematotoxicity

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

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Mitchell Wilbanks, Kurt Gust, Youping Deng, Sharon Meyer, and Edward Perkins

Point of Contact: Mitchell Wilbanks, Mitchell.S.Wilbanks@usace.army.mil

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
Cataia Ives   (email point of contact)

Contributors

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  • Mitchell S. Wilbanks
  • Cataia Ives

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for adoption Under Development 1.16 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leading to oxidation of heme iron(II) in hemoglobin to iron(III) December 03, 2016 16:37
Altered regulation, Alpha hemoglobin September 16, 2017 10:14
Propagation, Oxidative stress September 16, 2017 10:14
Damaging, Red blood cells; hemolysis September 16, 2017 10:14
Formation, Formation of hemoglobin adducts September 16, 2017 10:14
Down Regulation, Gulcose-6-phosphate dehydrogenase September 16, 2017 10:14
Increase, RBC congestion in liver September 16, 2017 10:14
Increase, Liver and splenic hemosiderosis September 16, 2017 10:14
N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number September 16, 2017 10:14
N/A, Cyanosis occurs December 03, 2016 16:33
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Propagation, Oxidative stress December 03, 2016 16:37
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Damaging, Red blood cells; hemolysis December 03, 2016 16:37
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Formation, Formation of hemoglobin adducts December 03, 2016 16:37
Damaging, Red blood cells; hemolysis leads to Increase, RBC congestion in liver December 03, 2016 16:37
Damaging, Red blood cells; hemolysis leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number December 03, 2016 16:37
Damaging, Red blood cells; hemolysis leads to Increase, Liver and splenic hemosiderosis December 03, 2016 16:37
Propagation, Oxidative stress leads to Down Regulation, Gulcose-6-phosphate dehydrogenase December 03, 2016 16:37
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Altered regulation, Alpha hemoglobin December 03, 2016 16:37
N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number leads to N/A, Cyanosis occurs December 03, 2016 16:37
Increase, RBC congestion in liver leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number December 03, 2016 16:37
Propagation, Oxidative stress leads to Damaging, Red blood cells; hemolysis December 03, 2016 16:37
Increase, Liver and splenic hemosiderosis leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number December 03, 2016 16:37

Abstract

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

Studies have shown that aniline, 2,4,6-trinitrotoluene (TNT) and 2,4-dinitrotoluene (2,4-DNT) are converted to the reactive metabolite and form free radicals leading to oxidization of heme Iron(II) in hemoglobin to Iron(III), a molecular initiating event. Damage then occurs to red blood cells (RBCs) and methemoglobinemia ensues which is characterized by reduced RBCs, hemoglobin concentration, and Heinz body formation (Ellis et al. 1985, Lee et al. 1976, 1978, Hazleton Laboratories 1977, 1982, Kozuka et al. 1978, 1979, Bolt et al. 2006). The adverse outcome due to such hematological effects is cyanosis with possible death if methemoglobin levels become severe. Hemoglobin adducts are also formed by these chemicals (Sabbioni et al. 2006). Sinusoidal congestion was noted in animals who were exposed to 2,4-DNT or 2,6-DNT (Deng et al. 2011) while hemosiderosis was reported in another study involving DNT (Lee et al. 1978) and in aniline studies. A compensatory response to possible anemic effects has been observed in animals including increased peripheral reticulocytes (Deng et al. 2011) and induction of genes associated with heme biosynthesis (CPOX and UROS) (Rawat et al. 2010). Oxidative stress is also induced upon this interaction with the RBC which may lead to DNA damage and cell death to not only the RBC but other cells such as hepatocytes (Deng et al. 2011). Glucose-6-phosphate dehydrogenase (G6pd) was found to be significantly down-regulated in animals treated with 2,4-DNT for 14 d which leads to decreased levels of NADPH, a coenzyme used to properly maintain glutathione levels and therefore protect cells, especially RBC, from oxidative damage (Wilbanks, et al., unpublished observations). In response to increased oxidative stress, protective mechanisms such as the Nrf2 mediated oxidative stress response may be induced (Deng et al. 2011). While this AOP specifically shows effects of 2,4-DNT and 2,6-DNT, the principal adverse pathways of oxidation of Fe(II) to Fe(III) leading to methemoglobinemia and its downsteam effects and oxidative stress formation leading to its downstream effects are shared with the more well characterized structurally similar compound group of N-hydroxyl anilines.

AOP Development Strategy

Context

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

Strategy

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

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Events:

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 213 N/A, Parent compound is converted to the reactive metabolite and forms free radicals leading to oxidation of heme iron(II) in hemoglobin to iron(III) N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin
KE 21 Altered regulation, Alpha hemoglobin Altered regulation, Alpha hemoglobin
KE 211 Propagation, Oxidative stress Propagation, Oxidative stress
KE 250 Damaging, Red blood cells; hemolysis Damaging, Red blood cells; hemolysis
KE 118 Formation, Formation of hemoglobin adducts Formation, Formation of hemoglobin adducts
KE 131 Down Regulation, Gulcose-6-phosphate dehydrogenase Down Regulation, Gulcose-6-phosphate dehydrogenase
KE 246 Increase, RBC congestion in liver Increase, RBC congestion in liver
KE 161 Increase, Liver and splenic hemosiderosis Increase, Liver and splenic hemosiderosis
KE 173 N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number
AO 321 N/A, Cyanosis occurs N/A, Cyanosis occurs

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
Title Adjacency Evidence Quantitative Understanding

Network View

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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
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High 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

This AOP is constructed using data from human, rat, mouse, avian, and fish based studies.

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

References

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

Bolt HM, Degen GH, Dorn SB, Plöttner S, Harth V (2006) Genotoxicity and potential carcinogenicity of 2,4,6-TNT trinitrotoluene: structural and toxicological considerations. Reviews on environmental health. Oct-Dec; 21(4):217-28.

Deng Y, Meyer SA, Guan X, Escalon BL, Ai J, et al. (2011) Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds. PLoS ONE. 6(2): e14662.

Ellis HV, Hong CB, Lee CC, et al. 1985. Subchronic and chronic toxicity studies of 2,4-dinitrotoluene. Part I. Beagle dog. J Am Co11 Toxicol. 4:233-242.

Jones, C.R., Liu, Y., Sepai, O., Yan, H., and Sabbioni, G. (2005). Hemoglobin adducts in workers exposed to nitrotoluenes. Carcinogenesis. 26(1):133-143.

Kozuka H, Mori M., Katayama K, Matsuhashi T, Miyahara T, Mori Y, and Nagahara S. 1978. Studies on the metabolism and toxicity of dinitrotoluenes-Metabolism of dinitrotoluenes by Rhodotorula glutinis and rat liver homogenate. Eisei Kagaku, 24: 252-259.

Kozuka H, Mori M, and Yoshifumi, N. 1979. Studies on the metabolism and toxicity of dinitrotoluenes: Toxicological study of 2,4-dinitrotoluene (2,4-DNT) in rats in long term feeding. The Journal of Toxicological Sciences. 4:221-228.

La, D.K. and Froines, J.R. (1992). Comparison of DNA adduct formation between 2,4 and 2,6-dintirotoluene by 32P-postlabelling analysis. Archives of Toxicology. 66(9):633-640.

Lee CC, Ellis HV, Kowalski JJ, et al. 1976. Mammalian toxicity of munitions compounds. Phase II: Effects of multiple doses. Part IIh 2,6-Dinitrotoluene. Progress report no. 4. Midwest Research Institute Project no. 3900-B. Contract no. DAMD-17-74-C-4073. From ASTDR.

Lee CC, Ellis HV, Kowalski JJ, et al. 1978. Mammalian toxicity of munitions compounds. Phase II: Effects of multiple doses. Part Il: 2,4-Dinitrotoluene. Progress report No. 3. Midwest Research Institute, Kansas City, MO. Contract no. DAMD 17-74-C-4073. From ASTDR.

Hazleton Laboratories. 1977. A thirty-day toxicology study in Fischer-344 rats given dinitrotoluene, technical grade. Full report. Submitted to Chemical Industry Institute of Toxicology, Research Triangle Park, NC.

Hazleton Laboratories. 1982. 104-week chronic study in rats. Dinitrotoluene. Final report Volume I of II. Submitted to Chemical Industry Institute of Toxicology, Research Triangle Park, NC.

Rawat A, Gust KA, Deng Y, Garcia-Reyero N, Quinn MJ Jr, Johnson MS, Indest KJ, Elasri MO, Perkins EJ. From raw materials to validated system: the construction of a genomic library and microarray to interpret systemic perturbations in Northern bobwhite. Physiol Genomics. 42: 219–235, 2010.

Sabbioni G, Jones CR, Sepai O, et al. 2006. Biomarkers of exposure, effect, and susceptibility in workers exposed to nitrotoluenes. Cancer Epidemiol Biomarkers. Prev 15(3):559-66.

Wintz H, Yoo LJ, Loguinov A, Wu Y, Steevens JA, Holland RD, Beger RD, Perkins EJ, Hughes O, Vulpe CD. Gene expression profiles in fathead minnow exposed to 2,4-DNT: correlation with toxicity in mammals. Toxicol Sci. 94: 71–82, 2006.