Aop:31

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Status

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AOP Title

Oxidation of iron in hemoglobin leading to hematotoxicity
Short name: Hemoglobin oxidation leading to hematotoxicity

Authors

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

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

Status

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OECD Project 1.16: The Adverse Outcome Pathway Describing Hematotoxicity due to Nitroaromatics and N-hydroxyl anilines.

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

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maintain glutathione levels and therefore protect cells, especially RBC, from oxidative damage (Wilbanks, et al., unpublished observations).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.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
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 Strong

Key Events

Event Support for Essentiality
Alpha hemoglobin, Altered regulation Moderate
Oxidative stress, Propagation Moderate
Red blood cells; hemolysis, Damaging Strong
Formation of hemoglobin adducts, Formation Moderate
Gulcose-6-phosphate dehydrogenase, Down Regulation Moderate
RBC congestion in liver, Increase Moderate
Liver and splenic hemosiderosis, Increase Strong
Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number, N/A Strong

Adverse Outcome

Adverse Outcome
Cyanosis occurs, N/A

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
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 Directly Leads to Oxidative stress, Propagation Moderate
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 Directly Leads to Red blood cells; hemolysis, Damaging Strong
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 Directly Leads to Formation of hemoglobin adducts, Formation Strong
Red blood cells; hemolysis, Damaging Directly Leads to RBC congestion in liver, Increase Moderate
Red blood cells; hemolysis, Damaging Directly Leads to Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number, N/A Strong
Red blood cells; hemolysis, Damaging Directly Leads to Liver and splenic hemosiderosis, Increase Strong
Oxidative stress, Propagation Directly Leads to Gulcose-6-phosphate dehydrogenase, Down Regulation Weak
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 Indirectly Leads to Alpha hemoglobin, Altered regulation Weak
Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number, N/A Directly Leads to Cyanosis occurs, N/A Strong
RBC congestion in liver, Increase Directly Leads to Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number, N/A Moderate
Oxidative stress, Propagation Directly Leads to Red blood cells; hemolysis, Damaging Strong
Liver and splenic hemosiderosis, Increase Directly Leads to Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number, N/A Moderate

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
Mus musculus Mus musculus Strong NCBI
Rattus norvegicus Rattus norvegicus Strong NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

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

Weight of Evidence Summary

Summary Table
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Quantitative Considerations

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Applicability of the AOP

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Considerations for Potential Applications of the AOP (optional)

References

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.