Abstract
To develop read-across assessment for chemicals with the potential of inducing hemolytic anemia, we took the category approach based on similarities of the chemical structure and mode of action. Firstly, an integrated database was constructed by collecting repeated dose toxicity datasets and metabolism information from Hazard Evaluation Support System Integrated Platform (HESS) in addition to various toxicology databases including ToxRef, COSMOS, and RepDose. In the database, approximately 447 of 1550 substances were identified as those of hematotoxicity that induced hemolytic anemia. Secondly, the category approach based on chemical structures and toxicity mechanisms of the hematotoxic substances led to the following categories: anilines (Category 1), nitrobenzenes (Category 2), nitroanilines (Category 3), hydrazines (Category 4), oximes (Category 5), ethylene glycol and alkyl ethers (Category 6). The mechanisms of toxicity were postulated that: reactive metabolites of substances in Categories 1 to 3 oxidize hemoglobin; substances in Categories 4 and 5 directly oxidize hemoglobin; and reactive metabolites of Category 6 substances modify erythrocyte membrane. Toxic mechanisms of the substances in these categories were directly linked to hemolysis, whereas hematotoxicity induced by a number of substances unclassified to the categories may have indirectly occurred. These categories that are helpful to further clarify structural boundaries associated with hematotoxicity and contribute to constructing AOPs should support read-across assessment for predictive toxicology.
