Alternative Multiorgan Initiation–Promotion Assay for Chemical Carcinogenesis in the Wistar Rat

Abstract

The medium-term multiorgan initiation-promotion chemical bioassay (diethylnitrosamine, methyl-nitrosourea, butyl-hydroxybutylnitrosamine, dihydroxypropylnitrosamine, dimethylhydrazine [DMBDD]) with the Fischer 344 rat was proposed as an alternative to the conventional 2-year carcinogenesis bioassay for regulatory purposes. The acronym DMBDD stands for the names of five genotoxic agents used for initiation of multiorgan carcinogenesis. The Brazilian Agency for the Environment officially recognized a variation of this assay (DMBDD) as a valid method to assess the carcinogenic potential of agrochemicals. Different from the original protocol, this DMBDD is 30-week long, uses Wistar rats and two positive control groups exposed to carcinogenesis promoters sodium phenobarbital (PB) or 2-acetylaminofluorene (2-AAF). This report presents the experience of an academic laboratory with the DMBDD assay and contributes to the establishment of this alternative DMBDD bioassay in a different rat strain. Frequent lesions observed in positive groups to evaluate the promoting potential of pesticides and the immunohistochemical expressions of liver cytochrome P450 (CYP) 2B1/2B2 and CYP1A2 enzymes were assessed. Commonly affected organs were liver, kidney, intestines, urinary bladder, and thyroid. PB promoting activity was less evident than that of 2-AAF, especially in males. This study provides a repository of characteristic lesions occurring in positive control animals submitted to a modified alternative 2-stage multiorgan protocol for carcinogenesis in Wistar rat.

Application of Text Mining in Risk Assessment of Chemical Mixtures: A Case Study of Polycyclic Aromatic Hydrocarbons (PAHs)

“…By employing the CHAT tool and comparing the cancer hallmarks profiles of B[ a ]P and crystalline silica, we hypothesize that in a co-exposure setting, these chemicals could cause carcinogenic synergies. They may act in accordance with experimental studies employing initiation–promotion protocols ( Cohen and Ellwein 1990 ; Solano et al. 2016 ).…”

Chemopreventive Potential of Phyllanthus emblica Fruit Extract against Colon and Liver Cancer Using a Dual-Organ Rat Carcinogenesis Model

“…To address these challenges, researchers have developed multi-organ carcinogenesis models over the years, aiming to replicate real-world exposure to carcinogens and investigate the impact of environmental chemicals on cancer development across various organs within a single experimental framework. These models operate on the initiationpromotion concept of chemical carcinogenesis, employing multiple initiator carcinogens to evaluate the potential of environmental chemicals in promoting cancer development across multiple organs [16][17][18][19]. For instance, studies have demonstrated that the combined administration of N-nitroso diethylamine (NDEA) and azoxymethane (AOM) to initiate both liver and colon carcinogenesis results in more severe preneoplastic lesions in the liver compared to NDEA treatment alone [20].…”