Species differences in short term toxicity from inhalation exposure to bromobenzene

Abstract

Lung, liver and kidney injury were studied in mice, rats and rabbits 48 h after termination of a 4 h inhalation exposure to bromobenzene vapour (250-3400 ppm). Light and electron microscopy of lung tissue revealed injury to Clara cells and adjacent epithelium in mouse bronchioli (bromobenzene concentration 250 ppm and 1000 ppm) and to Clara cells of rat bronchi and bronchioli (1000 ppm bromobenzene) and of rabbit bronchi (2500 ppm and 3400 ppm). Histological and clinicochemical indices of liver damage were found in the same animals, whereas kidney toxicity was observed in mice (two out of ten showed tubular necrosis and elevated concentration of plasma urea) and rats (all had elevated plasma concentrations of creatinine) exposed to 1000 ppm bromobenzene. Inhalation exposure thus produced less kidney injury than expected from previous studies with equimolar doses given intraperitoneally. The mouse was the most severely affected species, followed by the rat, and lastly the rabbit. The animal susceptibility could not be ranked according to the rate of 14C-bromobenzene covalent binding in lung or liver, but it was inversely related to the rate of N-demethylation of benzphetamine (indicative of P450IIB activity) in both lung and liver microsomal preparations. Differences in a P450 mediated detoxification could therefore be of importance in species variability to bromobenzene injury.

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

“…A number of simple chemical compounds such as acetaminophen, bromobenzene, furosemide, methapyrilene (Graham et al 2008), and thiobenzamide (Ikehata et al 2008) produce hepatotoxicity, with damage to extrahepatic tissues in certain cases (bromobenzene is also pneumotoxic and nephrotoxic; Dahl et al 1990), in one or more rodent species after a single dose or a short-term regimen. The reproducibility of these injuries permits detailed mechanistic investigations that are impractical or unachievable in the case of idiosyncratic reactions; however, they may provide a source of crucial insights into the mechanisms of such reactions.…”

Comparative Proteomic Analysis of Liver Steatosis and Fibrosis after Oral Hepatotoxicant Administration in Sprague-Dawley Rats

“…Toxicants and drugs, including amiodarone, methotrexate, irinotecan, and glucocorticoids, are well recognized to cause steatosis (Rabinowich and Shibolet 2015). Although BB is best known as a metabolically activated necrosis-inducing toxicant, exposure has resulted in vacuolation with lipid accumulation indicative of steatosis (Heijne et al 2005; Wong, Card, and Racz 2000; Dahl et al 1990; Yoshioka et al 2017). In our study, BB administration resulted in histological features associated with nonalcoholic fatty liver disease (NAFLD), characterized by mild inflammation with vacuolation and positive staining for Oil Red O (i.e., presumptive lipid accumulation).…”