Hepatotoxic Mixtures---Animal Studies

Many laboratory animal studies have been carried out on the liver toxicity of halogenated hydrocarbon mixtures, with most of these devoted to the potentiation of carbon tetrachloride hepatotoxicity. Other studies have 

Mixtures of the polybrominated biphenyls, PCBs, or hexachlo-robenzene and carbon tetrachloride synergistically increase the toxic effects of carbon tetrachloride on the livers of ratsJ13  

The co-administration of the insecticide chlordecone and carbon tetrachloride potentiates the hepatotoxicity of carbon tetrachloride in laboratory animalsJ14,15  

Hypoxia potentiates the carbon tetrachloride hepatotoxicity in animals and in humans. I16l 

Trichloroethylene, tetrachloroethylene, and chloroform potentiate carbon tetrachloride-induced lipid peroxidation in insolated rat hepatocytesJ17,18  

---

The liver is essential in order to maintain life. Accordingly, xenobiotic attacks on it threaten life and well-being. Many chemicals are hepatotoxic, but mixtures of lipophilic and hydrophilic chemicals are liver toxins at exposure levels that are often far below those that are toxic for the single chemicals in those mixtures. Animal studies have demonstrated the... 

The animal studies just described serve as models for understanding hepatotoxicity of chemical mixtures in humans. Many case studies reporting hepatotoxicity of chemical mixtures in humans have been reported in the literature. The following are illustrative of these studies, which demonstrate the unanticipated hepatotoxic effects of mixtures of lipophiles and hydrophiles. Kqw values are included for each chemical to demonstrate lipophilic or hydrophilic character. 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Hepatic Effects. The hepatotoxic potential of PCB mixtures is well-documented in animals by oral and other routes of exposure. The spectrum of possible hepatic effects in animals is broad and includes microsomal enzyme induction, liver enlargement, increased serum levels of liver enzymes and lipids, and histopathologic alterations that progress to fatty and necrotic lesions and tumors. The findings of human studies, however, are not as obvious. Many of the human studies involving worker and other populations with high body burdens of PCBs report associations between PCBs and hepatic indices such as liver... 

Hepatotoxic effects commonly induced in laboratory animals exposed to commercial PCB mixtures include increased serum levels of liver enzymes indicative of hepatocellular damage (e.g., AST and ALT), serum and tissue biochemical changes indicative of fiver dysfunction (e.g., altered levels of lipids, cholesterol, porphyrins, and vitamin A), and histopathologic changes (particularly fat deposition), fibrosis, and necrosis. Intermediate- and chronic-duration oral studies have shown hepatotoxic effects in monkeys that include fatty degeneration, hepatocellular necrosis, and hypertrophic and hyperplastic changes in the bile duct at oral doses of PCBs as low as 0.1-0.2 mg/kg/day (Aroclor 1254 or 1248). 

---