PRINCIPLES OF TOXICOLOGY - Biology East Borneo

124 HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVERTo make things more complicated, cells go through a series of morphological changes as theyprogress to become a benign or malignant tumor. Thus, groups of cells that represent proliferation ofliver tissue, but are not (or not yet) tumors, may be described as nodular hyperplasia, focal hepatocellularhyperplasia, or foci of hepatocellular alteration, depending on their morphological characteristics.The foci of hepatocellular alteration represent the earliest stages that can be detected microscopically.These foci are small groups of cells that are abnormal, but have no distinct boundary separating themfrom adjacent cells. Their growth rate is such that they are producing little or no compression ofsurrounding cells. The abnormalities are subtle at this stage, and special stains and markers aresometimes used to help visualize them. Nodular hyperplasia is more readily observed; the group ofcells is more circumscribed and compression of adjacent cells is apparent. These cells are thought torepresent an intermediate step in tumor development. The significance of these lesions is not that theyare associated with any clinical signs or symptoms of disease, but rather that they may represent anarea from which a tumor may develop. Consequently, their appearance is important in the assessmentof the ability of a drug or chemical to cause cancer. For most chemicals, only a very smallpercentage—or perhaps none—of the neoplastic areas will go on to produce a malignant tumor.Consequently, the issue of how to use data regarding the appearance of these lesions in the assessmentof carcinogencity of a chemical is one of considerable discussion and debate among toxicologists.Liver tumors from chemical exposure can arise through numerous mechanisms. Some hepatocarcinogensform DNA adducts leading to mutations. Nitrosoureas and nitrosamines are examples ofhepatocarcinogens thought to produce tumors through this mechanism (see also Chapters 12 and 13for further discussion of genotoxicity and carcinogenicity). Many chemicals that produce liver tumorsare not genotoxic, however, and appear to work through epigenetic mechanisms. Nongenotoxichepatocarcinogens are many and diverse, and include tetrachlorodibenzo-p-dioxin, sex steroids,synthetic antioxidants, some hepatic enzyme inducing agents (e.g., phenobarbital), and peroxisomeproliferators (e.g., clofibrate). A discussion of the mechanisms underlying epigenetic carcinogenesis(e.g., inhibition of cell-to-cell communication, recurrent cellular injury, receptor interactions) isbeyond the scope of this chapter, and the reader is referred to Chapter 12 for more information on thissubject.Despite the many chemicals found to produce benign and malignant liver tumors in mice and rats,relatively few have been clearly associated with liver tumors in humans. Adenomas have beenassociated with the use of contraceptive steroids, and clinical and epidemiologic studies implicateanabolic steroids, arsenic, and thorium dioxide as causing hepatocellular carcinoma in humans.Hemangiosarcoma is a rare tumor that has been strongly linked to occupational exposure to vinylchloride, and has also been associated with arsenic and thorium dioxide exposure.5.3 EVALUATION OF LIVER INJURYSymptoms of Liver ToxicityAs discussed above, liver injury may be either acute or chronic, and may involve liver cell death, hepaticvascular injury, disruption of bile formation and/or flow, or the development of benign or malignanttumors. Obviously, the signs and symptoms that accompany this array of types of liver injury can varysignificantly. There are some generalizations that can be made, however. Common symptoms of liverinjury include anorexia (loss of appetite), nausea, vomiting, fatigue, and abdominal tenderness.Physical examination may reveal hepatomegaly (swelling of the liver) and ascites (the accumulationof fluid in the abdominal space). Patients whose liver toxicity involves impaired biliary function maydevelop jaundice, which results from the accumulation of bilirubin in the blood and tissues. Jaundicewill appear as a yellowish tint to the skin, mucous membranes, and eyes. Pruritis, or an itching sensationin the skin, will often accompany the jaundice.If the injury is particularly severe, it may lead to fulminant hepatic failure. When the liver fails,death can occur in as little as 10 days. There are several complications associated with fulminant hepatic