Synthetic and environmental hepatotoxins

Set of nongenotoxic chemicals that can cause specific organotoxicity in a variety of tissues is classified as peroxisome proliferators. Toxicity can occur when enzymes in the peroxisomes metabolize fatty acids to produce hydrogen peroxide. Chemicals that act as peroxisome proliferators, including drugs like clofibrate, pesticides like 2,4-D, and industrial chemicals like trichloroethylene, increase cell numbers, peroxisomes, and the size of liver and, upon repeated exposure, cause liver cancer in rodents. The issue is whether these chemicals can cause cancer in human beings also.

Peroxisomes are single-membrane cytoplasmic organelles that contain fine granular matrix. Present in all mammalian cells except red blood cells, peroxisomes carry out peroxidative functions through oxidase enzymes by metabolizing long-chain fatty acids. The number of peroxisomes, their size, and enzymatic profile can vary by tissue location. When exposed to certain chemicals called "peroxisome proliferators," these organelles readily multiply.

While these compounds seem to produce similar qualitative changes in rodent liver cells, their quantitative response is dose dependent and specie specific. Although the liver is the biggest target of peroxisome proliferators, morphological and/or biochemical changes occur in several tissues including the testis, thyroid, kidney, intestine, adrenal glands, and heart.

Also, in addition to liver tumors, a subset of peroxisome proliferators increase testicular and pancreatic tumors in rodents. Rodent hepatic cells, though, are the most responsive to peroxisome proliferators and the most extensively studied tissue.

Peroxisome proliferators are nongenotoxic carcinogens, which, unlike genotoxic carcinogens, do not directly damage DNA themselves. In the liver nongenotoxic carcinogens may cause hepatomegaly through their action on endoplasmic reticulum, by increasing the number of peroxisomes, or by increasing the number of mitochondria. Many nongenotoxic carcinogens are now being identified.

Liver size has been seen to increase dramatically in rodents after exposure to many peroxisome proliferators. In addition to hepatic hypertrophy, hepatocellular replication is responsible for much of the increase, through a self-limiting/ transient process that occurs during the early stages of exposure.

During the first week after exposure to most peroxisome proliferators, the cell replication rate may increase but soon returns to its baseline rate. Extensive experimental evidence proves there is more than a casual link between peroxisome proliferator-elicited hepatomegaly and subsequent liver tumors in rodents. This link, though, has not been established in humans yet.

Peroxisome proliferators are among the most extensively studied nongenotoxic carcinogens. Still, proposed peroxisome proliferator mechanisms of action, including oxidative stress, induction of hepatic cell proliferation, and the role of the peroxisome proliferator-activated receptor (PPAR), need to be sorted out properly. Until these mechanisms of rodent cancer induction are fully elucidated, it will be difficult to assess the health risk to humans.

Treatment with fluids can alleviate the initial symptoms, but there is no known cure for death cap poisoning. Death occurs in twenty percent to thirty percent of all known cases, and in more than 50 percent of cases for children under 10 years old.