Carcinogenicity of saccharin in laboratory animals and humans: letter to Dr. Harry Conacher of Health Canada.

We appreciate this opportunity to provide input to the Health Protection Branch's (HPB's) review of the artificial sweetener saccharin. Concerns with regard to the safety of saccharin are of great public health significance and of great interest to the public because saccharin is consumed by tens of millions of people, including children and fetuses. Any evidence of carcinogenesis--and there is ample such evidence--of such a widely used chemical should spur health officials to minimize human exposure to it. It is worth noting that on October 31, 1997, the Board of Scientific Counselors of the National Toxicology Program, a unit of the National Institute of Environmental Health Sciences (NIEHS), voted not to delist saccharin from its Report on Carcinogens.

The Biology of Carcinogen-Induced Hepatocyte Nodules and Related Liver Lesions in the Rats 1.

The only known sequence of tissue changes seen during liver cancer development involves microscopic foci or islands of altered hepatocytes, hepatocyte nodules, a subset of these nodules, the persistent nodules, nodules in nodules and ultimately hepatocellular carcinoma. The nodules show an array of architectural, fine ultrastructural, vascular, biochemical and physiological properties characteristic of this new population of hepatocytes. Despite their origin following initiation with a chemical carcinogen, the vast majority (98-99%) of nodules undergo a complex process of remodeling or redifferentiation to normal looking mature liver. A very small minority persist, continue to grow slowly and ultimately may act as a site of origin for new later precancerous nodules and metastasizing hepatocellular carcinoma. The basis for the different behaviour patterns, remodelling of the majority and persistence of the minority is not understood. Even though the vast majority of nodules do undergo remodelling and "disappear", it would be unwise at this time to ignore this key role of nodules in general in cancer development.

Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments.

Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs. Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity. Thus, hypolipidemics such as gemfibrozil or clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits.