ATHEROSCLEROTIC RISKS FROM CHEMICALS - PART I - TOXICOLOGICAL OBSERVATIONS AND MECHANISMS OF ATHEROSCLEROSIS

Atherosclerosis is a common disease, primarily of the large arteries, that begins in childhood and progresses with advancing age. Atheroscle rosis leads to coronary heart disease, the major cause of death in the United States. Several risk factors affect atherosclerosis, but high LDL cholesterol is the most important risk factor. In addition, high l evels of lipoprotein (a) appear to be associated with increased athero sclerosis and myocardial infarction. The level of lipoprotein (a) is g enetically determined and is not affected by diet or exercise. Studies on the pathogenesis of atherosclerosis suggest that several steps are involved, including endothelial injury, increased arterial permeabili ty to plasma lipoproteins, smooth muscle cell proliferation, and plate let aggregation Atherosclerotic plaques are benign neoplasms of the ar terial wall that result from the monoclonal proliferation of a single mutated smooth muscle cell. Abnormal proliferation of smooth muscle ce lls is the key event in the initiation and progression of atherosclero sis. Endothelial injury is another major contributory factor. Many fac tors associated with an increased risk of cancer are also associated w ith atherosclerosis. Cancer and atherosclerosis go through the same st ages of initiation, promotion, and complication. Both inflammatory and immune reactions play important roles in the progressions of the two diseases. Smooth muscle cells and endothelial cells produce and respon d to several cytokines and growth factors, which may influence the ini tiation, progression, and complication of the atherosclerotic lesions. Many studies have shown that the production of nitric oxide is decrea sed in atherosclerosis-reduction in the bioavailability of nitric oxid e in the arterial wall may lead to leukocyte adhesion and platelet agg regation, it should be noted additionally, nitric oxide is a mutagenic agent involved in the origin of neoplastic diseases. Atherosclerotic plaques express genes for products not found in the normal arterial wa ll. As with carcinogenesis, there may be more than one mechanism that promotes atherosclerotic lesions and there may be common mechanistic s imilarities between the two diseases. The purpose of this study is to establish an exploratory scientific hypothesis that will permit the us e of standardized toxicological test data to evaluate different chemic als. The companion paper that follows will use a method of relative to xicological potencies to develop tentative risk coefficients based on relative potency. These papers, in combination provide both a conceptu al and a quantitative hypothesis that can be tested with data from for thcoming epidemiological studies or animal test models.