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  • 1
    ISSN: 1432-0703
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Notes: Abstract. Atherosclerosis is a common disease, primarily of the large arteries, that begins in childhood and progresses with advancing age. Atherosclerosis 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 levels of lipoprotein (a) appear to be associated with increased atherosclerosis and myocardial infarction. The level of lipoprotein (a) is genetically 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 permeability to plasma lipoproteins, smooth muscle cell proliferation, and platelet aggregation. Atherosclerotic plaques are benign neoplasms of the arterial wall that result from the monoclonal proliferation of a single mutated smooth muscle cell. Abnormal proliferation of smooth muscle cells is the key event in the initiation and progression of atherosclerosis. Endothelial injury is another major contributory factor. Many factors associated with an increased risk of cancer are also associated with atherosclerosis. Cancer and atherosclerosis go through the same stages 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 respond to several cytokines and growth factors, which may influence the initiation, progression, and complication of the atherosclerotic lesions. Many studies have shown that the production of nitric oxide is decreased in atherosclerosis—reduction in the bioavailability of nitric oxide in the arterial wall may lead to leukocyte adhesion and platelet aggregation. 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 wall. As with carcinogenesis, there may be more than one mechanism that promotes atherosclerotic lesions and there may be common mechanistic similarities between the two diseases. The purpose of this study is to establish an exploratory scientific hypothesis that will permit the use of standardized toxicological test data to evaluate different chemicals. The companion paper that follows will use a method of relative toxicological potencies to develop tentative risk coefficients based on relative potency. These papers, in combination, provide both a conceptual and a quantitative hypothesis that can be tested with data from forthcoming epidemiological studies or animal test models.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0703
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Notes: Abstract A common definition of relative potency is the dose of a reference compound required to cause a particular incidence of a specific toxic response divided by the dose of a test compound needed to cause an equal incidence of that same effect. In this simple manner, toxicological assessments for a chemical of concern can be made in terms of another compound about which much is known from a human health perspective. Relative potency factors were used to compare 2,3,7,8-tetrachlorodibenzo-p-dioxin CAS # 1746-01-6 (TCDD) with 100 other compounds both individually and collectively. All results were standardized to a common scale that spanned many orders of magnitude and was indexed to an arbitrary potency of unity for benzo(a)pyrene [B(a)P]. From comparisons between 2,771 pairs of bioassay results (i.e., matched experimental design conditions) for TCDD compared with the 100 other compounds, it was found that TCDD is about 600 times as toxic as B(a)P (interquartile range of 130 to 1,900). The distribution of relative potency values is fitted accurately with a log-normal distribution function having an untransformed mean of 550 and an untransformed slope (i.e., the inverse of the standard deviation of the distribution) of 140. These factors combined with (a) a reference lifetime carcinogenic risk level of 1/100,000 and (b) a universal, potency-dependent risk coefficient (estimated from the collection of epidemiologically-based carcinogens) yielded estimates that equally toxic concentrations for TCDD should be in the range of 13 pg/m3 and 7 pg/L in air and water, respectively.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0703
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Notes: Abstract. As reviewed in the Part I companion manuscript by Basavaraju and Jones (Arch Environ Contam Toxicol), atherosclerosis and carcinogenesis may share some common mechanisms of toxicological action. On that hypothesis, standardized test data taken from the Registry of Toxic Effects of Chemical Substances (RTECS) were used to compute relative potency factors for chemical compounds associated with increased risk of atherosclerosis to humans. Potencies of the different compounds were computed relative to each of six reference compounds comprised of benzo(a)pyrene, nicotine, cisplatin, adriamycin, estrogen, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Reference-specific potencies were all converted to a common numerical scale adjusted to unit potency for B(a)P. Because the list of compounds contained several antibiotics, amino acids, hormones, chemotherapeutic agents, polynuclear aromatics, alkaloids, metals, and vitamins, the standardized estimates of potency varied significantly depending on which of the six reference compounds are considered as standards of comparison. For the n − 1 other substances. Estimates of relative potency, risk coefficients, and generalized risk equations are estimated for cigarette smoke condensate, dietary cholesterol, ethanol, and carbon disulfide. From data on atherosclerosis as a result of cigarette smoking, a tentative risk was estimated as Increased Relative Risk = S (mg/kg-day)−1× dose (mg/kg-day) × RP, where the dose is chronic intake per kilogram of body weight per day, RP is the potency of the compound of interest relative to that of benzo(a)pyrene, and S is 0.83, 0.25, 0.20, or 13 depending on whether cigarette smoke, cholesterol, ethanol, or carbon disulfide epidemiological data were used as a standard of comparison.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2021-03-01
    Electronic ISSN: 1525-2027
    Topics: Chemistry and Pharmacology , Geosciences , Physics
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