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Chemical-Induced Atrial Thrombosis in NTP Rodent Studies
1 Laboratory of Experimental Pathology Correspondence: Address correspondence to: Abraham Nyska, Laboratory of Experimental Pathology, NIEHS, Research Triangle Park, NC 27709, USA; e-mail:nyska{at}niehs.nih.gov
Cardiac thrombosis, one of the causes of sudden death throughout the world, plays a principal role in several cardiovascular diseases, such as myocardial infarction and stroke in humans. Data from studies of induction of chemical thrombosis in rodents help to identify substances in our environment that may contribute to cardiac thrombosis. Results for more than 500 chemicals tested in rodents in 2-year bioassays have been published as Technical Reports of the National Toxicology Program (NTP) Supplementary data referenced in this paper are not printed in this issue of Toxicologic Pathology. They are available as downloadable files at http:taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233. To access them, click on the issue link for 33(5), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.
Key Words: Heart • left atrium • atrial thrombosis • F344 rats • B6C3F1 mice • chemical-induced • NTP studies Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry • 2-BE, 2-butoxyethanol • Blue 15, C.I. Direct Blue 15 • CEM, bis(2-chloroethoxy)methane • COX-2, cyclo-oxygenase-2 • DAB, diazoaminobenzene • DEL, diethanolamine • DMOB, 3,3'-dimethoxybenzidine dihydrochloride • F344, Fischer 344 • HCE, hexachloroethane • IBT, isobutene • ICAM-1, intercellular adhesion molecule-1 • MEG, methyleugenol • NO, nitric oxide • NOS, nitric oxide synthase • NTP, National Toxicology Program • OZP, oxazepam • Red 23, C.I. Pigment Red 23 • Red 114, C.I. Acid Red 114 • TBBC, 4,4'-thiobis(6-t-butyl-m-cresol) • tPA, tissue-type plasminogen activator • TTP, thrombotic thrombocytopenic purpura • VCAM-1, vascular cell adhesion molecule-1
Toxicologic Pathology, Vol. 33, No. 5,
517-532 (2005) |
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. We evaluated atrial thrombosis induced by these chemical exposures and compared it to similarly induced lesions reported in the literature. Spontaneous rates of cardiac thrombosis were determined for control Fischer 344 rats and B6C3F1 mice: 0% in rats and mice in 90-day studies and, in 2-year studies, 0.7% in both genders of mice, 4% in male rats, and 1% in female rats. Incidences of atrial thrombosis were increased in high-dosed groups involving 13 compounds (incidence rate: 20–100%): 2-butoxyethanol, C.I. Direct Blue 15, bis(2-chloroethoxy)methane, diazoaminobenzene, diethanolamine, 3,3'-dimethoxybenzidine dihydrochloride, hexachloroethane, isobutene, methyleugenol, oxazepam, C.I. Pigment Red 23, C.I. Acid Red 114, and 4,4'-thiobis(6-t-butyl-m-cresol). The main localization of spontaneously occurring and chemically induced thromboses occurred in the left atrium. The literature survey suggested that chemical-induced atrial thrombosis might be closely related to myocardial injury, endothelial injury, circulatory stasis, hypercoagulability, and impaired atrial mechanical activity, such as atrial fibrillation, which could cause stasis of blood within the left atrial appendage, contributing to left atrial thrombosis.