{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T17:09:25Z","timestamp":1777914565341,"version":"3.51.4"},"reference-count":46,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[1996,5,1]],"date-time":"1996-05-01T00:00:00Z","timestamp":830908800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[1996,5]]},"abstract":"<jats:p>Apoptosis was evaluated in the livers of Fischer-344 rats following observations of increased hepatocellular proliferation from exposures, at low parts per million (ppm) levels, to a drinking water mixture of 7 groundwater contaminants during a 6-mo time-course study. The 7 chemicals used are among the most frequently detected contaminants associated with hazardous waste sites: arsenic, benzene, chloroform, chromium, lead, phenol, and trichloroethylene. Significant increases in 5-bromo-2'-deoxyuridine hepatocellular labeling were present in a unique pattern surrounding large hepatic veins (0.5-2.0 mm). This did not appear to be a regenerative response due to cytotoxicity, as assessed by the absence of increased plasma enzyme activity and the absence of hepatocellular lesions. Immunohistochemical staining for apoptosis, using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method showed patterns of labeling in treated animals that directly correlated to areas of increased hepatocyte proliferation. Apoptotic activity was maximum at the 1-mo exposure time point, whereas proliferating hepatocytes reached a maximum rate at the 10-day time point. This may have been triggered as a compensatory response to the increased cell proliferation or as a protective response to remove cells with altered DNA due to chemical mixture exposure. The principal findings of this paper are that (a) apoptosis directly correlated with changes in cell proliferation; (b) observed effects were produced by repeated exposures to a relatively low-level chemical mixture; and (c) the TUNEL method detected apoptotic cells at very early and late stages, potentially increasing the observable time period for apoptosis.<\/jats:p>","DOI":"10.1177\/019262339602400307","type":"journal-article","created":{"date-parts":[[2009,4,1]],"date-time":"2009-04-01T19:16:47Z","timestamp":1238613407000},"page":"315-322","source":"Crossref","is-referenced-by-count":14,"title":["Increased Rate of Apoptosis Correlates with Hepatocellular Proliferation in Fischer-344 Rats Following Long-Term Exposure to a Mixture of Groundwater Contaminants"],"prefix":"10.1177","volume":"24","author":[{"given":"Alexander A.","family":"Constan","sequence":"first","affiliation":[{"name":"Center for Environmental Toxicology and Technology, Department of Environmental Health,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen A.","family":"Benjamin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Colorado State University, Fort Collins, Colorado 80523"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John D.","family":"Tessari","sequence":"additional","affiliation":[{"name":"Center for Environmental Toxicology and Technology, Department of Environmental Health"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dale C.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Pathology, Colorado State University, Fort Collins, Colorado 80523"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond S.H.","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Environmental Toxicology and Technology, Department of Environmental Health"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[1996,5,1]]},"reference":[{"key":"atypb1","volume-title":"Toxicological Profile for Lead","author":"Agency for Toxic Substances and Disease Registry","year":"1993"},{"key":"atypb2","volume-title":"Toxicological Profile for Trichloroethylene","author":"Agency for Toxic Substances and Disease Registry","year":"1993"},{"key":"atypb3","unstructured":"Andrews LS and Snyder R. 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