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Oxidation products of lipids, proteins, and DNA in the blood, plasma, and urine of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. This article is the second report of the nationwide Biomarkers of Oxidative Stress Study using acute CCl4 poisoning as a rodent model for oxidative stress. The time-dependent (2, 7, and 16 h) and dose-dependent (120 and 1200 mg/kg i.p.) effects of CCl4 on concentrations of lipid hydroperoxides, TBARS, malondialdehyde (MDA), isoprostanes, protein carbonyls, methionine sulfoxidation, tyrosine products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), leukocyte DNA-MDA adducts, and DNA-strand breaks were investigated to determine whether the oxidative effects of CCl4 would result in increased generation of these oxidation products. Plasma concentrations of MDA and isoprostanes (both measured by GC-MS) and urinary concentrations of isoprostanes (measured with an immunoassay or LC/MS/MS) were increased in both low-dose and high-dose CCl4-treated rats at more than one time point. The other urinary markers (MDA and 8-OHdG) showed significant elevations with treatment under three of the four conditions tested. It is concluded that measurements of MDA and isoprostanes in plasma and urine as well as 8-OHdG in urine are potential candidates for general biomarkers of oxidative stress. All other products were not changed by CCl4 or showed fewer significant effects.

Diphenylhydantoin was tested in vivo in mice using a variety of cytogenetic endpoints to evaluate its genotoxicity. Injected doses of 125, 250 and 500 mg/kg failed to increase the number of chromosome aberrations in marrow cells at 17 h post-treatment, and 37.5, 75 and 150 mg/kg doses were likewise ineffective at 36 h. SCEs were significantly increased by doses of 125 mg/kg (but not 250 mg) after 23 h and modestly, in relation to dose, at 42 h. No increase in the number of micronuclei among marrow PCEs was seen following single i.v. injections ranging from 0.1 to 20 mg/kg. Three daily i.p. injections of doses up to 70 mg/kg also failed to increase the number of micronuclei in either marrow or peripheral blood PCEs. Some cytotoxic effect was evident following relatively high doses.