Previous studies have demonstrated that various compounds, including the common groundwater contaminants trichloroethylene (TCE) and chloroform (CHCl³), can produce a synergistic toxic response when coadministered with the model hepatotoxicant carbon tetrachloride (CCI₄). This phenomenon has not, however, been demonstrated following administration of these compounds in drinking water. Initial experiments indicated that Fischer 344 (F-344) rats were significantly more sensitive to these effects than the more commonly utilized Sprague–Dawley strain. To establish the suitability of this strain as a model, a variety of indicators of hepatotoxicity was evaluated and compared to histological evidence of injury 24 hr after dosing with CCl₄ or a combination of CCl₄ + TCE. Plasma alanine aminotransferase (ALT) activity was the most reliable indicator of hepatic injury and was well-correlated with the histologic data. Dose–response studies utilizing simultaneous ip dosing confirm the sensitivity of the F-344 rat, demonstrating synergistic toxicity at doses as low as 0.165 mmol/kg of CCl₄ and 0.6 mmol/kg of TCE. Synergism was also detected following simultaneous ip administration of 1 mmol/kg CCl₄ and 0.5 mmol/kg of CHCl₃. To evaluate the effects of drinking water exposure, rats were pretreated for 3 days with solutions containing TCE (0–40 mM) or CHCl₃ (0–8 mM) stabilized with 1% Emulphor (EL-620P) as their only source of fluids. A single, ip dose of CCl₄ (1 mmol/kg) was then administered and 24 hr later animals were killed for examination of liver histology and determination of ALT activity. Although none of the pretreatments were detectably hepatotoxic, rats which drank 15 and 40 mm TCE or 8 mm CHCl₃ exhibited an enhanced response to CCl₄