Octarmethylcyclotetrasiloxane (D(sub 4)) has been shown in previous studies to be capable of inducing an apparent dose dependent but reversible liver enlargement in some animal species when exposed either orally or via inhalation. Rats, mice and hamsters have shown liver enlargement, whereas rabbits and guinea pigs have not. The present study was conducted to further characterize the species differences of liver response by studying the urinary metabolites, induction of selected liver enzymes and cell replication. Groups of male and female Sprague-Dawley CD(trademark) mice, Golden Syrian hamsters, New Zealand white rabbits and Hartley guinea pigs were repeatedly exposed to D (sub 4) via inhalation at either 10 or 700 ppm for 6 hours per day, 5 days per week for 5 weeks. Urine samples from these species were collected on days 1, 3, 5, 12, 19 and 25. Five animals were used from each group and sex and only day 3 and day 25 samples were analyzed to determine the amounts of Me2SiO ('D') and MeSiO3/2('T') moieties. The cell replication assays were performed on male and female rats (10/sex/group) exposed to 700ppm D (sub 4) for 6 hours a day for 3 or 5 days and also on a group of rats which was exposed for 5 days and then allowed to recover for 14 days prior to sacrifice. The cell replication assays were performed by a standard method developed by the Chemical Industry Institute of Toxicology. The method involves osmotic pump administration of 5-bromo-2'-deoxyuridine (BrdU) and immunohistochemistry to determine hepatocellular proliferation. In addition to BrdU labeled cells, mitotic cell and apoptotic cell counts were also performed. The number of each cell type was counted based on 2,000 cells. The enzyme studies were performed on glutathione S-transferase (GSHT), epoxide hydrolase (EH), and ethoxycoumarin-O-deethtylase (ECOD). Five males and five female rats and guinea pigs from each group were exposed to either 0 or 700ppm D (sub 4) for 6 hours per day for 5 consecutive days. Microsomal and cytosoilic fractions were obtained from all livers following standard procedures and respective enzyme assays were conducted. The overall mean concentrations to which the urine metabolite and liver enzyme groups were exposed were 10 and 705 ppm. The mean exposure concentration for the cell replication groups was 701 ppm. No mortality or overt signs of toxicity were observed in any of the control and treated animals. A statistically significant increase in liver weights was observed in male and female hamsters, mice and rats exposed to 700 ppm D(sub 4). No statistically significant increase in liver weights was observed in rabbits and guinea pigs exposed to 700 ppm D(sub 4).