The relationship between perturbation of the cell cycle and induction of cell death by benzo[a]pyrene diol epoxide (BPDE) or N-acetoxy-2-acetylaminofluorene (AcAAF) in exponentially proliferating T5-1 human lymphoblastoid cells was studied. Both BPDE and AcAAF caused cells to accumulate in the S phase of the cell cycle. Perturbation of the cell cycle preceded reduction of cell viability and was associated with inhibition of population growth. Effects on each of the three parameters were noted during the first population doubling, suggesting that they occurred during the first cell cycle after exposure. BPDE-exposed cells accumulated initially in early to mid-S phase and then moved parasynchronously through the remainder of this phase. In contrast, AcAAF-exposed cells accumulated uniformly at all points of the S phase. High doses of either compound froze cell cycle progression, completely inhibited population growth, and killed nearly all cells in the population. Our results suggest that perturbation of DNA replication mediates cell death after exposure to doses of either chemical that cause less than complete inhibition of cell proliferation. However, additional processes, such as perturbation of transcription, may be involved in lethality after exposure to doses that immediately and completely inhibit population growth.