The effect of propanil on mouse peritoneal macrophages (m phi) was measured by determining cytotoxicity via the P815 cell line, which is resistant to tumor necrosis factor alpha (TNF-alpha). Although control animals showed a typical pattern of requiring both interferon (IFN)-gamma and lipopolysaccharide (LPS) for m phi activation, m phi from propanil-treated animals were cytotoxic when induced with LPS alone. This suggested that propanil influenced endogenous IFN levels. This was confirmed by the abrogation of cytotoxicity upon addition of anti-IFN to the cultures. When cells were assayed for IFN transcript, mRNA in resident m phi was present in higher concentrations in propanil-treated animals. IFN mRNA was present in even higher concentrations in m phi from propanil-treated animals after 30 min of culture with LPS, whereas control m phi required 4 hr in culture with LPS to produce similar levels. IFN protein levels were also higher in propanil-treated m phi after culture in the presence of LPS. Thus, propanil induces increased levels of endogenous IFN which probably works in conjunction with LPS to induce P815 cytotoxicity. Because of the known influence IFN has on the increased secretion of TNF-alpha, we tested the tumoricidal activity of m phi from propanil-treated animals against TNF-alpha-sensitive cell lines. When using WEHI-164 or L929 cells, m phi from propanil-treated animals revealed tumoricidal activity with just the addition of LPS or IFN-gamma. This implies that the additional endogenous levels of IFN, combined with other propanil-induced effects, caused increased secretion of TNF-alpha from m phi.