The discovery that phorbol ester tumor promoters inhibit metabolic cooperation between cultured cells in proportion to their promoting activity in vivo suggests that such inhibition may be a mechanism in tumor promotion. Because metabolic cooperation appears to be essential for normal cell differentiation and tissue development, the concept that chemicals might be toxic by blocking this process may, in theory, be extended to reproductive system toxicants. The authors are testing these hypotheses using an assay developed with V79 cells. Effects of chemicals on metabolic cooperation are assessed by adding test chemical and selective agent (6-thioguanine) simultaneously to co-cultivated mutant (HGPRT(-)) and wild-type (HGPRT(+)) cells in reconstructed mutant selection experiments. Effects of test chemicals are measured as a function of mutant cell recovery relative to that in a control. The studies indicate that in addition to phorbol ester promoters (PMA, PDBu), nonphorbol ester promoters (BHT, cyclamate), cocarcinogenic or teratogenic solvents (ETOH, DMSO), and potentially epigenetic carcinogens (DEPH, NTA) inhibit metabolic cooperation. Some promoters (phenol) do not appear to block metabolic cooperation directly, but yield metabolites which do.