Human lymphoblasts were exposed in vitro to various concentrations of formaldehyde (HCHO) in single and multiple treatment regimens to determine relative mutagenic efficiency. Single treatments of HCHO (0-150 microM X 2 h) resulted in a nonlinear increase in induced mutant fraction at the thymidine kinase locus with increasing slope at concentrations above 125 microM. Only HCHO exposures of 125 microM X 2 h or greater produced significant effects on the growth rate of the lymphoblasts. Cultures were also exposed to either three treatments of 50 microM X 2 h, five treatments of 30 microM X 2 h, or ten treatments of 15 microM X 2 h; multiple treatments were administered on different days. These multiple treatments resulted in increases in mutant fraction, although their combined effect was less than a single treatment of equivalent concentration X time (150 microM X 2 h). Exposure of lymphoblasts to four treatments of 150 microM X 2 h HCHO failed to induce mutations at the ouabain resistance locus. Cultures of lymphoblasts receiving a single treatment of HCHO (0-600 microM X 2 h) were analyzed by the alkaline elution technique to detect the presence of DNA-protein crosslinks. HCHO treatment resulted in a significant nonlinear increase in DNA-protein crosslinks at concentrations greater than 50 microM X 2 h, which correlated with the onset of significant toxicity in this cell line. Holding the culture for 24 h resulted in complete removal of the crosslinks. These data indicate that both the induction of mutations and the formation of DNA-protein crosslinks by HCHO are nonlinear functions in human lymphoblasts and occur at overlapping concentration ranges.