CORRELATION OF REGIONAL AND NONLINEAR FORMALDEHYDE-INDUCED NASAL CANCER WITH PROLIFERATING POPULATIONS OF CELLS

Formaldehyde induces nonlinear, concentration-related increases in nas al epithelial cell proliferation and squamous cell carcinomas (SCC) in rats. A formaldehyde carcinogenicity study was conducted in which a m ajor end point was correlation of cell proliferation indices with site s of formaldehyde-induced SCC. A poor correlation in certain sites led to incorporation of the number of cells in each site into the correla tion. Rats were exposed (6 h/day, 5 days/week) to formaldehyde (0, 0.7 , 2, 6, 10, or 15 ppm) for up to 24 months with interim sacrifice time points at 3, 6, 12, and 18 mo. A unit length labeling index (ULLI; S- phase nuclei/mm basement membrane) was determined for specific nasal r egions in addition to a population-weighted ULLI (PWULLI). The PWULLI was defined as the product of regional ULLI and total number of nasal epithelial cells in the respective site. Nasal SCC sites of origin wer e mapped. Formaldehyde induced SCC in a highly nonlinear fashion, with no observed effect at the level of 2 ppm, a minimal response at 6 ppm , and a sharp increase at 10 and 15 ppm. The tumor incidence was 1, 22 , and 47% at 6, 10, and 15 ppm, respectively. ULLI was significantly ( P < 0.05) increased at 10 and 15 ppm but not at the lon er concentrati ons. There was a good correlation between PWULLI and regional tumor in cidence (R(2) = 0.88), while the correlation of regional SCC with ULLI was relatively poor (R(2) = 0.46). We conclude that target cell popul ation size and sustained increases of cell proliferation in these popu lations, determined by differences in regional airflow-driven formalde hyde dose to these sites, coupled with the known nonlinear kinetics of formaldehyde binding to DNA, can together account for the nonlinearit y and site specificity of formaldehyde-induced nasal SCC in rats.