DNA--Protein Cross-links and Cell Replication at Specific Sites in the Nose of F344 Rats Exposed Subchronically to Formaldehyde

Chronic exposures to high concentrations (>6 ppm) of formaldehyde(HCHO) induce cell proliferation, squamous metaplasia, and squamouscell carcinomas in F344 rats. To assess the cancer risk associatedwith HCHO exposure, DNA-protein cross-links (DPX) formed ina single exposure of naive (previously unexposed) rats and monkeyshave been used as a surrogate for the internal dose. Since thequantity of DPX may differ in subchronically exposed animals,the effects of preexposure to HCHO on the acute DPX yield (concentrationof DPX following a single exposure) and the cumulative DPX yield(concentration of DPX following repeated exposures) were determined.Male F344 rats were preexposed (PE) to 0.7, 2, 6, or 15 ppmof HCHO (6 hr/day, 5 days/week, 11 weeks + 4 days). Naive (N)rats were exposed to room air. On the 5th day of the 12th week,PE and N rats were simultaneously exposed (3 hr) to H¹⁴CHO atthe same concentrations used for preexposure. Acute DPX yieldsand cell replication (incorporation of ¹⁴C into DNA) were determinedin the mucosal lining of the nasal lateral meatus (LM) (hightumor site in HCHO bioassay) and the medial and posterior meatuses(M:PM) (low tumor site in bioassay). DPX yields in the LM wereapproximately sixfold higher than in the M:PM. At 0.7 and 2ppm, no differences between PE and N rats were detected in eithertissue. At 6 and 15 ppm, acute DPX yields in the LM of PE ratswere approximately half those of N rats, but no differenceswere detected in the M:PM. Cell proliferation was induced inPE rats at 6 ppm (LM only) and especially at 15 ppm (LM andM:PM). Cumulative DPX yields were measured indirectly by determiningthe decrease in extractability of DNA from proteins. PE ratswere preexposed to 6 or 10 ppm as above, while N rats were exposedto room air. Both groups (PE and N) were then exposed (3 hr)to the same concentration of unlabeled HCHO. DPX yields increasedin a concentration-dependent manner in both groups, but theyields were smaller in PE than N rats, suggesting that no accumulationof DPX occurred in PE rats. The results demonstrate that atconcentrations <2 ppm, N and PE rats are equivalent withrespect to the formation of DPX. At concentrations >6 ppm,N and PE rats are not equivalent, but the impact of this high-doseeffect on low-dose cancer risk estimates derived with the linearizedmultistage model is small.