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 (> or = 6 ppm) of formaldehyde (HCHO) induce cell proliferation, squamous metaplasia, and squamous cell carcinomas in F344 rats. To assess the cancer risk associated with HCHO exposure, DNA-protein cross-links (DPX) formed in a single exposure of naive (previously unexposed) rats and monkeys have been used as a surrogate for the internal dose. Since the quantity of DPX may differ in subchronically exposed animals, the effects of preexposure to HCHO on the acute DPX yield (concentration of 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 ppm of 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 at the same concentrations used for preexposure. Acute DPX yields and cell replication (incorporation of 14C into DNA) were determined in the mucosal lining of the nasal lateral meatus (LM) (high tumor site in HCHO bioassay) and the medial and posterior meatuses (M:PM) (low tumor site in bioassay). DPX yields in the LM were approximately sixfold higher than in the M:PM. At 0.7 and 2 ppm, no differences between PE and N rats were detected in either tissue. At 6 and 15 ppm, acute DPX yields in the LM of PE rats were approximately half those of N rats, but no differences were detected in the M:PM. Cell proliferation was induced in PE rats at 6 ppm (LM only) and especially at 15 ppm (LM and M:PM). Cumulative DPX yields were measured indirectly by determining the decrease in extractability of DNA from proteins. PE rats were preexposed to 6 or 10 ppm as above, while N rats were exposed to room air. Both groups (PE and N) were then exposed (3 hr) to the same concentration of unlabeled HCHO. DPX yields increased in a concentration-dependent manner in both groups, but the yields were smaller in PE than N rats, suggesting that no accumulation of DPX occurred in PE rats. The results demonstrate that at concentrations < or = 2 ppm, N and PE rats are equivalent with respect to the formation of DPX.(ABSTRACT TRUNCATED AT 400 WORDS)
Casanova
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Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Morgan
K T
KT
Gross
E A
EA
Moss
O R
OR
Heck
H A
HA
D000280:Administration, Inhalation; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D005557:Formaldehyde / Q000633:toxicity*; D008297:Male; D008679:Metaplasia / Q000139:chemically induced; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment; D014116:Toxicology / Q000379:methods
D011506:Proteins; D005557:Formaldehyde; D004247:DNA