Pharmacodynamics of Formaldehyde: Applications of a Model for the Arrest of DNA Replication by DNA–Protein Cross-Links

Abstract

A variety of evidence suggests that formaldehyde (HCHO)-induced DNA–protein cross-links (DPX) are genotoxic as a result of their ability to arrest DNA replication. Although DPX can be removed and the DNA can be repaired, failure to remove the blockage prior to cell division or excision followed by incomplete repair could cause cell death or a mutation. To characterize the concentration and time dependence of this mechanism, a biologically based model for DNA replication in the presence of DPX was developed based on the assumptions that (1) DPX are formed randomly in the DNA and (2) a replication fork can advance up to but not past a DPX. Using a combination of Poisson and binomial statistics, a quantitative relationship between the amount of newly synthesized DNA and the concentration of DPX was derived, which predicts that the rate of DNA replication should decrease nonlinearly with increasing concentrations of DPX. Because the latter is a nonlinear function of the airborne concentration of HCHO, an inverse sigmoidal relationship is predicted between the rate of DNA replication and the concentration of inhaled formaldehyde. The model was parameterized using data derived from a study of the incorporation of [methyl-14C]thymidine monophosphate into the DNA of the nasal respiratory mucosa of Fischer-344 rats exposed to 3HCHO and H14CHO (6 ppm, 6 h). The model was then applied to measurements of DNA replication in the nasal mucosa of experimental animals exposed to wide ranges of H14CHO (rats: 0.7, 2, 6, or 15 ppm, 3 h; rhesus monkeys: 0.7, 2, or 6 ppm, 6 h). The results indicate that, at airborne concentrations above 6 ppm in rats, there is a marked decrease (ca. 62% at 15 ppm) in the amount of newly synthesized DNA due to DPX formation during a single 6-h exposure to HCHO. The arrest of DNA replication at high HCHO concentrations could result in cytolethality or genotoxicity, both of which are critical factors in the induction of rat nasal cancer by HCHO. However, at concentrations below 2 ppm in monkeys or 1 ppm in rats, the decrease in the rate of DNA replication is predicted to be <1% after a 6-h exposure. This small decrease is probably undetectable using currently available techniques. The parameterized model suggests that the arrest of DNA replication by DPX is mainly a high-dose phenomenon and that at ambient exposure concentrations it is unlikely to be a major risk factor.