PROPYLENE-OXIDE - MUTAGENESIS, CARCINOGENESIS AND MOLECULAR DOSE

The results from mutagenic and carcinogenic studies of propylene oxide (PO) and the current efforts to develop molecular dosimetry methods f or PO-DNA adducts are reviewed. PO has been shown to be active in seve ral bacterial and mammalian mutagenicity tests and induces site of con tact tumors in rodents after long-term administration. Quantitation of N7-(2-hydroxypropyl)guanine (7-HPG) in nasal and hepatic tissues of m ale F344 rats exposed to 500 ppm PO (6 h/day; 5 days/week for 4 weeks) by inhalation was performed to evaluate the potential of high concent rations of PO to produce adducts in the DNA of rodent tissues and to o btain information necessary for the design of molecular dosimetry stud ies, The persistence of 7-HPG in nasal and hepatic tissues was studied in rats killed three days after cessation of a 4-week exposure period . DNA samples from exposed and untreated animals were analyzed for 7-H PG by two different methods. The first method consisted of separation of the adduct from DNA by neutral thermal hydrolysis, followed by elec trophoretic derivatization of the adduct and gas chromatography-high r esolution mass spectrometry (GC-HRMS) analysis. The second method util ized P-32-postlabeling to quantitate the amount of this adduct in rat tissues. Adducts present in tissues from rats killed immediately after cessation of exposure were 835.4 +/- 80.1 (respiratory), 396.8 +/- 53 .1 (olfactory) and 34.6 +/- 3.0 (liver) pmol adduct/mu mol guanine usi ng GC-HRMS, Lower values, 592.7 +/- 53.3, 296.5 +/- 32.6 and 23.2 +/- 0.6 pmol adduct/mu mol guanine were found in respiratory, olfactory an d hepatic tissues of rats killed after three days of recovery. Analysi s of the tissues by P-32-postlabeling yielded the following values: 44 5.7 +/- 8.0 (respiratory), 301.6 +/- 49.2 (olfactory) and 20.6 +/- 1.8 (liver) pmol adduct/mu mol guanine in DNA of rats killed immediately after exposure cessation and 327.1 +/- 21.7 (respiratory), 185.3 +/- 2 9.2 (olfactory) and 15.7 +/- 0.9 (liver) pmol adduct/mu mol guanine af ter recovery. Current methods of quantitation did not provide evidence for the endogenous formation of this adduct in control animals. These studies demonstrated that the target tissue for carcinogenesis has mu ch greater alkylation of DNA than liver, a tissue that did not exhibit a carcinogenic response. (C) 1997 Elsevier Science B.V.