Propylene Oxide: Genotoxicity Profile of a Rodent Nasal Carcinogen

Abstract

Propylene oxide (PO) is a DNA-reactive genotoxic agent; that is, it reacts with DNA to produce lesions in the genetic material. PO also induces tumors in rodents, although only at high concentrations and at portals of entry. This review of PO's genotoxicity profile is organized according to endpoints measured, that is, nonmutational or mutational endpoints, and as to whether the results were from in vitro or in vivo studies. In addition to results of experimental studies, PO's genotoxicity for humans is assessed by reviewing results of published biomarker studies. The weight of evidence indicates that although it is genotoxic, PO's potency as a DNA-reactive mutagen is weak. Other aspects of PO's overall tissue toxicities are also reviewed, with attention to glutathione (GSH) depletion and its consequences, that is, cell proliferation, death, and necrosis. These toxic tissue responses occur in the same anatomical regions in rodents as do the PO-induced tumors. Furthermore, some of these tissue toxicities can produce effects that may either augment PO's DNA-reactive mutagenicity or be genotoxic in themselves, not dependent on PO's DNA reactivity. Although its DNA reactivity may be a necessary component of PO's overall genotoxicity and rodent carcinogenicity, it is likely not sufficient, and the associated tissue toxicities, which are rate-limiting, also seem to be required. This complex mode of action has implications for estimations of PO's cancer potential in humans, especially at low exposure concentrations.

1,2‐Epoxypropane [MAK Value Documentation, 2013]

“…After repeated exposure to 1,2-epoxypropane concentrations of 2 ml/m 3 , the HOPrVal level in the steady state was 2.56 ± 0.34 nmol/g globin (Boogaard 2002;Boogaard et al 1999;). This is consistent with values obtained from animal studies (Albertini and Sweeney 2007;Osterman-Golkar et al 2003).…”

“…N7-HPG is the quantitatively most important DNA lesion caused by 1,2-epoxypropane. Normally, these purine-free lesions are rapidly repaired; the endogenous frequency of purine-free sites was determined to be 1 per 10 5 nucleotides (Albertini and Sweeney 2007). No difference was found between the number of purine-free sites in DNA found in the tissues of rats exposed to 500 ml/m 3 and that in the control animals (Ríos-Blanco et al 2000).…”

“…1,2-Epoxypropane induces DNA damage and gene mutations in bacteria; it causes gene mutations in yeasts and fungi and mitotic gene conversion in Saccharomyces cerevisiae. In mammalian cells, 1,2-epoxypropane induces DNA damage, gene mutations, SCE and chromosomal aberrations (Albertini and Sweeney 2007;European Commission 2002;IARC 1994).…”

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

“…The type of adduct, and the cell type in which it is formed, can profoundly influence the mechanisms and efficiency of its repair, and the likelihood that it would lead to a mutation. Examples of adducts not considered to be promutagenic include small N7-alkylguanine adducts such as N7-methylguanine, N7-hydroxyethylguanine, and N7-hydroxypropylguanine (Boysen et al, 2009;Albertini & Sweeney, 2007). Thus, studies that identify the specific adduct(s) have greater use in risk assessment than studies that identify only total adduct levels without characterizing them.…”

Propylene Oxide

“…PO directly alkylates proteins and DNA, induces gene mutations in all microorganisms tested, and induces chromosomal aberrations in mammalian cells in vitro [159][160][161][162][163][164][165]. In vivo, although an increased frequency of micronuclei was induced in mice after repeated intraperitoneal injections of PO [166], neither oral administration, even at near-lethal doses, nor chronic inhalation exposure to high levels, induced genotoxic effects [165]. No clear dominant lethal effects were found in rodents or monkeys [159,167].…”