Dose and temporal evaluation of ethylene oxide-induced mutagenicity in the lungs of male big blue mice following inhalation exposure to carcinogenic concentrations.
Ethylene oxide (EO) is a direct acting alkylating agent; in vitro and in vivo studies indicate that it is both a mutagen and a carcinogen. However, it remains unclear whether the mode of action (MOA) for cancer for EO is a mutagenic MOA, specifically via point mutation. To investigate the MOA for EO-induced mouse lung tumors, male Big Blue (BB) B6C3F1 mice (10/group) were exposed to EO by inhalation, 6 hr/day, 5 days/week for 4 (0, 10, 50, 100, or 200 ppm EO), 8, or 12 weeks (0, 100, or 200 ppm EO). Lung DNA samples were analyzed for cII mutant frequency (MF) at 4, 8 and 12 weeks of exposure; the mutation spectrum was analyzed for mutants from control and 200 ppm EO treatments. Although EO-induced cII MFs were 1.5- to 2.7-fold higher than the concurrent controls at 4 weeks, statistically significant increases in the cII MF were found only after 8 and 12 weeks of exposure and only at 200 ppm EO (P ≤ 0.05), which is twice the highest concentration used in the cancer bioassay. Consistent with the positive response, DNA sequencing of cII mutants showed a significant shift in the mutational spectra between control and 200 ppm EO following 8 and 12 week exposures (P ≤ 0.035), but not at 4 weeks. Thus, EO mutagenic activity in vivo was relatively weak and required higher than tumorigenic concentrations and longer than 4 weeks exposure durations. These data do not follow the classical patterns for a MOA mediated by point mutations. Environ. Mol. Mutagen. 58:122-134, 2017. © 2017 Wiley Periodicals, Inc.
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas.
Mugimane G
MG
Manjanatha
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas.
Sharon D
SD
Shelton
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas.
Ying
Y
Chen
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas.
Barbara L
BL
Parsons
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas.
Meagan B
MB
Myers
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas.
Karen L
KL
McKim
Toxicology and Environmental Research and Consulting, Dow Chemical Company, Midland, Michigan.
B Bhaskar
BB
Gollapudi
Toxicology and Environmental Research and Consulting, Dow Europe GmbH, Horgen, Switzerland.
Nigel P
NP
Moore
Environmental Health, Toxicology Excellence for Risk Assessment, Cincinnati, Ohio.
Lynne T
LT
Haber
Independent Consultant, Chapel Hill, North Carolina.
Bruce
B
Allen
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US FDA, Jefferson, Arkansas.
Martha M
MM
Moore
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005027:Ethylene Oxide / Q000633:toxicity*; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000633:toxicity*; D017354:Point Mutation; D013997:Time Factors
D002273:Carcinogens; D009153:Mutagens; D005027:Ethylene Oxide
cII gene; mode-of-action for cancer; mutation spectrum; transgenic mice