MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU.
Although there are a multitude of in vitro and in vivo studies on the genotoxic activity of EMS, no lifetime carcinogenicity studies, repeat dose mutation data or exposure analysis are available to serve as a solid basis for risk assessment for human exposure cases. The present studies were undertaken to investigate whether a threshold for mutagenic and clastogenic activity in vivo could be established, using the bone marrow micronucleus (MNT) and MutaMouse test systems, in the hope to provide reassurance to the patients that their accidental exposure to EMS at doses up to 0.055 mg/kg did not carry a toxicological risk. Dose levels ranging from 1.25 to 260 mg/kg/day were applied orally for up to 28 days. As a reference we included ENU at doses of 1.1-22 mg/kg/day. Our studies showed that daily doses of up to 25mg/kg/day (bone marrow, GI tract) and 50 mg/kg/day (liver) did not induce mutations in the lacZ gene in the three organs tested. Doses up to 80mg/kg/day (7-day dosing regime) did not induce micronuclei in mouse bone marrow. The genotoxic activity of EMS became apparent only at higher dose levels. Dose fractionation of EMS (28 times 12.5mg/kg versus a single high dose 350 mg/kg) provided further evidence for the thresholded dose response of EMS and showed that no cumulation of gene mutations below a threshold was occurring. In contrast, for ENU no threshold was apparent and dose fractionation indicated full additivity of individual dose effects.
Gocke
Elmar
E
Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland. elmar.gocke@roche.com
Ballantyne
Mark
M
Whitwell
James
J
Müller
Lutz
L
D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D004247:DNA / Q000032:analysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination; D004781:Environmental Exposure; D005020:Ethyl Methanesulfonate / Q000633:toxicity*; D005038:Ethylnitrosourea / Q000633:toxicity*; D006801:Humans; D007763:Lac Operon / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects*; D018570:Risk Assessment; D014633:Valine / Q000031:analogs & derivatives / Q000633:toxicity
D009153:Mutagens; D004247:DNA; D005020:Ethyl Methanesulfonate; D014633:Valine; D005038:Ethylnitrosourea