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MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU.
Toxicol Lett. 2009 Nov 12; 190(3):286-97.TL

Abstract

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.

Authors+Show Affiliations

Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland. elmar.gocke@roche.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19446969

Citation

Gocke, Elmar, et al. "MNT and MutaMouse Studies to Define the in Vivo Dose Response Relations of the Genotoxicity of EMS and ENU." Toxicology Letters, vol. 190, no. 3, 2009, pp. 286-97.
Gocke E, Ballantyne M, Whitwell J, et al. MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU. Toxicol Lett. 2009;190(3):286-97.
Gocke, E., Ballantyne, M., Whitwell, J., & Müller, L. (2009). MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU. Toxicology Letters, 190(3), 286-97. https://doi.org/10.1016/j.toxlet.2009.03.021
Gocke E, et al. MNT and MutaMouse Studies to Define the in Vivo Dose Response Relations of the Genotoxicity of EMS and ENU. Toxicol Lett. 2009 Nov 12;190(3):286-97. PubMed PMID: 19446969.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU. AU - Gocke,Elmar, AU - Ballantyne,Mark, AU - Whitwell,James, AU - Müller,Lutz, Y1 - 2009/04/01/ PY - 2009/01/30/received PY - 2009/03/16/revised PY - 2009/03/23/accepted PY - 2009/5/19/entrez PY - 2009/5/19/pubmed PY - 2009/11/11/medline SP - 286 EP - 97 JF - Toxicology letters JO - Toxicol Lett VL - 190 IS - 3 N2 - 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. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/19446969/MNT_and_MutaMouse_studies_to_define_the_in_vivo_dose_response_relations_of_the_genotoxicity_of_EMS_and_ENU_ DB - PRIME DP - Unbound Medicine ER -