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Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate.
Toxicol Lett. 2009 Nov 12; 190(3):254-65.TL

Abstract

In order to assess the risk of patients being exposed to an anti-AIDS medication contaminated with EMS we have performed in depth genotoxicity, general toxicity and DMPK investigations. The results of these studies are reported in the accompanying papers of this issue. Prior to starting our investigations we searched the literature for toxicity data on this well established mutagen with specific attention to dose-response relations in in vivo genotoxicity studies, since, obviously, in vivo data are pivotal for risk assessment. There are numerous published in vivo genotoxicity studies on EMS, with generally 50mg/kg - or higher - being the minimal dose used. The dose of 50mg/kg induced effects in some, but not all studies, while the dose of 100mg/kg was clearly positive in most studies, except for heritable mutations where a single dose of 100mg/kg was not observed to induce measurable effects in post-meiotic stages and even the maximal dose of 250 mg/kg was negative in pre-meiotic stages of male germ cell development. For somatic cells, NOEL values could not be derived for any of the endpoints studied. Although a large number of genotoxicity studies are available, none of the studies was sufficiently detailed to allow unambiguous conclusions about the presence of a (practical) threshold. But in most cases the dose-responses show a sublinear relationship (i.e. the slope increases with dose) which indicates that the data would not be incompatible with a threshold dose-response relationship. This stands in contrast to data on ethylnitrosourea (ENU) which has been studied concommittantly with EMS in several in vitro and in vivo genotoxicity investigations. ENU generally appeared to induce genotoxic effects with linear dose relationships. We also review the more limited data reported on teratogenicity and carcinogenicity of EMS. Induction of fetal malformations in mice appeared to have a NOEL of 100mg/kg. Classical life-time carcinogenicity studies have not been performed with EMS. Induction of mammary, lung, kidney, brain, and liver tumors has been observed after various short term treatment regimes. In none of the published studies a no effect level was reported and no exposure data are available. Overall, the experimental data do not fully characterize the carcinogenic potential of EMS and are insufficient for a risk extrapolation to humans. Although the data on teratogenicity and carcinogenicity are insufficient for assessing dose-response relations it is generally accepted that the genotoxic property of EMS is at the base of the teratogenic and carcinogenic effects.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

19857796

Citation

Gocke, Elmar, et al. "Literature Review On the Genotoxicity, Reproductive Toxicity, and Carcinogenicity of Ethyl Methanesulfonate." Toxicology Letters, vol. 190, no. 3, 2009, pp. 254-65.
Gocke E, Bürgin H, Müller L, et al. Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate. Toxicol Lett. 2009;190(3):254-65.
Gocke, E., Bürgin, H., Müller, L., & Pfister, T. (2009). Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate. Toxicology Letters, 190(3), 254-65. https://doi.org/10.1016/j.toxlet.2009.03.016
Gocke E, et al. Literature Review On the Genotoxicity, Reproductive Toxicity, and Carcinogenicity of Ethyl Methanesulfonate. Toxicol Lett. 2009 Nov 12;190(3):254-65. PubMed PMID: 19857796.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate. AU - Gocke,Elmar, AU - Bürgin,Heinrich, AU - Müller,Lutz, AU - Pfister,Thomas, Y1 - 2009/03/28/ PY - 2009/01/30/received PY - 2009/02/26/revised PY - 2009/03/05/accepted PY - 2009/10/28/entrez PY - 2009/10/28/pubmed PY - 2009/11/11/medline SP - 254 EP - 65 JF - Toxicology letters JO - Toxicol Lett VL - 190 IS - 3 N2 - In order to assess the risk of patients being exposed to an anti-AIDS medication contaminated with EMS we have performed in depth genotoxicity, general toxicity and DMPK investigations. The results of these studies are reported in the accompanying papers of this issue. Prior to starting our investigations we searched the literature for toxicity data on this well established mutagen with specific attention to dose-response relations in in vivo genotoxicity studies, since, obviously, in vivo data are pivotal for risk assessment. There are numerous published in vivo genotoxicity studies on EMS, with generally 50mg/kg - or higher - being the minimal dose used. The dose of 50mg/kg induced effects in some, but not all studies, while the dose of 100mg/kg was clearly positive in most studies, except for heritable mutations where a single dose of 100mg/kg was not observed to induce measurable effects in post-meiotic stages and even the maximal dose of 250 mg/kg was negative in pre-meiotic stages of male germ cell development. For somatic cells, NOEL values could not be derived for any of the endpoints studied. Although a large number of genotoxicity studies are available, none of the studies was sufficiently detailed to allow unambiguous conclusions about the presence of a (practical) threshold. But in most cases the dose-responses show a sublinear relationship (i.e. the slope increases with dose) which indicates that the data would not be incompatible with a threshold dose-response relationship. This stands in contrast to data on ethylnitrosourea (ENU) which has been studied concommittantly with EMS in several in vitro and in vivo genotoxicity investigations. ENU generally appeared to induce genotoxic effects with linear dose relationships. We also review the more limited data reported on teratogenicity and carcinogenicity of EMS. Induction of fetal malformations in mice appeared to have a NOEL of 100mg/kg. Classical life-time carcinogenicity studies have not been performed with EMS. Induction of mammary, lung, kidney, brain, and liver tumors has been observed after various short term treatment regimes. In none of the published studies a no effect level was reported and no exposure data are available. Overall, the experimental data do not fully characterize the carcinogenic potential of EMS and are insufficient for a risk extrapolation to humans. Although the data on teratogenicity and carcinogenicity are insufficient for assessing dose-response relations it is generally accepted that the genotoxic property of EMS is at the base of the teratogenic and carcinogenic effects. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/19857796/Literature_review_on_the_genotoxicity_reproductive_toxicity_and_carcinogenicity_of_ethyl_methanesulfonate_ DB - PRIME DP - Unbound Medicine ER -