title: Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.
abstract: The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany. Electronic address: eric.fabian@basf.com.
authors.forename: E
authors.initials: E
authors.lastname: Fabian
authors.affiliation: metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany. Electronic address: natalie@bordag.com.
authors.forename: N
authors.initials: N
authors.lastname: Bordag
authors.affiliation: metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany. Electronic address: michael.herold@metanomics.de.
authors.forename: M
authors.initials: M
authors.lastname: Herold
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kamp
authors.affiliation: BASF SE, Scientific Computing, B009 67056 Ludwigshafen, Germany. Electronic address: gerhard.krennrich@basf.com.
authors.forename: G
authors.initials: G
authors.lastname: Krennrich
authors.affiliation: metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany; BASF Schwarzheide GmbH, Schiphauer Strasse 1, 01986 Schwarzheide, Germany. Electronic address: ralf.looser@metanomics.de.
authors.forename: R
authors.initials: R
authors.lastname: Looser
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany. Electronic address: lan.ma-hock@basf.com.
authors.forename: L
authors.initials: L
authors.lastname: Ma-Hock
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany. Electronic address: werner.mellert@basf.com.
authors.forename: W
authors.initials: W
authors.lastname: Mellert
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany. Electronic address: Gina.MONTOYAPARRA@danone.com.
authors.forename: G
authors.initials: G
authors.lastname: Montoya
authors.affiliation: metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany. Electronic address: erik.peter@metanomics.de.
authors.forename: E
authors.initials: E
authors.lastname: Peter
authors.affiliation: metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany. Electronic address: alexander.prokudin@metanomics.de.
authors.forename: A
authors.initials: A
authors.lastname: Prokudin
authors.affiliation: metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany. Electronic address: michael.spitzer@metanomics.de.
authors.forename: M
authors.initials: M
authors.lastname: Spitzer
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany. Electronic address: volker.strauss@basf.com.
authors.forename: V
authors.initials: V
authors.lastname: Strauss
authors.affiliation: metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany. Electronic address: tilmann.walk@metanomics.de.
authors.forename: T
authors.initials: T
authors.lastname: Walk
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany. Electronic address: rene.zbranek@basf.com.
authors.forename: R
authors.initials: R
authors.lastname: Zbranek
authors.affiliation: BASF SE Experimental Toxicology and Ecology, Z 470 67056 Ludwigshafen, Germany. Electronic address: bennard.ravenzwaay@basf.com.
authors.forename: B
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002725:Chloroform / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D016208:Databases, Factual; D004126:Dimethylformamide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D019570:Inhalation Exposure; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D025341:Principal Component Analysis; D017208:Rats, Wistar; D018570:Risk Assessment; D018675:Toxicity Tests
chemical_list: D000814:Aniline Compounds; D001555:Benzene Derivatives; D005026:Ethylene Glycols; D005663:Furans; C018674:tetrahydrofuran; D002725:Chloroform; D004126:Dimethylformamide; C005219:methyl cellosolve; C004912:ethylbenzene; C023650:aniline
keywords: Oral versus inhalative exposure; Plasma metabolome; Rat