title: New investigations into the genotoxicity of cobalt compounds and their impact on overall assessment of genotoxic risk.
abstract: The genotoxicity of cobalt metal and cobalt compounds has been widely studied. Several publications show induction of chromosomal aberrations, micronuclei or DNA damage in mammalian cells in vitro in the absence of S9. Mixed results were seen in gene mutation studies in bacteria and mammalian cells in vitro, and in chromosomal aberration or micronucleus assays in vivo. To resolve these inconsistencies, new studies were performed with soluble and poorly soluble cobalt compounds according to OECD-recommended protocols. Induction of chromosomal damage was confirmed in vitro, but data suggest this may be due to oxidative stress. No biologically significant mutagenic responses were obtained in bacteria, Tk(+/-) or Hprt mutation tests. Negative results were also obtained for chromosomal aberrations (in bone marrow and spermatogonia) and micronuclei at maximum tolerated doses in vivo. Poorly soluble cobalt compounds do not appear to be genotoxic. Soluble compounds do induce some DNA and chromosomal damage in vitro, probably due to reactive oxygen. The absence of chromosome damage in robust GLP studies in vivo suggests that effective protective processes are sufficient to prevent oxidative DNA damage in whole mammals. Overall, there is no evidence of genetic toxicity with relevance for humans of cobalt substances and cobalt metal.
authors.affiliation: Kirkland Consulting, PO Box 79, Tadcaster LS24 0AS, United Kingdom. Electronic address: dkirkland@genetoxconsulting.co.uk.
authors.forename: David
authors.initials: D
authors.lastname: Kirkland
authors.affiliation: Division of Occupational and Environmental Medicine, Department of Community & Family Medicine, Box 3400, Duke University Medical Center, Durham, NC 27705, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Brock
authors.affiliation: CitoxLab, BP 563, 27005 Evreux, Cedex, France.
authors.forename: Hasnaà
authors.initials: H
authors.lastname: Haddouk
authors.affiliation: Genetic Toxicology, Covance Laboratories Limited, Otley Road, Harrogate HG3 1PY, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hargeaves
authors.affiliation: Genetic Toxicology, Covance Laboratories Limited, Otley Road, Harrogate HG3 1PY, UK.
authors.forename: Melvyn
authors.initials: M
authors.lastname: Lloyd
authors.affiliation: Genetic Toxicology, Covance Laboratories Limited, Otley Road, Harrogate HG3 1PY, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mc Garry
authors.affiliation: Charles River Laboratories Preclinical Services, Montreal, 22022 Transcanadienne, Senneville, Quebec H9X 3R3, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Proudlock
authors.affiliation: CitoxLab, BP 563, 27005 Evreux, Cedex, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Sarlang
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany.
authors.forename: Katherina
authors.initials: K
authors.lastname: Sewald
authors.affiliation: CitoxLab, BP 563, 27005 Evreux, Cedex, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sire
authors.affiliation: Harlan Cytotest Cell Research, In den Leppsteinswiesen 19, 64380 Roßdorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sokolowski
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ziemann
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations / Q000139:chemically induced; D003035:Cobalt / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects
chemical_list: D009153:Mutagens; D003035:Cobalt
keywords: Cobalt compounds; Genotoxicity; Overall assessment