title: Analyzing cytotoxic effects of selected isothiazol-3-one biocides using the toxic ratio concept and structure-activity relationship considerations.
abstract: To demonstrate how baseline toxicity can be separated from other more specific modes of toxic action and to address possible pitfals when dealing with hydrophobic substances, the four isothiazol-3-one biocides N-methylisothiazol-3-one (MIT), 5-chloro-N-methylisothiazol-3-one (CIT), N-octylisothiazol-3-one (OIT), and 4,5-dichloro-N-octylisothiazol-3-one (DCOIT) as an example for reactive electrophilic xenobiotics were tested for their cytotoxic effects on the human hepatoblastoma cell line Hep G2, on the marine bacterium Vibrio fischeri, and on the limnic green alga Scenedesmus vacuolatus. In each of the three test systems, toxic effects were observed in a consistent pattern. The two chlorinated compounds and OIT were found to be significantly more toxic than MIT. As compared to baseline toxicants, the small and polar MIT and CIT exhibited pronounced excess toxicity in each of the three test systems that is presumably triggered by their intrinsic reactivity toward cellular thiols. In contrast, OIT and DCOIT showed mainly toxicities that could be explained by their hydrophobicity. Analyzing and comparing these results using the toxic ratio concept and with data that indicate a dramatic depletion of cellular glutathione levels after incubation with DCOIT reveals that for highly hydrophobic substances, baseline level toxicity in an assay for acute toxicity can lead to an oversight of other more specific modes of toxic action that may cause significant effects that might be less reversible than those caused by unreactive baseline toxicants. This possibility should be taken into account in the hazard assessment of chemicals that are both hydrophobic and reactive.
authors.affiliation: Department 3 Sustainability in Chemistry, UFT-Centre for Environmental Research and Sustainable Technology, University of Bremen, Leobener Strasse, D-28359 Bremen, Germany. jarning@unibremen.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Arning
authors.forename: Marianne
authors.initials: M
authors.lastname: Matzke
authors.forename: Stefan
authors.initials: S
authors.lastname: Stolte
authors.forename: Frauke
authors.initials: F
authors.lastname: Nehen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bottin-Weber
authors.forename: Andrea
authors.initials: A
authors.lastname: Böschen
authors.forename: Salha
authors.initials: S
authors.lastname: Abdulkarim
authors.forename: Bernd
authors.initials: B
authors.lastname: Jastorff
authors.forename: Johannes
authors.initials: J
authors.lastname: Ranke
mesh_terms: D048908:Aliivibrio fischeri / Q000187:drug effects; D004202:Disinfectants / Q000737:chemistry / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D044444:Scenedesmus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000633:toxicity*
chemical_list: D004202:Disinfectants; D013844:Thiazoles; D005978:Glutathione