title: Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.
abstract: PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.
authors.affiliation: Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland; Department of Environmental Science, University of Eastern Finland, Kuopio, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Viluksela
authors.affiliation: Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkinen
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Leo T M
authors.initials: LT
authors.lastname: van der Ven
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Filip
authors.initials: F
authors.lastname: Rendel
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Roos
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Elche (Alicante), Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Esteban
authors.affiliation: Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Korkalainen
authors.affiliation: Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland; Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Lensu
authors.affiliation: Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Miettinen
authors.affiliation: ISLAB Laboratory Centre, Kuopio, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Savolainen
authors.affiliation: Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Sankari
authors.affiliation: Center of Toxicology, IPA - Institute for Prevention and Occupational Medicine, German Social Accident Insurance, Ruhr University of Bochum, Bochum, Germany.
authors.forename: Hellmuth
authors.initials: H
authors.lastname: Lilienthal
authors.affiliation: Department of Physiology, University of Turku, Turku, Finland.
authors.forename: Annika
authors.initials: A
authors.lastname: Adamsson
authors.affiliation: Department of Physiology, University of Turku, Turku, Finland; Department of Paediatrics, University of Turku, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Herlin
authors.affiliation: Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Finnilä
authors.affiliation: Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Tuukkanen
authors.affiliation: Institute for Environmental Studies, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Leslie
authors.affiliation: Institute for Environmental Studies, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Timo
authors.initials: T
authors.lastname: Hamers
authors.affiliation: Institute of Food Chemistry and Food Biotechnology, Justus-Liebig University, Giessen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hamscher
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lauy
authors.initials: L
authors.lastname: Al-Anati
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Stenius
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Kine-Susann
authors.initials: KS
authors.lastname: Dervola
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Inger-Lise
authors.initials: IL
authors.lastname: Bogen
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Frode
authors.initials: F
authors.lastname: Fonnum
authors.affiliation: Chemistry Department, Umeå University, Umeå, Sweden.
authors.forename: Patrik L
authors.initials: PL
authors.lastname: Andersson
authors.affiliation: Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Schrenk
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Krister
authors.initials: K
authors.lastname: Halldin
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helen
authors.initials: H
authors.lastname: Håkansson
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000302:Adrenal Cortex / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000378:metabolism; D012737:Sex Factors; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D004785:Environmental Pollutants; D006454:Hemoglobins; D012176:Retinoids; D013963:Thyroid Hormones; C410127:PCB 180; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D011078:Polychlorinated Biphenyls