title: Physiologically-based pharmacokinetic modelling of immune, reproductive and carcinogenic effects from contaminant exposure in polar bears (Ursus maritimus) across the Arctic.
abstract: Polar bears (Ursus maritimus) consume large quantities of seal blubber and other high trophic marine mammals and consequently have some of the highest tissue concentrations of organohalogen contaminants (OHCs) among Arctic biota. In the present paper we carried out a risk quotient (RQ) evaluation on OHC-exposed polar bears harvested from 1999 to 2008 and from 11 circumpolar subpopulations spanning from Alaska to Svalbard in order to evaluate the risk of OHC-mediated reproductive effects (embryotoxicity, teratogenicity), immunotoxicity and carcinogenicity (genotoxicity). This RQ evaluation was based on the Critical Body Residue (CBR) concept and a Physiologically-Based Pharmacokinetic Modelling (PBPK) approach using OHC concentrations measured in polar bear adipose or liver tissue. The range of OHC concentrations within polar bear populations were as follows for adipose, sum polychlorinated biphenyls ∑PCBs (1797-10,537 ng/g lw), sum methylsulphone-PCB ∑MeSO2-PCBs (110-672 ng/g lw), sum chlordanes ∑CHLs (765-3477 ng/g lw), α-hexachlorocyclohexane α-HCH (8.5-91.3 ng/g lw), β-hexachlorocyclohexane β-HCH (65.5-542 ng/g lw), sum chlorbenzenes ∑ClBzs (145-304 ng/g lw), dichlorodiphenyltrichloroethane ∑DDTs (31.5-206 ng/g lw), dieldrin (69-249 ng/g lw), polybrominated diphenyl ethers ∑PBDEs (4.6-78.4 ng/g lw). For liver, the perfluorooctanesulfonic acid (PFOS) concentrations ranged from 231-2792 ng/g ww. The total additive RQ from all OHCs ranged from 4.3 in Alaska to 28.6 in East Greenland bears for effects on reproduction, immune health and carcinogenicity, highlighting the important result that the toxic effect threshold (i.e. RQ>1) was exceeded for all polar bear populations assessed. PCBs were the main contributors for all three effect categories, contributing from 70.6% to 94.3% of the total risk and a RQ between 3.8-22.5. ∑MeSO2-PCBs were the second highest effect contributor for reproductive and immunological effects (0.17<RQ<1.4), whereas PFOS was the second highest effect contributor for carcinogenic (genotoxic) effects (0.35<RQ<2.5). The results from this study corroborate and lend further support to previous assessments of the possible adverse health effects of exposure to known and measured OHCs in polar bears. We therefore suggest that Critical Daily Doses (CDD) should be investigated in "ex vivo" dose-response studies on polar bears to replace laboratory studies on rats (Rattus rattus) to reveal whether high RQs are maintained.
authors.affiliation: Department of Bioscience, Arctic Research Centre, Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde, Denmark. Electronic address: rdi@bios.au.dk.
authors.forename: Rune
authors.initials: R
authors.lastname: Dietz
authors.affiliation: Department of Bioscience, Arctic Research Centre, Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde, Denmark. Electronic address: kig@bios.au.com.
authors.forename: Kim
authors.initials: K
authors.lastname: Gustavson
authors.affiliation: Department of Bioscience, Arctic Research Centre, Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde, Denmark. Electronic address: csh@bios.au.dk.
authors.forename: Christian
authors.initials: C
authors.lastname: Sonne
authors.affiliation: Department of Bioscience, Arctic Research Centre, Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde, Denmark. Electronic address: jpd@bios.au.dk.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Desforges
authors.affiliation: Department of Bioscience, Arctic Research Centre, Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde, Denmark. Electronic address: ffr@dmu.dk.
authors.forename: Frank F
authors.initials: FF
authors.lastname: Rigét
authors.affiliation: Department of Bioscience, Arctic Research Centre, Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde, Denmark.
authors.forename: Viola
authors.initials: V
authors.lastname: Pavlova
authors.affiliation: Department of Natural Resources and the Environment, University of Connecticut, Storrs, CT 06269, USA; Center for Environmental Sciences and Engineering, University of Connecticut, Storrs, CT 06269, USA. Electronic address: melissa.mckinney@uconn.edu.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: McKinney
authors.affiliation: Ecotoxicology and Wildlife Health Division, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, ON, Canada K1A 0H3. Electronic address: Robert.Letcher@ec.gc.ca.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Letcher
mesh_terms: D000818:Animals; D001110:Arctic Regions; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity*; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D007107:Immune System / Q000187:drug effects*; D008297:Male; D012098:Reproduction / Q000187:drug effects*; D066007:Toxicokinetics; D001503:Ursidae
chemical_list: D002273:Carcinogens; D004785:Environmental Pollutants
keywords: Critical body residue; Immune suppression; Organohalogen contaminants; PBPK modelling; Polar bear; Reproductive toxicity; Risk quotient