PCB metabolites in humans with focus on OH-PCBs and MeSO 2 -PCBs

Transcription

1 PCB metabolites in humans with focus on OH-PCBs and MeSO 2 -PCBs Åke Bergman Department of Environmental Chemistry Stockholm University Sweden 1. History 2. Reactive PCB metabolites 3. The PCB methyl sulfone metabolites - MeSO 2 -PCBs 4. Polychlorobiphenylol metabolites - OH-PCBs 5. Conclusions and future questions

2 Jensen and Jansson, Ambio, 5 (1976) Sören Jensen and the sulfone discovery MeSO 2 -PCBs and DDE in Grey seal blubber 1976

3 Ingvar Brandt and the specific MeSO 2 -PCBs lung tissue retention Lung retention of a PCB methyl sulfone (Brandt, Thesis 1977) Brandt & Bergman, Experientia, 1976, Brandt, thesis 1977

4 MeSO 2 -PCB binding to uteroglobin In the mouse lung and in interaluminal uterine fluid and the MeSO 2 -PCB are specifically localized to the ara cells Brandt et al., Drug Metab. Dispos. 13 (1985)

5 Route of MeSO 2 -PCB formation Dr. J. Bakke Bakke, Bergman & Larsen, Science 217 (1982) 645

6 Reactive PCB metabolites CB-52 Arene oxides, semiquinones, and quinones are ROS The question: Do they play a role in cancer development? O O OH O O Adducts to DNA, RNA, Proteins, Lipids

7 PCB methyl sulfones in grey seal blubber 14 Isomer specific analysis of PCB and DDE methyl sulfones 16 3-MeSO 2 -DDE ? 17 1? 2 3 4? 5 6? MeSO 2 -DDE?

8 Intense Japanese Synthesis of MeSO 2 -PCBs NH 2 SCH 3 H 3 CS SCH 3 SCH 3 + H 2 N IAN SO 2 CH 3 SO 2 CH 3 SO 2 CH 3 SO 2 CH 3 Haraguchi et al. J. Agric.Food Chem I Sn(CH 3 ) 3 SO 2 CH 3 + Pd 0 SO 2 CH 3 Mortimer and Newsome Chemosphere 1996

9 Major MeSO 2 -PCBs in humans and the environment Parent PCBs CB-101 CB-132 CB-149 SO 2 CH 3 4 -MeSO 2 -CB101 SO 2 CH 3 3 -MeSO 2 -CB101 SO 2 CH 3 SO 2 CH 3 4 -MeSO 2 -CB MeSO 2 -CB132 4-MeSO 2 -CB149 5-MeSO 2 -CB149 SO 2 CH 3 SO 2 CH 3

10 Intense international MeSO 2 -PCB/DDE chemical analysis of wildlife Species Location Tissue ΣMeSO2 -PCB ΣMeSO 2 -PCB/ (ng/g l.w.) ΣPCB Marine mammals Ringed Seal Canadian Arctic blubber Grey seal Baltic Sea blubber Terrestial mammals 1 Human Sweden plasma Human Slovak Republic plasma * Otter Sweden adipose Polar bear Canadian Arctic fat Birds 1 Sea eagle Sweden egg <100 <0.1 1 Herring gull Lake Ontario egg 10 Fish 1 Rainbow trout Japan whole 4 4 Deppwater sculpin Great Michigan whole *4-MeSO 2 -CB149 (only) 1 Letcher et al., In New Types of Persistent Halogenated Compounds 2000; 2 Larsson et al. ms., submitted 2003; 3 Hovander et al., personal commun. 2003; 4 Stapleton et al. ES&T. 35(2001)

11 eanup of PCB methyl sulfones MeSO 2 -PCBs Blood plasma (5 g) Denaturation and extraction Neutral compounds Phenolic compounds DMSO partitoning PCBs MeSO 2 -PCBs conc H 2 SO 4 Silica gel: H 2 SO 4 (2:1) column Column Silica gel: 90% H 2 SO 4 (2:1, 0.8 g) Silica gel: 0.85M KOH (2:1, 0.4 g) Silica gel (0.1 g) GC(ECD) GC/MS L. Hovander Stockholm University

12 Concentrations (median) of 4-MeSO 2 -CB149 in different human matrices 3,5 3 ng/g lipids 2,5 2 1,5 1 0, / b Liver b Adipose c Plasma a Human milk Sweden d Plasma Slovakia a Noren et al 1996, b Weistrand and Noren 1997, c Weistrand et al 1997, d Hovander et al pers comm.

13 MeSO 2 -PCB in plasma from the Michalovce area The Slovak Republic 3-MeSO 2 -CB49 4-MeSO 2 -CB49 3-MeSO 2 -CB101 4-MeSO 2 -CB101 3-MeSO 2 -CB87 3-MeSO 2 -CB149 4-MeSO 2 -CB87 4-MeSO 2 -CB149 3-MeSO 2 -CB132 4-MeSO 2 -CB141 I.S. 3-MeSO 2 -DDE 20:00 23:20 26:40 30:00 (min) L. Hovander Stockholm University

14 Enantioselective separation of MeSO 2 -PCB atropisomers in human plasma from Slovakia Standard Human plasma (+) 5-MeSO 2 -CB149 (- ) (+) 4-MeSO 2 -CB149 (-) 5-MeSO 2 -CB149 (-) 4-MeSO 2 -CB149 (+) Internal standard Internal standard L. Hovander Stockholm University

15 MeSO 2 -PCBs in rat (n=8) tissues after exposure to ophen A50 Enantiomeric fractions (EFs) Congener Adipose (EF) Liver (EF) Lung (EF) 4-MeSO 2 -CB MeSO 2 -CB < MeSO 2 -CB '-MeSO 2 -CB Larsson et al. Environ. Sci. Technol. 36 (2002)

16 EF bar diagram of chiral MeSO 2 -PCBs in tissues of Grey seal (n=5), from the Baltic Sea EFs (A a1 /(A a1 +A a2 )) and range for eight MeSO 2 -PCB atropisomers 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Blubber Liver Lung '-132 4' '-132 5'-174 racemate Larsson et al. ms submitted 2003

17 More recent data on atropisomeric specificities EFs of five MeSO 2 -PCBs in Porpoise liver 1,20 1,00 0,80 0,60 0,40 0,20 0,00 4-MeSO2-CB149 4-MeSO2-CB174 5-MeSO2-CB132 5-MeSO2-CB149 5-MeSO2-CB174 4-MeSO2-CB149 4-MeSO2-CB174 5-MeSO2-CB132 5-MeSO2-CB149 5-MeSO2-CB174 Absolute structures known for: 4 -MeSO 2 -CB MeSO 2 -CB132 5-MeSO 2 -CB149 5-MeSO 2 -CB174 Chu et al., ES&T 2003 Döbler et al., J Molec. Stru., 586 (2002)

18 General PCB metabolism scheme O O? HO H H OH O OH-PCBs GS O GS HO SG HO SG SO 2 CH 3 SO 2 CH 3

19 Halogenated Phenolic Compounds (HPCs) in human blood 4 PCP 7 * Triclosan 10 OH-PCBs I.S. OH-PBDE (min) From: Hovander et al., Arch Environ. Contam. Toxicol, 42 (2002) 105

20 Major PCB/OH-PCB metabolite pairs CB-105 CB-118 CB-153 CB-138 CB-187 CB-183 OH OH OH 4-OH-CB107 4-OH-CB146 4-OH-CB187 From: Sjödin et al., Organohal. Comp. 37 (1998) 365

21 OH-PCBs in human plasma - the GC peak pattern 3-OH-CB153 4-OH-CB107 4-OH-CB146 OH 4-OH-CB187 OH OH OH IS IS min

22 Method for clean up of PCB metabolites Plasma Extraction OH-PCB Phenols KOH-hexane partitioning Neutrals Derivatization CH 2 N 2 MeSO 2 -PCB DMSO partitioning PCB H 2 SO 4 - treatment SiO 2 /KOH/H 2 SO 4 column H 2 SO 4 - treatment SiO 2 /H 2 SO 4 column SiO 2 /H 2 SO 4 column GC/ECD GC/MS GC/ECD Hovander et al., PCBRISK

23 OH-PCB levels from three countries % quartiles ng/g lipid weight OH-CB107 4-OH-CB146 4-OH-CB187 0 Slovak Republic 1 Faroe Islands 2 Netherlands Exposed 1 B. Fängström et al S. Soechitram et al., 2004

24 Concentrations (median) of 4-OH-CB187 in plasma and cordplasma from different geographical areas ng/g lipid weight low high low high cord low high female male cord blood Sweden Lativa Netherlands Faroe Slovakia Quebec Nicaragua Islands Canada Sjödin et al 200, Soechitram et al 2004, Fängström et al 2002, Hovander et al,sandau et al 2000 Sandau et al 2002, Cuadra et al 2004, A1 A2 low high Russian Artic

25 Pharmacokinetics of 4-OH-CB107 and 4-OH-CB187 in rat blood 18,0 nmol/ml plasma 16,0 14,0 12,0 10,0 8,0 6,0 4,0 2,0 0,0 4-OH-CB107 4-OH-CB time (h) Elimination half-life: 4-OH-CB107 4 days 4-OH-CB days Pharmacokinetic calculations are based on the mean plasma concentration-time curves using WinNonlin Pro 3.1 Malmberg et al., Xenobiotica 36 (2004)

26 PCP, OH-PCB, OH-PBDE characteristics Compound p s K a Log K ow (cal) TTR rel. bind. Potency PCP OH-CB OH-CB OH-CB OH-CB OH-CB OH-CB OH-BDE OH-BDE OH-BDE OH-BDE Malmberg et al., 2004

27 Concluding remarks OH-PCBs are retained in similar concentrations in human and wildlife blood as the PCB congeners which makes them particularly important since they will reach all cells and tissues in the body The sulfones are present at much lower concentrations but with very high tissue selectivity, high congener selectivity and with high enantioselectivity

28 Thank You With special thanks: for all support from colleagues and Ph.D. students at my department in Stockholm and to my Dear colleagues in Sweden and around the world that made this possible