Chapter 15 Toxicological Implications of PCBs, PCDDs and PCDFs in Mammals

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1 Chapter 15 Toxicological Implications of PCBs, PCDDs and PCDFs in Mammals Matthew Zwiernik 1 Frouke Vermeulen 2 Steven Bursian 1 1 Michigan State University, College of Veterinary Medicine, Department of Animal Science. 2 ARCADIS, Belgium

Goals of Chapter Revisions Update information (1995-2010) Broaden the scope Highlight mechanisms of action Add discussions on related compounds Examine the TEF

2 Goals of Chapter Revisions Update information ( ) Broaden the scope Highlight mechanisms of action Add discussions on related compounds Examine the TEF approach Discuss measurement endpoints, dose response relationships Provide some guidance for interpreting wildlife tissue concentrations of PCBs, PCDFs, and PCDDs

3 The Process kinetic from mink information Matt? in what? contradiction TFFs = review field exposure Blankenship lack mink MESSAGE comments talk about OLD TITLE NEW introduction Toxicological implications of PCB residues in Mammals brainstorm PCB and dioxin-like compounds in mammals Why do we care? Nature & Extent of Exposure Spatial trends Bioaccumulation Temporal trends disease terrestrial mink aquatic correlation marine f (availability) introduction species lab CHAPTER_SETAC Biological responses Risk???? trends uptake introduction bioaccumulation disease terrestrial mink aquatic correlation marine f (availability) species metabolism [ tissue ] temporal terrestrial trends spatial exposure/trv/response f (population) field ef ects exposure source [ tissue ] varies Mind mapping = [ diet ] different [tissue] exposure/trv/response f (individual) f (species) congener mix differences = species Matt papers available sledge dogs & polar bears response exposure in housatonic examples saginaw specifically absolute relative marine temporal trends spatial [ tissue ] aquatic temporal trends spatial [aquatic] > [terrestrial] Identify and understand the structure of a subject, and the way that pieces of information fit together Literature search based on mind map Use a multi-level criteria based filter to identify relevant literature

4 The Process: Mind Map TITLE OLD NEW Toxicological implications of PCB residues in Mammals brainstorm PCB and dioxin-like compounds in mammals kinetic mink from information Matt? in what? contradiction TFFs = review field exposure lack Blankenship mink MESSAGE comments talk about introduction Why do we care? Nature & Extent of Exposure Spatial trends Bioaccumulation Temporal trends disease mink correlation terrestrial aquatic marine f (availability) introduction species lab CHAPTER_SETAC Biological responses Risk???? trends uptake introduction bioaccumulation disease terrestrial mink aquatic f (availability) species correlation marine exposure/trv/response f (population) field ef ects exposure metabolism [ tissue ] terrestrial trends source [ tissue ] temporal spatial varies = [ diet ] ifferent [tissue] sledge dogs & polar bears housatonic saginaw exposure/trv/response f (individual) f (species) congener mix = species differences Matt papers available response exposure in examples specifically absolute relative marine temporal trends spatial [ tissue ] aquatic temporal trends spatial [aquatic] > [terrestrial]

5 The Process: Literature Search Strategy Search string TOPIC = (PCB* or polychlorinated-biphenyl* or dioxin or dioxin-like or TCDD or PCDD or PCDF or furan or furans) and (tissue or tissues or organ or organs) and (concentration or concentrations or residue or residues) and (mammal or mammals or mammalian or wildlife) NOT (human or humans) NOT (rat or rats) NOT (mice or mouse) Selection by publication year Rank the records by : Published year From resulting list mark years 1990 through 2009 View records (~1800) Export records + abstract as tab-delimited file for Mac

6 The Process: Literature Search Strategy Selection by relevance By Title Read title and if RELEVANT put X in column RELEVANT If not sure leave blank and proceed to abstract sort By Abstract Read abstract and if RELEVANT put X in column RELEVANT Export RELEVANT references to Endnote

7 The Process: Literature Search Strategy Divide publications among authors Mechanism of action Spatial and temporal trends TEF approach Aquatic non-marine Marine Terrestrial Remove duplicates Summarize and attach to Mind Map (385 Papers, 160 cited)

8 The Process: Mind Map TITLE OLD NEW Toxicological implications of PCB residues in Mammals brainstorm PCB and dioxin-like compounds in mammals kinetic mink from information Matt? in what? contradiction TFFs = review field exposure lack Blankenship mink MESSAGE comments talk about introduction Why do we care? Nature & Extent of Exposure Spatial trends Bioaccumulation Temporal trends disease mink correlation terrestrial aquatic marine f (availability) introduction species lab CHAPTER_SETAC Biological responses Risk???? trends uptake introduction bioaccumulation disease terrestrial mink aquatic f (availability) species correlation marine exposure/trv/response f (population) field ef ects exposure metabolism [ tissue ] terrestrial trends source [ tissue ] temporal spatial varies = [ diet ] ifferent [tissue] sledge dogs & polar bears housatonic saginaw exposure/trv/response f (individual) f (species) congener mix = species differences Matt papers available response exposure in examples specifically absolute relative marine temporal trends spatial [ tissue ] aquatic temporal trends spatial [aquatic] > [terrestrial]

9 Chapter Subject: Compounds Furans (PCDFs) Polychlorodibenzofurans O (Cl)n (Cl)n

10 Chapter Subject: Compounds Biphenyls (PCBs) Polychlorinated biphenyls 3 2 2' 3' (Cl)n 4 4' (Cl)n 5 6 6' 5'

11 Chapter Subject: Compounds Dioxins (PCDDs) Polychlorodibenzo-p-dioxins Cl 1 O 9 Cl 2 8 Cl 3 4 O 6 7 Cl

12 Compound Characteristics 4 O Structurally related Bioacumulative Toxicity by similar mode of action Found in the environment as mixtures Regulated as a group under the TEF system (Cl)n (Cl)n ' 3' (Cl)n 4 4' (Cl)n 5 6 6' 5' Cl 1 O 9 Cl Cl 4 O 6 Cl

13 Toxicity Activate a chemical-responsive DNA binding protein the aryl hydrocarbon receptor (AhR) May elicit mutagenic, teratogenic and histologic effects Suspected carcinogenic effects

Toxic Equivalents (TEQs) Dioxin-like compounds expressed as TEQs A TEQ is the product of the total concentration of a congener and it relative potency to

14 Toxic Equivalents (TEQs) Dioxin-like compounds expressed as TEQs A TEQ is the product of the total concentration of a congener and it relative potency to 2,3,7,8 TCDD Uncertainties associated with TEQs Assumptions of additivity Between species variations Extrapolation from cellular to whole animal response

15 Mammalian Tissue Spatial and Temporal Trends Northern hemisphere greater than southern Colder climates my experience cold condensation Marine mammals foraging close to costal areas Males generally have greater tissue burdens than reproducing females General increase in background levels until 80 s

16 Data Organization By food web type Terrestrial (such as shrews, voles, mice) Marine (such as whales, dolphins, seals, sea otters and polar bears) Aquatic (mink and river otters)

17 Study Selection Studies were selected based on quality criteria Dosing regime Potential for co contaminants Tissue type Measurement endpoint Establishment of effects concentrations

18 Measurement Endpoints Focus on ecologically relevant endpoints Impaired reproduction Reduced offspring survivability Reduced offspring growth Additionally included Vitamin A and hormone concentrations Immunological parameters Tissue morphology

19 Approach to developing Threshold Tissue Residue Concentrations (TTRC) Focus on controlled studies Examine multiple methodologies Ground truth with field data Compare with other published TTRCs Schwacke et al Kannan et al. 2000

20 Data Availability Terrestrial mammals Limited number of controlled studies Many field studies but none with dose response data Marine mammals Limited number of controlled captive or semi captive studies A great number of wildlife based studies some with both tissue and response data

21 Data Availability Aquatic mammals The most robust data set for controlled studies Many field studies including those with of tissue concentrations to effects data The greatest majority of the data pertains to a American mink

22 Data Interpretation Threshold Tissue Residue Concentrations (TTRC) were derived for terrestrial, marine and aquatic mammalian species based on the geometric mean of the No Observable Adverse Effect Concentrations (NOAEC) Lowest Observable Adverse Effects Concentration (LOAEC)

23 Disclaimer Given the available data we proposes a number of threshold tissue residue concentrations for PCBs and related compounds There is a significant amount of uncertainty associated with these estimates Expressing concentrations on a ΣPCB basis when congener mixtures vary from site to site Uncertainty associated with TEFs for specific congeners in specific species

24 Terrestrial Mammal TTRC ΣPCBs TEQs Liver 46 mg/kg lipid 32 ug/kg lipid ΣPCB calculated from 2 generation feeding study using Sherman Rats, based on litter size ( Grant et al. 1975, Linder et al. 1974) TEQs calculated from 3 generation feeding study using Sprague Dawley rats, based on litter size (Murry et al. 1979, Kociba et al. 1979)

25 Marine Mammal TTRC ΣPCBs TEQs Liver and Blood 8.6 mg/kg lipid 1292 ng/kg lipid Blubber 17 mg/kg lipid 160 ng/kg lipid Liver and Blood TTRCs based on geometric mean of NOAEC and LOAECs for seals, otter and mink Blubber ΣPCBs based on Reddy et al. 1998, Kannan et al Blubber TEQs based on seal data derived by Kannan et al. 2000

26 Aquatic Mammal TTRC ΣPCBs TEQs Liver 41mg/kg lipid 1,540 ng/kg lipid Geometric mean of NOAEC and LOAEC based on lipid normalized mink hepatic concentrations from Heaton et al. 1995/Tillitt et al. 1996, Bursian et al. 2006a,2006b and 2006c

27 Mammal TTRC Comparisons Mammal Type Tissue Type ΣPCBs TEQs Terrestrial Liver 46 mg/kg lipid 32,255 ng/kg lipid Marine Liver and Blood 8.6 mg/kg lipid 1,292 ng/kg lipid Blubber 17 mg/kg lipid 160 ng/kg lipid Aquatic Liver 41 mg/kg lipid 1,540 ng/kg lipid Liver based tissue threshold residue concentrations are surprisingly consistent with the exception of TEQs for terrestrial mammals Marine mammal blubber based tissue threshold residue concentrations were generally lesser than overall liver TTRCs

28 Conclusions Mammalian exposure to PCBs, PCDF, and PCDDs appears to be decreasing There are significant uncertainties associated with predicting effects associated with PCB/ PCDF/ PCDD exposure Ideally, threshold tissue residue concentrations for PCBs/PCDDs/PCDFs should be site specific and speciesspecific The presented values should be used with caution

29 Questions? Dr. Matthew Zwiernik Dr. Steve Bursian

Mink and PCDF/D s in the Tittabawassee River Basin

Mink and PCDF/D s in the Tittabawassee River Basin Matthew Zwiernik 1 Jeremy Moore 1 Dustin Tazelaar 1 Denise Kay 2 David Hamman 1 Alan Blankenship 2 John P. Giesy 1 1 2 Field Studies in Support of a Baseline