Lecture 2010 Zwiernik SETAC - · PDF file• Literature search based on mind map ... Terrestrial Liver 46 mg/kg lipid 32,255 ng/kg lipid Marine Liver and Blood 8.6 mg/kg lipid 1,292

National Food Safety and Toxicology Center

Chapter 15Toxicological Implications of PCBs, PCDDs and PCDFs in

Mammals

Matthew Zwiernik1

Frouke Vermeulen2

Steven Bursian1

1Michigan State University, College of Veterinary Medicine, Department of Animal Science.

2ARCADIS, Belgium


Goals of Chapter Revisions

• Update information (1995-2010)

• 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


The Process

• Mind mapping 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

CHAPTER_SETAC

TITLEOLD

Toxicological implications of PCB residues in Mammals

NEWbrainstorm PCB and dioxin-like compounds in mammals

introduct ion

Why do we care?

Nature & Extent of Exposure

Spatial t rends

Bioaccumulat ion

Temporal trends

Biological responses

Risk

????

exposure

introduct ion

trendsuptakebioaccumulation

metabolism

absolute

terrestrial

[ tissue ]

trendstemporalspatial

source

marine

[ tissue ] varies


aquatic

[ tissue ]


relat ive[aquatic] > [terrestrial]

ef ects

introduct ion

labspeciesf (availability)

terrestrial

aquat icmink

marinecorrelationdisease

field

speciesf (availability)

terrestrial

aquat icmink


f (population)exposure/TRV/response

f (individual)exposure/TRV/response

response

differencesf (species)

= speciescongener mix

inexposure

papers available

Matt

sledge dogs & polar bears= [ diet ]

different [tissue]

specificallyexampleshousatonic

saginaw

talk about

MESSAGE

informationfromkinetic

mink

contradictionin what?Matt?

comments

TFFs

minkBlankenship= review

lackfield exposure


The Process: Mind Map

CHAPTER_SETAC

TITLEOLD



introduction

Why do we care?


Spatial t rends

Bioaccumulation

Temporal t rends


Risk

????

exposure

introduct ion


metabolism

absolute

terrestrial

[ tissue ]


source

marine

[ tissue ] varies


aquatic

[ tissue ]



ef ects

introduction


terrestrial

aquaticmink


field


terrestrial

aquat icmink




response



inexposure

papers available

Matt


different [tissue]


saginaw

talk about

MESSAGE


mink


comments

TFFs


lackfield exposure


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



• 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



• 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)


The Process: Mind Map

CHAPTER_SETAC

TITLEOLD



introduction

Why do we care?


Spatial t rends

Bioaccumulation

Temporal t rends


Risk

????

exposure

introduct ion


metabolism

absolute

terrestrial

[ tissue ]


source

marine

[ tissue ] varies


aquatic

[ tissue ]



ef ects

introduction


terrestrial

aquaticmink


field


terrestrial

aquat icmink




response



inexposure

papers available

Matt


different [tissue]


saginaw

talk about

MESSAGE


mink


comments

TFFs


lackfield exposure


• Furans (PCDFs) Polychlorodibenzofurans

4

3

2 1 9 8

7

6O

(Cl)n(Cl)n

Chapter Subject: Compounds


• Biphenyls (PCBs) Polychlorinated biphenyls

5

4

3 2 2' 3'

4'

5'6'6(Cl)n

(Cl)n



• Dioxins (PCDDs) Polychlorodibenzo-p-dioxins

Cl

ClCl

Cl

43

21 O 9

8

76O



• Structurally related

• Bioacumulative

• Toxicity by similar mode of action

• Found in the environment as mixtures

• Regulated as a group under the TEF system

Compound Characteristics

Cl

ClCl

Cl

43

21 O 9

8

76O

4

3

2 1 9 8

7

6O

(Cl)n(Cl)n

5

4

3 2 2' 3'

4'

5'6'6(Cl)n

(Cl)n


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 2,3,7,8 TCDD

• Uncertainties associated with TEQs Assumptions of additivity

Between species variations

Extrapolation from cellular to whole animal response


Mammalian Tissue Spatial andTemporal 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


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)


Study Selection

• Studies were selected based on quality criteria Dosing regime

Potential for co‐contaminants

Tissue type

Measurement endpoint

Establishment of effects concentrations


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


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. 2002

Kannan et al. 2000


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


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


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)


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


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)


Marine Mammal TTRC

• 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. 2000• Blubber TEQs based on seal data derived by Kannan et al. 2000

ΣPCBs TEQs

Liver and Blood 8.6 mg/kg lipid 1292 ng/kg lipid

Blubber 17 mg/kg lipid 160 ng/kg lipid


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


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


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 species‐specific

• The presented values should be used with caution


Questions ?

Dr. Matthew [email protected]

Dr. Steve [email protected]

Documents

Lecture 2010 Zwiernik SETAC - · PDF file• Literature search based on mind map ... Terrestrial Liver 46 mg/kg lipid 32,255 ng/kg lipid Marine Liver and Blood 8.6 mg/kg lipid 1,292