lecture 2010 zwiernik setac - · pdf file• literature search based on mind map ......
TRANSCRIPT
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
trendstemporalspatial
aquatic
[ tissue ]
trendstemporalspatial
relat ive[aquatic] > [terrestrial]
ef ects
introduct ion
labspeciesf (availability)
terrestrial
aquat icmink
marinecorrelationdisease
field
speciesf (availability)
terrestrial
aquat icmink
marinecorrelationdisease
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
National Food Safety and Toxicology Center
The Process: Mind Map
CHAPTER_SETAC
TITLEOLD
Toxicological implications of PCB residues in Mammals
NEWbrainstorm PCB and dioxin-like compounds in mammals
introduction
Why do we care?
Nature & Extent of Exposure
Spatial t rends
Bioaccumulation
Temporal t rends
Biological responses
Risk
????
exposure
introduct ion
trendsuptakebioaccumulation
metabolism
absolute
terrestrial
[ tissue ]
trendstemporalspatial
source
marine
[ tissue ] varies
trendstemporalspatial
aquatic
[ tissue ]
trendstemporalspatial
relat ive[aquatic] > [terrestrial]
ef ects
introduction
labspeciesf (availability)
terrestrial
aquaticmink
marinecorrelationdisease
field
speciesf (availability)
terrestrial
aquat icmink
marinecorrelationdisease
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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)
National Food Safety and Toxicology Center
The Process: Mind Map
CHAPTER_SETAC
TITLEOLD
Toxicological implications of PCB residues in Mammals
NEWbrainstorm PCB and dioxin-like compounds in mammals
introduction
Why do we care?
Nature & Extent of Exposure
Spatial t rends
Bioaccumulation
Temporal t rends
Biological responses
Risk
????
exposure
introduct ion
trendsuptakebioaccumulation
metabolism
absolute
terrestrial
[ tissue ]
trendstemporalspatial
source
marine
[ tissue ] varies
trendstemporalspatial
aquatic
[ tissue ]
trendstemporalspatial
relat ive[aquatic] > [terrestrial]
ef ects
introduction
labspeciesf (availability)
terrestrial
aquaticmink
marinecorrelationdisease
field
speciesf (availability)
terrestrial
aquat icmink
marinecorrelationdisease
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
National Food Safety and Toxicology Center
• Furans (PCDFs) Polychlorodibenzofurans
4
3
2 1 9 8
7
6O
(Cl)n(Cl)n
Chapter Subject: Compounds
National Food Safety and Toxicology Center
• Biphenyls (PCBs) Polychlorinated biphenyls
5
4
3 2 2' 3'
4'
5'6'6(Cl)n
(Cl)n
Chapter Subject: Compounds
National Food Safety and Toxicology Center
• Dioxins (PCDDs) Polychlorodibenzo-p-dioxins
Cl
ClCl
Cl
43
21 O 9
8
76O
Chapter Subject: Compounds
National Food Safety and Toxicology Center
• 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
National Food Safety and Toxicology Center
Toxicity
• Activate a chemical-responsive DNA binding protein the aryl hydrocarbon receptor (AhR)
• May elicit mutagenic, teratogenic and histologic effects
• Suspected carcinogenic effects
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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)
National Food Safety and Toxicology Center
Study Selection
• Studies were selected based on quality criteria Dosing regime
Potential for co‐contaminants
Tissue type
Measurement endpoint
Establishment of effects concentrations
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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)
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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)
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
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
National Food Safety and Toxicology Center
Questions ?
Dr. Matthew [email protected]
Dr. Steve [email protected]