adverse outcome pathway for effects of anticoagulant ... · adverse outcome pathway for effects of...
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Adverse Outcome Pathway for Effects of Anticoagulant
Rodenticides on Predatory Birds
Barnett A. Rattner and Rebecca S. Lazarus USGS, Patuxent Wildlife Research Center, Beltsville, MD, USA
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1
Hemostasis
2
Hemostasis
3
Hemostasis
Adapted from Cleveland Clinic Center for Continuing Education
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Anticoagulant Rodenticides
Block Vitamin K cycle Inhibits formation active clotting Factors II, VII, IX, and X, resulting in hemorrhage
Oxidized Vitamin K Reduced Vitamin K
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1st Generation Anticoagulant Rodenticides – FGARs Warfarin (1948) Diphacinone (1960) intermediate generation Chlorophacinone (1971) intermediate generation
Multiple feeding to cause death (short half-life) Genetic changes in rats (Scotland, Europe, Japan) – “Resistance”
2nd Generation Anticoagulant Rodenticides - SGARs Brodifacoum (1979), Bromadiolone, Difethialone, Difenacoum
Single feeding can cause death More toxic, longer half-life (potentially PBT)
Greater hazard to Non-target Species
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Widespread Use Residential, Urban, Agriculture, Island Restoration
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Primary Exposure Humans (AAPCC: >12,000 calls/yr)
Companion animals (APCC: 8,000 calls/yr)
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Exposure in Predatory Birds and Mammals High detection rates in liver of wildlife (principally SGARs)
Canada 70% of 164 owls Albert et al. 2010 France 73% of 30 raptors Lambert et al. 2007 France 12% of 122 mustelids Fournier-Chambrillon et al. 2004
Scotland 47% of 773 raptors Hughes et al. 2013 Britain 37% of 351 raptors Walker et al. 2008 Britain 26% of 717 barn owls Newton et al.1999 Britain 31% of 100 polecats Shore et al. 2003
New Zealand Various species Eason et al. 1995, 2002 United States 79% of 58 fishers Gabriel et al. 2012
United States 90% of 39 bobcat Riley et al. 2007
United States 49% of 265 raptors Stone et al. 2003 United States 86% of 161 raptors Murray 2011
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Ankley et al. 2010. Environmental Toxicology & Chemistry
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Toxicant
hydroxycoumarin
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Structure Activity Relationship Models
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Macromolecular Interactions
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Macromolecular Interactions
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Cascade Model
Intrinsic Pathway Extrinsic Pathway
Common Pathway
https://ahdc.vet.cornell.edu/clinpath/modules/coags/introf.htm
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Cascade Model
Vit K Dependent
Vit K Dependent
Vit K Dependent
Vit K Dependent
https://ahdc.vet.cornell.edu/clinpath/modules/coags/introf.htm
Intrinsic Pathway Extrinsic Pathway
Common Pathway
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Macromolecular to the Cellular Response Cell-based Model of Hemostasis
Hoffman and Monroe. 2001. Thrombosis and Haemostasis
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Macromolecular to the Cellular Response Cell-based Model of Hemostasis
Hoffman and Monroe. 2001. Thrombosis and Haemostasis
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Lag for Onset of Coagulopathy Clearance of “functional” clotting factors in humans
Appearance of “des-carboxy dysfunctional” factors
Clotting Factor II VII IX X Half-Life 48-120 hr 2-6 hr 18-40 hr 30-70 hr
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Other Cellular Responses
Vitamin K cycle-related
-reduced bone density
- anti-inflammatory and immune signaling
-inhibits cell proliferation Uncouple oxidative phosphorylation (mitochondrial toxicity) Peroxisome proliferator-activated receptor
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Multiple Organ Response
Hemorrhage due to coagulopathy: Skin Musculoskeletal Respiratory Renal Gastrointestinal Reproductive Central Nervous System
Gabriel et al. 2012. PLOS ONE
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Blood Loss and Anemia
Reduced RBC count and hematocrit resulting in pallor Metabolic acidosis Increased cardiac output Hypovolemic shock Severe hypoperfusion Localized ischemia, hypox Organ dysfunction Necrosis
Plausible Linkage ia
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Organism Response
Lethargy (“weakness, fatigue”) ↓ Body condition, reduced fitness ↑ Blood loss from minor trauma Susceptibility to disease (notoedric mange) Alter predator-prey dynamics?
Reproductive toxicants
Recovery or Death
Hypothetical Linkage
http://www.urbancarnivores.com/notoedric-mange-a-disease-of/
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Population Response Incidence of confirmed poisoning of total exposures (~10%)
Thomas, Mineau, Shore et al. 2011. Environment International
Canada 6 of 114 owls Albert et al. 2010 France 3 of 16 mustelids Fournier-Chambrillon et al. 2004 Scotland 15 of 362 raptors Hughes et al. 2013 Britain 9 of 187 barn owls Newton et al. 1999 USA 4 of 46 fishers Gabriel et al. 2012
9 of 139 raptors Murray 2011
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Species of Special Conservation Status
Weka New Zealand Red kite France San Joaquin kit fox US Bald eagle US Barn owl Canada
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Rattner et al. 2014. Environmental Science & Technology
Adverse Outcome Pathway
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Adverse Outcome Pathway
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Adverse Outcome Pathway
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Data Gaps and Research Needs Interspecific differences in sensitivity (raptors > granivores) -VKOR activity -Are there sensitive sub-populations or conserved across species -Metabolism and elimination Relative potency of ARs for VKOR (additive tox models for mixtures) Role of vitamin K status Significance of sublethal effects at individual- and population-level Quantitative estimates non-target predator mortality
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Regulatory Application
Anticoagulant Rodenticide AOP for “non-target predatory wildlife”
Perkins et al. 2014. Advancing AOPs for Integrated Toxicology and Regulatory Applications
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Toxicity Reference Values Cumulative Probability Survival Curves
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Regulatory Application of the AR-AOP? The train already left the station – major regulatory decisions already made in U.S. EPA,
EC and EU in the past 5 years without AOP framework AR-AOP could provide biological plausibility for a decision
(EIA) Good communication tool for regulatory agencies and
public Increase confidence in a risk assessment by using Weight
of Evidence Approach in an AOP Framework
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Conclusions
Mechanism of action at molecular level well-known Relative potency of ARs only partially understood Limited demographic studies in areas of high AR use Development of mechanistic dynamic models in silico Look at other toxicants (Pb) that may have same AO (anemia)
through a different MIE
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Questions?