environmental health
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Environmental Health. Interactions and Mixtures Week 9. Cumulative risks. Which mixtures are important for Public Health? What is the nature, magnitude of cumulative exposures? What is the mechanism of interactions?. Sexton 2007 and supplement. Biological Chemical Physical Psychosocial. - PowerPoint PPT PresentationTRANSCRIPT
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Environmental Health
Interactions and MixturesWeek 9
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Cumulative risks
• Which mixtures are important for Public Health?
• What is the nature, magnitude of cumulative exposures?
• What is the mechanism of interactions?
Sexton 2007 and supplement
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Types of mixtures
• Biological• Chemical• Physical • Psychosocial
• Similar properties• Defined (diesel)• Coincidental (time,
place)
Past and present, all routes, pathways and sources
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High priority mixtures
• Scope: large number of people exposed
• Nature of exposure: magnitude, frequency
• Severity of effects: unacceptable risks
• Potential for interactions
See: Sexton 2007 supplement
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See: Sexton 2007 supplement
Total body burden over time based on exposure frequency and kinetics of a chemical
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See: Sexton 2007 supplement
Total body burden from two chemicals relative to a health benchmark
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Interactions among what?
• Drug-drug
• Environmental pollutants
• Drug-environmental exposure
• Diet-drug
• Diet-environmental pollutant
• Genes and all the above
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When, who, how?
• Exposures – Concurrent – Sequential– Order
• Physiology differences – Children– Elderly– Pre-existing conditions, overall health– Genetic disposition
• Route of exposure• Amount
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Types of interactions
Dose additivity - if mechanism is similarResponse additivity - if acting independently
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Putting a number to them
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Antagonism of many kinds
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So, what interaction is this?
Q. A dose of 4 mg of an insecticide causes 20% toxicity whereas the same dose of another insecticide produces 30% toxicity. If 8 mg of a formulation containing both insecticides in equal concentrations causes 50% toxicity, the interaction is known as:
AdditivityAntagonismSynergism
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…and, what about this?
Q. Piperonyl butoxide added to pyrethrum insecticide results in a pyrethrum formulation having about 100 times the toxicity of pyrethrum alone. The interaction of this combination is:
Additivity
Antagonism
Synergism
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Main types of interactions
• Physical prior to absorption
• Toxicokinetic interactions
• Toxicodynamic interactions
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Toxicokinetic Interactions
• One chemical affects the kinetic disposition of another:– Absorption– Distribution– Metabolism– Elimination
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Performing in vitro CYP450 induction screens, to evaluate potential multi-chemical interactions
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“A” increases toxicity of “B” by inhibiting a detox enzyme
A B
B metabolite
Excretion
Enzyme X (Phase I)
Enzyme Y (Phase II)
+ Toxic effect
inactive
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“A” is protective by inhibiting a metabolic activation reaction
A B
B metabolite
Excretion
Enzyme X (Phase I)
Enzyme Y (Phase II)
+ inactive
Toxic effect
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“A” is protective by inducing a detox enzyme
A B
B metabolite
Excretion
Enzyme X (Phase I)
Enzyme Y (Phase II)
+ Toxic effect
inactive
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“A” increases toxicity of “B” by inducing enzyme of metabolic activation
A B
B metabolite
Excretion
Enzyme X (Phase I)
Enzyme Y (Phase II)
+
Toxic effect
inactive
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Toxicodynamic Interactions
• One chemical’s biological activity is related to the biological activity of the other– Changing cell signaling (phosphorylation cascades)– Altering gene expression and genomic repair– Modulating cell communication– Altering cell cycle– Affecting the same biochemical pathway at a different
step– Affecting a related biochemical pathway– Systemic level cross-talk interference– Autoimmune effects
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See: Sexton 2007 supplement
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Competitive inhibition of a enzyme reaction, transporter activity
First order Michaelis-Menten kinetics of enzyme reaction:
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Uncompetitive inhibition of a enzyme reaction, transporter activity
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Change in slope as indicator of interactions
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See Gennings 2005
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Slopes must be compared at the same effect regions
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See Gennings 2005
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Interaction of piperonyl butoxide with malathion
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Non-linear models
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Binary endpoints and probability of response
A - Changing concentrations of one chemical with fixed concentration of the other
B - Changing concentrations of both chemicals
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Carpenter, 1998
Thyroid effects of PCBs
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Carpenter, 1998
PTU: propylthiouracil, known to produce hypthyroidismLTP: long term potential, electrophysiological measure indicating cognitive functionEPSP: excitatory postsynaptic potential, reflects LTP
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Carpenter, 1998
Parent compound and metabolite have opposite effects
TrCB is also antiestrogenic by virtue of inducing the metabolism of E2
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Increased estrogenic effects of combined PCBs or organochlorines
Carpenter, 1998
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Carpenter, 1998
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Carpenter, 1998
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Models of interactions
See Groten 2001
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Combined effects of UV filter mixtures on ER activation (yeast)
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A - synergismCurve shift to the left
B - antagonismCurve shift in-between
Kunz 2006
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Most binary mixtures show synergism at EC25, EC50 and EC75 effect levels
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Kunz 2006
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Synergism of mixtures of 4 UV filters at BC10 and NOEC effect levels
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Kunz 2006
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Effect of mixture of 4 UV filters at BC10 and NOEC
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Kunz 2006
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Effect of mixtures (4 or 8) is stronger at NOEC than at BC10
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Kunz 2006
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Mixtures of 4 are as potent as the most potent one (BP1)
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Relative potencies are compared to E2 Kunz 2006
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Approaches to toxicity of simple mixtures
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Simple mixtures toxicity testing
Bottom-up approach
Systematic studies of binary combinations of chemicals in the mixture based on mechanisms
Top-down approach
Start from the most complete mixture and continue with subfractions by separating components
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Bottom-up
• Kepone’s impairment of liver regeneration will affect the toxicity of liver toxins– CCl4– 1,1,2,2-Tetrachloroethane– Hexachloro-1,3-butadiene
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Kepone + CCl4• Kepone 10ppm (low environmental level)• CCl4 100ul/kg (injected) - only marginally toxic level• Combination increased lethality by 67-fold
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Modeling of CCl4 liver toxicity +/- Kepone
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CCl4 only CCl4 and Kepone
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Top-Down
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Approaches to toxicity of complex mixtures
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Dietary factors
• Red meat, processed meat, well-done meat
• Vitamins and antioxidants
• Trace elements, metals
• Alcohol
• Phytochemicals (isothiocyanates)
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