environmental health

Environmental Health

Interactions and MixturesWeek 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

Types of mixtures

• Biological• Chemical• Physical • Psychosocial

• Similar properties• Defined (diesel)• Coincidental (time,

place)

Past and present, all routes, pathways and sources

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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Total body burden over time based on exposure frequency and kinetics of a chemical


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Total body burden from two chemicals relative to a health benchmark

Interactions among what?

• Drug-drug

• Environmental pollutants

• Drug-environmental exposure

• Diet-drug

• Diet-environmental pollutant

• Genes and all the above

When, who, how?

• Exposures – Concurrent – Sequential– Order

• Physiology differences – Children– Elderly– Pre-existing conditions, overall health– Genetic disposition

• Route of exposure• Amount

Types of interactions

Dose additivity - if mechanism is similarResponse additivity - if acting independently

Putting a number to them

Antagonism of many kinds

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

…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

Main types of interactions

• Physical prior to absorption

• Toxicokinetic interactions

• Toxicodynamic interactions

Toxicokinetic Interactions

• One chemical affects the kinetic disposition of another:– Absorption– Distribution– Metabolism– Elimination

Performing in vitro CYP450 induction screens, to evaluate potential multi-chemical interactions

“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

“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

“A” is protective by inducing a detox enzyme

A B

B metabolite

Excretion

Enzyme X (Phase I)

Enzyme Y (Phase II)

+ Toxic effect

inactive

“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

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




Competitive inhibition of a enzyme reaction, transporter activity

First order Michaelis-Menten kinetics of enzyme reaction:



Uncompetitive inhibition of a enzyme reaction, transporter activity



Change in slope as indicator of interactions



See Gennings 2005

Slopes must be compared at the same effect regions



See Gennings 2005

Interaction of piperonyl butoxide with malathion

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





Carpenter, 1998

Thyroid effects of PCBs





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



Increased estrogenic effects of combined PCBs or organochlorines

Carpenter, 1998



Carpenter, 1998



Models of interactions

See Groten 2001



Combined effects of UV filter mixtures on ER activation (yeast)



A - synergismCurve shift to the left

B - antagonismCurve shift in-between

Kunz 2006

Most binary mixtures show synergism at EC25, EC50 and EC75 effect levels



Kunz 2006

Synergism of mixtures of 4 UV filters at BC10 and NOEC effect levels



Kunz 2006

Effect of mixture of 4 UV filters at BC10 and NOEC



Kunz 2006

Effect of mixtures (4 or 8) is stronger at NOEC than at BC10



Kunz 2006

Mixtures of 4 are as potent as the most potent one (BP1)



Relative potencies are compared to E2 Kunz 2006



Approaches to toxicity of simple mixtures

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

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

Kepone + CCl4• Kepone 10ppm (low environmental level)• CCl4 100ul/kg (injected) - only marginally toxic level• Combination increased lethality by 67-fold



Modeling of CCl4 liver toxicity +/- Kepone





CCl4 only CCl4 and Kepone

Top-Down





Approaches to toxicity of complex mixtures

Dietary factors

• Red meat, processed meat, well-done meat

• Vitamins and antioxidants

• Trace elements, metals

• Alcohol

• Phytochemicals (isothiocyanates)

environmental health

Documents

toxicity of pyrethrum

increases toxicity of

toxic effectinactivea

pyrethrum formulation

pyrethrum insecticide

otherchanging cell

supplementtotal body

environmental pollutantgenes