Effects of toxic mixtures

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Effects of toxic mixtures

• Topic 9

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Learning objectives

• To learn and to understand the concept of toxic
  units
• To understand additivity, antagonism and
  synergism between contaminants
• Apply your knowledge to determine from an
  example whether contaminants act synergistically,
  antagonistically or have an additive effect

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Toxic mixtures

• From one dimension to multi-dimensional world

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Effects of individual toxicants vs toxic mixtures
I Crazy math

• Additivity
• Toxicity of the mixture of toxicants A and B is
  the same as the sum of toxicities of toxicants A
  and B when applied individually
• 224

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Effects of individual toxicants vs toxic mixtures
II Crazy math

• Antagonism
• Toxicity of the mixture of toxicants A and B is
  lower than the sum of toxicities of toxicants A
  and B when applied individually
• 222

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Effects of individual toxicants vs toxic mixtures
III Crazy math

• Synergism
• Toxicity of the mixture of toxicants A and B is
  higher than the sum of toxicities of toxicants A
  and B when applied individually
• 226
• Potentiation
• One chemical, which is not toxic on its own,
  enhances toxicity of the second chemical in the
  mixture
• 204

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How to determine antagonism or synergism of
contaminants?
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Toxic units

• Concentrations of toxicants expressed in units of
  lethality or in units of effect (relative to
  LD50, LC50 or EC50)
• Chemical A has LD50 of 100 ?M.
• 1 TU100 ?M
• 50 ?M?

100 ?M
Concentration of A High Low
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Toxic units (cont.)

• Chemical B has LD50 of 50 ?M.
• 1 TU50 ?M
• 0.5 TU?

50 ?M
Concentration of B High Low
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Toxic units (cont.)

• Take a mixture containing 50 ?M A and 25 ?M B
• How many toxic units does it contain?

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Additive index (Marking Dawson 1975)
S1 additivity Slt1 toxicants are
antagonistic Sgt1 toxicants are synergistic
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Synergism
Additivity
Toxic units
Antagonism
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In-class exercise

• Determine whether two toxin have additive,
  synergistic or antagonistic effects in the mixture

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Mechanisms of antagonism
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Antagonism

• Functional
• Chemical
• Dispositional
• Receptor antagonism

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Functional antagonism

• Two chemicals having opposite physiological effect

ROS
DMSO
Cu2
Cu2 DMSO no effect or less effect
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Chemical antagonism

• Chemicals in the mixture combine to produce a
  less toxic complex
• Organic acids chelation of heavy metals
• 2CN-Cd2 -gt Cd(CN)2

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Dispositional antagonism

• When one toxicant affects uptake, transport or
  elimination of the other
• Zn2 often reduces Cd2 uptake in a mixture
• Ethanol enhances mercury elimination in mammals

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Receptor antagonism

• Two or more toxicants bind to the same receptor
  and each toxicants blocks the other from fully
  expressing toxicity

CO
O2
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Synergism

• The combined effect of two or more contaminants
  is stronger than their additive effects
• Often contaminants that act through the same
  mechanisms show additive or antagonistic effects,
  and those that have different mechanisms act
  synergistically 19 organic toxicants in E. coli
  Chen Lu (2002)

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Synergistic effects of PCBs and methylmercury on
brain function in birds
Bemis Seegal (1999) EHP
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Potentiation

• Enhancement of the effects of a toxicant by a
  non-toxic compound

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CYP450
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Take-home messages

• Toxicity of contaminant mixtures is not directly
  predictable from the toxicity of single compounds
• The only reliable way to determine toxicity of
  mixtures is testing although understanding of the
  mechanisms of action of each component may help
  to make a priori predictions
• Toxicity of mixtures is important because in the
  environment the toxicants come in mixtures!