“The Dose makes the Poison” Paracelcus (1567). What is "Toxicity”?
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Transcript of “The Dose makes the Poison” Paracelcus (1567). What is "Toxicity”?
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“The Dose makes the Poison”
Paracelcus (1567)
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What is "Toxicity”?
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TOXICITY IN GUPPIES(From : data from Abernethy et al. 1987)
Chemical log Kow LC50(umol/L)
Monochlorobenzene 2.8 170
Dichlorobenzene 3.4 50
Trichlorobenzene 4 12
Tetrachlorobenzene 4.5 3.7
Pentachlorobenzene 5 1
Hexachlorobenzene 5.5 none
Lipid Content of the guppies : 4%Solubility of Hexachlorobenzene in water: 1.7.10^-5 mmol/L
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TOXICITY IN GUPPIES(From : data from Abernethy et al. 1987)
Chemical log Kow LC50 Cfish(umol/L) (umol/kg)
Monochlorobenzene 2.8 170 4291
Dichlorobenzene 3.4 50 5024
Trichlorobenzene 4 12 4800
Tetrachlorobenzene 4.5 3.7 4680
Pentachlorobenzene 5 1 4000
Hexachlorobenzene 5.5 none
Lipid Content of the guppies : 4%Solubility of Hexachlorobenzene in water: 1.7.10^-5 mmol/L
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TOXICITY IN GUPPIES(From : data from Abernethy et al. 1987)
Chemical log Kow LC50 Cfish(umol/L) (umol/kg)
Monochlorobenzene 2.8 170 4291
Dichlorobenzene 3.4 50 5024
Trichlorobenzene 4 12 4800
Tetrachlorobenzene 4.5 3.7 4680
Pentachlorobenzene 5 1 4000
Hexachlorobenzene 5.5 none
Lipid Content of the guppies : 4%Solubility of Hexachlorobenzene in water: 1.7.10^-5 mmol/L
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Internal concentrationfor acute toxicity : 5 mmol/kg
Fish-water Bioconcentration Factor : 0.04 8 105.5 = 12,600
Water Concentration needed : 5 / 12,600 = 4 .10-4 mmol/L
Water Solubility : 1.7 .10-5 mmol/L
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Ferguson cut-off
Chemical concentration in the water that is required to produce the internal concentration in the organism that is needed to trigger the effect exceeds the chemical’s water solubility.
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Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect)
Toxic Effect = f(EXPOSURE, POTENCY)
Toxic Effect = f(EXPOSURE, TOXICITY)
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What is the difference?
•Dose makes the Poison
•Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect)
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What is the difference?
•Dose makes the Poison
•Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect)
External
Internal
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To agree or not agree?
Chemicals that cause the same effect at the same internal concentration have the same potency / toxicity
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Non-Polar Narcosis
similarity with anesthetics: chloroform
Lethality at an internal concentration: 3 to 6 mmol/kg
All chemicals & all organisms
mechanism unknown
likely affect membranes:
swells membranes causing a physical effect
affects membrane proteins
Narcosis is the most basic mode of toxic action.
Chemicals will have at least this toxicity or they may have
a greater toxicity.
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FISH 1 FISH 2
Volume Total (m3) 1 1Volume Water (m3) 0.9 0.5Volume Lipid (m3) 0.1 0.5Concentration in water 1.10-6 1.10-6
(mol/m3)
ZW 1 1fW 1.10-6 1.10-6
fL 1.10-6 1.10-6
ZL 104 104
Cw 1.10-6 1.10-6
CL 1.10-2 1.10-2
VW.CW 0.9 . 10-6 0.5 . 10-6
VL.CL 0.1 . 10-2 0.5 . 10-2
Vi.Ci ~0.1 . 10-2 ~0.5 . 10-2
Ci ~0.1 . 10-2 ~0.5 . 10-2
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Toxic Effect =
f(fugacity at the active site, fugacity at the active site associated with the effect)
f(f at the active site, f at the active site associated with the effect)
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Toxic Effect =
f(fugacity at the active site, fugacity at the active site associated with the effect)
f(f at the active site, f at the active site associated with the effect)
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Acute vs. Chronic Toxicity
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0
500
1000
1500
2000
2500
3000
3500
4000
4500
0 5 10 15
Time (days)
Co
nce
ntr
atio
n (
pg
/kg
)
1 pg/L
0.5 pg/L
0.1 pg/L
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So what??
You want to protect all aquatic life by setting a water quality criterion for chemical X, i.e. a water concentration that should not be exceeded.
So, what do you do?
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So what??
You want to protect all aquatic life by setting a water quality criterion for chemical X, i.e. a water concentration that should not be exceeded.
So, what do you do?
This WQC is derived from a study of LC50 or NOAEC derived in the lab, and you take the lowest LC50 divide it by a safety factor (e.g. 10), and this becomes your criterion.
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So what??
You want to protect all aquatic life by setting a water quality criterion for chemical X, i.e. a water concentration that should not be exceeded.
So, what do you do?
This WQC is derived from a study of LC50 or NOAEC derived in the lab, and you take the lowest LC50 divide it by a safety factor (e.g. 10), and this becomes your criterion.
Then you manage environmental quality by a monitoring program that measures water concentrations & compares them with the WQC.
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Tissue Residue Approach for Characterizing Toxicity
Merits:
eliminates transport/bioaccumulation from the external environment (Exposure), including:
•bioavailability
•dietary uptake and biomagnification
•metabolism
•accumulation kinetics
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Mixtures of Chemicals
If Shared Mode of Toxic Action:
Toxic Effect = f(Cinternal, Potency)
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Species Differences
Toxic Effect =
f(fugacity at the active site, fugacity at the active site associated with the effect)
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Dose - Response Relationship
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Application of Toxicity Data to conduct Hazard and Risk Assessment
General Problem:
The Concentration of Trichlorobenzene in River Water is: 5.10-6 mmol/L
LC50 in guppies (48 hr) : 5.10-4 mmol/kg
What is the hazard and/or risk to rainbow trout?
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Application of Toxicity Data to conduct Hazard and Risk Assessment
General Problem:
The ingested dose of Trichlorobenzene by (humans or sea otters) in food items is: 5.10-2 mg/kg/day
LD50 in rats (14 days) : 50 mg/kg/day
LOAEL : 5 mg/kg/day
What is the hazard and/or risk to humans or sea otters?
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Hazard :
Potential for a toxicological effect occurring
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Assessment of Hazard
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Reference Dose
Is an estimate of the daily dose to a population that is unlikely to produce an appreciable risk of adverse effect during a life time. Similar to an acceptable daily intake.
Reference Concentration
Is an estimate of the concentrations to a population that is unlikely to produce an appreciable risk of adverse effect during a life time. Similar to an acceptable concentration.
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Hazard Index
H = dose / Rfd
< 1.0 There is no hazard
> 1.0 There is a hazard
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Hazard Index
Rfd = 5 mg/kg/day(LOAEL)/1000 = 5.10-3
H = 5.10-2 / 5.10-3 = 10
There is a hazard
> 1.0 There is a hazard
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Risk
Probability of a toxicological effect occuring
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Single-Point Exposure and Effects Comparison
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Quotient-Method
•Cexposure / Ceffect
•Ceffects can be: LC50, LD50, EC50, NOAEL, LOAEL, LC5 etc.
•Sometimes combined with a safety-factor
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Example:
LC5 = 50 ng/L
Exposure Concentration : 30 ng/L
Cexposure/LC5 = 60%
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Cell B4 Frequency Chart
Certainty Range is from -Infinity to 1.00
5,000 Trials Shown
.000
.009
.018
.028
.037
0
46
92
138
184
-0.75 -0.13 0.50 1.13 1.75
Forecast: B4
Example:
LC5 = 50 ng/L
Exposure Concentration : 30 15 ng/L (normal)
8.3%
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Example:
LC5 = 50 ng/L
Exposure Concentration : 30 15 ng/L (log-normal)
Cell B4 Frequency Chart
Certainty Range is from -Infinity to 1.00
4,990 Trials Shown
.000
.013
.026
.039
.052
0
64.7
129
194
259
0.00 1.00 2.00 3.00 4.00
Forecast: B4
22%