Chemical concentration, activity, fugacity, and toxicity: dynamic implications
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Transcript of Chemical concentration, activity, fugacity, and toxicity: dynamic implications
Chemical concentration, activity, fugacity, and toxicity:dynamic implications
Jon Arnot and Don Mackay
Trent University
McKim Conference
Duluth, MN
September, 2007
Overview
• Building on Part I by Don Mackay – Four chemicals, log KOW = 2, 4, 6, 8
– Two organisms, fish and mammal
• Objectives– Reference point for acute “baseline” toxicity (narcosis)
– Data quality
• Assumptions vs reality – Dynamic profiles and “complicating” factors
(biotransformation rates, absorption efficiency)
• Internal vs external concentrations and activities
• Lethality is “well defined”
• Toxic Ratio (TR) or “excess toxicity” = CBRX
(mmol.kg-1) / CBRN (mmol.kg-1)
• If CBRN = 3 mmol.kg-1 and TR > ~10 then
chemical “x” has greater “potency”
Reference point for hazard identification
Equilibrium partitioning (EqP)
Complete bioavailability
No biotransformation or growth dilution
EqP = activity in exposure medium = activity in organism
log BCF = 1.0 log KOW - 0.9
0
2
4
6
8
10
0 2 4 6 8 10
log KOW
log
BC
F
log (1/LC50) = 1.0 log KOW - 1.4
log activity = 0.06 log KOW - 1.6
-2
0
2
4
6
8
0 2 4 6 8 10
log KOW
log
(1/L
C50
mol
.m-3
)
-2
-1.5
-1
-0.5
0
log
acti
vity
• Illustrations using a kinetic mass balance model1. Fish
2. Mammal
• Exposure concentrations based on EqP assumptions to exert a toxic effect at 3 mmol.kg-1 or 3 mol.m-3 whole body concentration, i.e., narcosis
• Four chemicals, each with three different metabolic biotransformation rates (0, 0.1, 1.0 d-1)
Series of toxicity “experiments”
70% water20% NLOM
10% lipid
Dietary intake; kD
Respiratory exchange; k1 and k2
Fecal egestion; kE
Metabolic biotransformation; kM
Growth dilution; kG
Two organisms – same properties and processes (air vs water)
NLOM equivalent to
3.5% lipid
(both 100 g)
Model
kD
k1
k2
kM
kG
kE
CB = ((k1 • CWD ) + (kD • CD)) / (k2 + kE + kM + kG)
kT
Time
Con
cent
rati
on
Time
Con
cent
rati
on
steady state
A B C D
Log Kow 2 4 6 8
Concn in fish mol/m3 or mmol/kg 3 3 3 3
BCF (fish/water) 1.14E+01 1.07E+03 1.07E+05 1.07E+07
Concn in water mol/m3 2.63E-01 2.80E-03 2.80E-05 2.80E-07
Concn in water g/m3 2.63E+01 4.20E-01 5.61E-03 7.01E-05
Activity in water and fish 0.033 0.042 0.056 0.070
Equilibrium partitioning: fish
Chemical
0
1
2
3
4
0 0.25 0.5 0.75 1time (d)
Cfi
sh (
mol
.m-3
)
k M = 0 d-1; t99 = 8.4 h
k M = 0.1 d-1; t99 = 8.3 h
k M = 1.0 d-1; t99 = 7.8 h
Chemical ACwater = 0.263 mol.m-3
activity in fish activity in water 0.03
No big difference!
short
0
1
2
3
4
0 10 20 30 40time (d)
Cfi
sh (
mol
.m-3
)
k M = 0 d-1; t99 = 18.7 d; amax = 0.04
k M = 0.1 d-1; t99 = 13.3 d; amax = 0.028
k M = 1 d-1; t99 = 3.7 d; amax = 0.008
Chemical BCwater = 0.0028 mol.m-3
awater = 0.04
substantial differences in activity and tsteady state
0
1
2
3
4
0 10 20 30 40time (d)
Cfi
sh (
mol
.m-3
)
k M = 0 d-1; t99 = 18.7 d; amax = 0.04
k M = 0.1 d-1; t99 = 13.3 d; amax = 0.028
k M = 1 d-1; t99 = 3.7 d; amax = 0.008
Chemical BCwater = 0.0028 mol.m-3
awater = 0.04
substantial differences in activity and tsteady state
Need to increase Cwater !!
activity in fish activity in water!!
Factor of 5; awater ~ 0.2
Chemical CCwater = 0.028 mmol.m-3
awater = 0.056
0.00
0.05
0.10
0.15
0.20
0 20 40 60 80time (d)
Cfi
sh (
mol
.m-3
)
k M = 0 d-1; t99 = 294 d; amax = 0.008
k M = 0.1 d-1; t99 = 40 d; amax = 0.001
k M = 1.0 d-1; t99 = 4.5 d;
amax = 10-4
big differences in activity and tsteady state
Chemical CCwater = 0.028 mmol.m-3
awater = 0.056
0.00
0.05
0.10
0.15
0.20
0 20 40 60 80time (d)
Cfi
sh (
mol
.m-3
)
k M = 0 d-1; t99 = 294 d; amax = 0.008
k M = 0.1 d-1; t99 = 40 d; amax = 0.001
k M = 1.0 d-1; t99 = 4.5 d;
amax = 10-4
big differences in activity and tsteady state
Need to increase Cwater !!BUT, exceed water
solubility limits
i.e., awater > 1 X
Chemical DCS
S = Cwater = 0.074 µmol.m-3
awater = 0.07
0.0
0.1
0.2
0.3
0.4
0 20 40 60 80time (d)
Cfi
sh (
mm
ol.m
-3)
k M = 0 d-1; t99 = 321 d; amax = 10-4
k M = 0.1 d-1; t99 = 40 d; amax = 10-5
k M = 1.0 d-1; t99 = 4.5 d;
amax ~ 10-6
huge differences in activity and tsteady state
Chemical DCS
S = Cwater = 0.074 µmol.m-3
awater = 0.07
0.0
0.1
0.2
0.3
0.4
0 20 40 60 80time (d)
Cfi
sh (
mm
ol.m
-3)
k M = 0 d-1; t99 = 321 d; amax = 10-4
k M = 0.1 d-1; t99 = 40 d; amax = 10-5
k M = 1.0 d-1; t99 = 4.5 d;
amax ~ 10-6
No chance!
huge differences in activity and tsteady state
A B C D
Log Kow 2 4 6 8
Concn in mammal mol/m3 or mmol/kg 3 3 3 3
BCF (mammal/air) 1.26E+03 1.77E+05 2.65E+07 3.53E+09
Concn in air mol/m3 2.39E-03 1.70E-05 1.13E-07 8.49E-10
Concn in air g/m3 2.39E-01 2.54E-03 2.26E-05 2.12E-07
Activity in air and mammal 0.033 0.042 0.056 0.070
Chemical
Equilibrium partitioning: mammal
0
1
2
3
4
0 5 10 15 20time (d)
Cm
amm
al (
mol
.m-3
)
k M = 0 d-1; t99 = 9.5 d; amax = 0.03
k M = 0.1 d-1; t99 = 7.9 d; amax = 0.03
k M = 1.0 d-1; t99 = 3 d amax = 0.01
Chemical ACair = 0.0024 mol.m-3 aair = 0.03
Lower concentrations in air compared to water
“minor” differences
0.00
0.05
0.10
0.15
0.20
0 20 40 60 80time (d)
Cm
amm
al (
mol
.m-3
) k M = 0 d-1; t99 = 331 d; amax = 0.01
k M = 0.1 d-1; t99 = 40 d; amax = 10-3
k M = 1.0 d-1; t99 = 4.5 d;
amax = 10-4
Chemical BCair = 0.017 mmol.m-3
aair = 0.04
0.00
0.05
0.10
0.15
0.20
0 20 40 60 80time (d)
Cm
amm
al (
mol
.m-3
) k M = 0 d-1; t99 = 331 d; amax = 0.01
k M = 0.1 d-1; t99 = 40 d; amax = 10-3
k M = 1.0 d-1; t99 = 4.5 d;
amax = 10-4
Chemical BCair = 0.017 mmol.m-3
aair = 0.04
Maximum activity in mammal activity in air!!
Need to increase Cair !!BUT, exceed air
solubility limits, i.e., vapor pressure
Chemical CCair = 0.11 mol.m-3
aair = 0.056
0.0
0.5
1.0
1.5
2.0
0 20 40 60 80time (d)
Cm
amm
al (
mm
ol.m
-3)
k M = 0 d-1; t99 = 436 d; amax = 10-4
k M = 0.1 d-1; t99 = 41.7 d; amax = 10-5
k M = 1.0 d-1; t99 = 4.6 d;
amax = 10-6
“same story”
~ 560x
~ 5,600x
~ 56,000x
Chemical DPS
S = Cair = 0.22 nmol.m-3
aair = 0.07
0
1
2
3
4
0 20 40 60 80time (d)
Cm
amm
al (
um
ol.m
-3) k M = 0 d-1; t99 = 442 d; amax = 10-6
k M = 0.1 d-1; t99 = 42 d; amax = 10-7
k M = 1.0 d-1; t99 = 4.6 d;
amax = 10-8
“same story”
A view to a kill (96 h LD50)
kM
Organism Parameter Units 0 d-1 0.1 d-1 1 d-1
Fish CD (mg/kg) 165,000 200,000 580,000
Fish t99 (d) 294 40 4.5
Mammal CD (mg/kg) 102,000 124,000 360,000
Mammal t99 (d) 436 42 4.6
Chemical C; fed 2x/d
Inhalation exposure is assumed “irrelevant”
not at steady state or equilibrium!
BMFs are larger in the mammal
A view to a kill (96 h lethal dose)
Chemical C; but 0.5 * ED
Have to double the dose!
kM
Organism Parameter Units 0 d-1 0.1 d-1 1 d-1
Fish CD (mg/kg) 330,000 400,000 X
Fish t99 (d) 294 40 4.5
Mammal CD (mg/kg) 204,000 248,000 720,000
Mammal t99 (d) 436 42 4.6
• Uptake times can be long and can exceed standard test durations, combined exposure routes may be necessary
• Exposure concentrations and activities “rarely” approximate internal concentrations and activities
• Metabolites that may be toxic will further complicate interpretation of toxicity measurements
• Need to measure both internal and external concentrations to identify “more potent” chemical
• Need for a quality toxicity dataset
• Uncertain data result in uncertain models
Summary
Careful inspection of the toxicity data can support Ferguson’s proposal that activity be used to interpret toxicity data such that “the disturbing effect of phase distribution
is eliminated from the comparison of toxicities”
Ferguson 1939
Thank you!