1
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
2
• 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
act
ivit
y
3
• Illustrations using a kinetic mass balance model
1. 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)
4
Model
kD
k1
k2
kM
kG
kE
CB = ((k1 • CWD ) + (kD • CD)) / (k2 + kE + kM + kG)
kT
Time
Co
ncentr
atio
n
Time
Co
ncentr
atio
n 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
5
0
1
2
3
4
0 0.25 0.5 0.75 1
time (d)
Cfi
sh (
mo
l.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 A
Cwater = 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 (
mo
l.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 B
Cwater = 0.0028 mol.m-3
awater = 0.04
substantial differences in activity and tsteady state
6
0
1
2
3
4
0 10 20 30 40time (d)
Cfi
sh (
mo
l.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 B
Cwater = 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
7
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
8
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
9
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 A
Cair = 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 (
mo
l.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 B
Cair = 0.017 mmol.m-3
aair = 0.04
10
0.00
0.05
0.10
0.15
0.20
0 20 40 60 80time (d)
Cm
amm
al (
mo
l.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 B
Cair = 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 C
Cair = 0.11 µmol.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
11
Chemical D
PSS = 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
12
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