Supplemental Information
Using a Biokinetic Model to Quantify and Optimize Cortisol Measurements for Acute and Chronic
Environmental Stress Exposure During Pregnancy
M Smith1, WC Griffith1, S Beresford2,4, M Vredevoogd1,3, EM Vigoren1,3, EM Faustman1,3
1
Institute for Risk Analysis and Risk Communication, Department of Environmental and Occupational
Health Sciences 2Department of Epidemiology and 3Northwest Center for the National Children’s Study,
University of Washington, Seattle, WA; 4Cancer Epidemiology, Prevention and Control, Fred Hutchinson
Cancer Research Center, Seattle, WA
Summary of Contents: This file contains equation S1, showing the corticosteroid binding globulin
(CBG) and albumin binding properties of cortisol, Table S1 showing model input and running
parameters. The figures show blood protein distribution profiles (Figure S1), construction of diurnal
cortisol profiles (Figure S2), partitioning of cortisol between binding proteins (Figure S3), accumulation
of cortisol in hair (Figure S4) and diurnal variability of blood cortisol concentrations (Figure S5).
Supplementary Equation 1:
Cubic Equation for Free Cortisol from Dorin et al 20091:
F3+pF2+qF+r=0,
Where p=TotA+TotC−TotF+KA+KC,
q=TotA×KC+TotC×KA−TotF×(KA+KC)+KAKC, and
r=−KAKC×TotF.
F is free cortisol, TotA is total albumin, TotC is total CBG, KC is and KA is the mean albumin
concentration and KC is the mean CBG concentration. KC and KA distributions used in this model are
presented in figure S2.
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Table S1: Parameters used to construct and validate our biokinetic model. Modeled free cortisol pulse
characteristics summarized from parameters in 2. Rate constant parameters are given with relevant
references used in their derivation.
Use in Model
Episodic Stressors
Diurnal Variation- baseline
decreased by 50% at night
Rate Constants
Protein Binding Parameters
Relevant
References
Parameter
Value
Pulse Frequency
GM 38 and GSD 13
Pulses/Day
2
Pulse Height
GM 80 and GSD 44 nmol/L
2
Interclass Correlation
Coefficient
Baseline Average
0.37
3
Half-life
GM 49 and GSD 42 minutes
Metabolism Rate Constant
26.7 hours -1
2,5
Rate constant for
Incorporation into Hair
2.96e-5 hours -1
6-9
Rate Constant for Transfer
to Saliva
0.00242 hours -1
Rate Constant for Urinary
Excretion
0.304 hours -1
2,5
Albumin Concentration
GM 710 and GSD 1.05 µmol/L
12
CBG Concentration
GM 765 and GSD 1.27 nmol/L
1,13
CBG Dissociation Constant
33nM
1
Albumin Dissociation
Constant
137,800 nM
1
Serum Saliva Equilibrium
Constant
2.6
14
Saliva per Day
1.5 L
11
Serum Volume
2.7 L
11
Mean Free Blood Cortisol
Concentrations
7.12 nmol/L
1,2
Urinary Free Cortisol per Day
1440 nmol
5
Hair Cortisol Concentration
21 pg/mg
9
GM 66 and GSD 50 nmol
2,4
2
10,11
Physiological Parameters
Average Cortisol
Concentrations
*Geometric Mean=GM, Geometric Standard Deviation= GSD, CBG= Corticosteroid Binding Globulin
2
Figure S1: Cortisol binding protein concentrations and variability used in this model. We used means
and standard deviations from 13 for CBG concentrations (A-C) and12 for albumin concentrations (D).
Using this data we ran 1000 simulations to create the distributions shown above. We used distributions A
and D in our model. The geometric mean for the CBG distribution in A is 765 nmol/L with a geometric
standard deviation of 1.27 nmols/L. The geometric mean and standard deviation for the albumin
distribution in D is 710µmol/L with a geometric standard deviation of 1.05 µmol/L. During pregnancy,
CBG concentrations incrementally increase to approximately 1950nmol/L by the end of the third
trimester.
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Figure S2: Construction of a daily blood cortisol profile showing first baseline diurnal variation, then
pulsatile cortisol secretion and finally a combination of the two, reflecting a complete blood cortisol
profile for one day. Because pulsatile secretion varies by individual and by day, pulses are introduced
probabilistically.
Figure S3: Modeling of concentrations of CBG bound (pink), albumin bound (blue) and free cortisol
(black) following a physiologically relevant 100 nmol/l pulse in blood already containing a 150 nmol/l
total cortisol. The half-lives above reflect the differences in binding affinity, saturation and ability for
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cortisol to be metabolized in each state. CBG has a stronger affinity for cortisol and therefore increases
the half-life compared to free and albumin bound cortisol.
Figure S4: The accumulation of cortisol in hair (pink) based on the pulsatile secretion of cortisol in the
blood shown in blue and black. The accumulation in hair corresponds to a concentration of 25.8 pg
cortisol/mg hair.
Figure S5: Variability in total cortisol concentration (nmols/L) in blood across 500 simulations of 1 day,
shown in 24-hour time. The horizontal bar indicates the mean concentration, the shorter vertical bar
represents the 95% Confidence Interval and the longer vertical bar with points on the end represents the
modeled distribution for cortisol at each time-point. Variability is based on changing baseline (as shown
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in figure 2) and a probabilistic distribution of pulses introduced based experimental data obtained from
the literature.
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