Impact of Biological and Environmental Variabilities on Biological Monitoring An Approach Using Toxicokinetic Models

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1 ONLINE SUPPLEMENTAL APPENDIX Impact of Biological and Environmental Variabilities on Biological Monitoring An Approach Using Toxicokinetic Models by A. Berthet, A. de Batz, R. Tardif, G. Charest-Tardif, G. Truchon, D. Vernez, and P.O. Droz Table AI presents the data used in the CBTK models for all 14 chemicals. The first line for each chemical indicates the physiological identity of each compartment and chemical species. Then individual parameters are presented. Flow data both at rest and at 50W are indicated. Symbol nomenclature used in Table AI is shown in Table AII. The equations used to calculate each model parameter in Table AI are described by Pierrehumbert et al. (10) in more detail. TABLE AI. Chemical Specific Parameters Used in the Simulations for Each Substance Studied with CBTK Models Chemical/Volumes of Distribution Parameters Symbol At Rest At 50 W Arsenic (As) Central= Total body water (TBW), Metabolite 1 (M1) = TBW Exposure (µg/m 3 ) C exp 10 C Total body volume (TBV) A FV C Liver blood flow B BF M (24) 0.16 (24) Total body volume (TBV): blood partition coefficient for inorganic arsenic (-) P TBV:blood 45 (25) TBV: blood partition coefficient for monomethylarsonic acid (MMA) (-) P TBV:blood, M1 8.6 (25) TBV:blood partition coefficient for dimethylarsonic acid (DMA) (-) P TBV:blood, M2 6.7 (25) Liver permeability coefficient for inorganic arsenic (-) P p (25) Liver permeability coefficient for MMA (-) P M (25) Maximum metabolism rate of inorganic arsenic (µmol/h/kg 0.75 ) V MM (25) Michaelis-Menten constant for inorganic arsenic (µmol/l) K MM (25) Maximum metabolism rate of MMA (µmol/h/kg 0.75 ) V MM (25) Michaelis-Menten constant for MMA (µmol/l) K MM2 0.5 (25) Renal Clearance (l/h per kg -0.3 ) RC C 24 (24) Cadmium (Cd) Central = Total body water, Peripheral = kidneys Exposure (µg/m 3 ) C exp 50 D (14) - Kidneys Kidney volume A FV P (25) Kidney blood flow B BF P 0.11 (25) 0.2 (25) TBW: blood affinity coefficient (-) P TBW:blood 60 E Kidney permeability coefficient (-) P P 50 E

2 Kidney: blood affinity coefficient (-) P kidney:blood 60,000,000,000 F Renal Clearance (l/h per kg -0.3 ) RC C 200 F Carbon monoxide (CO) Central=Whole blood Exposure (ppm) C exp 35 (14) Deposit rate (%) 100 G Blood volume A FV P 0.07 (25) Blood: air affinity coefficient (-) P blood:air 500 H Hemoglobin concentration (g Hb/l) 150 (1) Link rate (%) 85 (1) Affinity (ml CO/g Hb) 1.49 (1) Chromium (Cr) Central=Total body water, Peripheral=richly perfused tissues (RP) (i.e., heart, liver, brain) Exposure (µg/m 3 ) C exp 50 I (14) - RP RP volume A FV P (10) RP blood flow B BF P 0.70 (10) 0.43 (10) TBW: blood affinity coefficient (-) P TBW:blood 17 J RP permeability coefficient (-) P P 4 K RP: blood affinity coefficient (-) P RP:blood 400,000 L Renal Clearance (l/h per kg -0.3 ) RC C (25) Cobalt (Co) Central=TBW, Peripheral=richly perfused tissues (RP) Exposure (µg/m 3 ) C exp 50 M (14) - RP RP volume A FV P (10) RP blood flow B BF P 0.70 (10) 0.43 (10) TBW: blood affinity coefficient (-) P TBW:blood 2 N RP permeability coefficient (-) P P 65 N RP: blood affinity coefficient (-) P RP:blood O Urinary excretion constant (h -1 /kg -0.3 ) k u,c P Ethylbenzene Central=Richly (RP) and slowly perfused tissues (SP), Peripheral=Fat Exposure (ppm) C exp 100 (14) Deposit rate (%) 60 (14) RP and SP volume 1 FV C Fat Fat volume A FV P 0.19 (24) Fat blood flow B BF P 0.05 (24) 0.06 (24) Liver blood flow B BF M (24) 0.16 (24) RP and SP: air partition coefficient (-) P RP and SP:air (24) Blood: air partition coefficient (-) P blood:air (24) Fat: air partition coefficient (-) P fat:air (24) Maximum metabolism rate (µmol/h/kg 0.75 ) V MM (24) Michaelis-Menten constant (µmol/l) K MM (24) Ethylbenzene fraction metabolized to mandelic acid / Ethylbenzene fraction metabolized to phenylglyoxilic acid F 2 /F 1 2 (24) Mandelic acid excretion rate (h -1 /kg -0.3 ) k u,m (24)

3 Fluorides Central=Total body water, Peripheral=bones Exposure (mg/m 3 ) C exp 2.5 Q (14) Skeleton volume A FV P (26) Skeleton blood flow B BF P (26) TBW: blood affinity coefficient (-) P TBW:blood 3 R Bones permeability coefficient (-) P P R Bones: blood affinity coefficient (-) P bones:blood 662 S Renal Clearance (l/h per kg -0.3 ) RC C T Ethyleneglycol monomethylether (EGEE) Central=Total body water, Metabolite1 (M1)=Total body water Exposure (ppm) C exp 5 (14) Deposit rate (%) 80 (27) Liver blood flow B BF P 0.26 (10,24) 0.16 (10,24) Water: air partition coefficient EGEE (-) P water:air (27) Blood: air partition coefficient EGEE (-) P blood:air (27) Water: blood partition coefficient of 2-ethoxyacetic acid (EAA) (-) P water:blood 1.00 (28) Maximum metabolism rate (µmol/h/kg 0.75 ) V MM (29) Michaelis-Menten constant (µmol/l) K MM (29) EGEE fraction metabolized to EAA / fraction metabolized to ethylene glycol (EG) (-) F 2 /F (29) EAA renal Clearance (l/h per kg -0.3 ) k u,m D Inorganic mercury (IHg) Central Total body water, Peripheral=kidneys Exposure (µg/m 3 ) C exp 25 (14) - Kidney Kidney volume A FV P (26) Kidney blood flow B BF P 0.11 (26) Kidney: blood partition coefficient (-) P kidney:blood 473,396,562 U Kidney permeability coefficient (-) P P U Renal excretion constant (h 1 per kg 0.3 ) k u,c U Biliary excretion constant (h 1 per kg 0.3 ) k f,p U Methyl isobutyl ketone (MIBK) Central=Total body water, Peripheral=Fat Exposure (ppm) C exp 50 (14) Deposit rate (%) 80 (30) Fat volume A FV P 0.19 (10) Fat blood flow B BF P 0.05 (10) 0.06 (10) Water: air partition coefficient (-) P water:air 79 (14) Blood: air partition coefficient (-) P blood:air 90 (14) Fat: air partition coefficient (-) P fat:air 926 (14) Urinary excretion constant (h -1 /kg -0.3 ) k u,p V Metabolism constant (h -1 /kg -0.3 ) K MM V Pentachlorophenol Central=Total body water, Metabolite=undefined

4 Exposure (µg/m 3 ) C exp 500 (14) Deposit rate (%) 80 W Central: air affinity coefficient (-) P central:air 125,000 X Blood: air affinity coefficient (-) P blood:air 250,000 X Urinary excretion constant (h -1 /kg -0.3 ) for free PCP k u,p X Metabolism constant (h -1 /kg -0.3 ) K MM X Urinary excretion constant (h -1 /kg -0.3 ) for combined PCP k u,p X Phenol (Ph) Central=TB Exposure (ppm) C exp 5 (14) Total body water (TBW) A FV C Renal Clearance (l/h per kg -0.3 ) RC C Y Lead (Pb) Central=Total body water minus peripheral compartment, Peripheral=skeleton Exposure (µg/m 3 ) C exp 150 (14) Total body volume (TBV) A FV C Skeleton Skeleton volume A FV P (26) Skeleton blood flow B BF P (26) TBV: blood partition coefficient (-) P TBV:blood Z Bones: blood partition coefficient (-) P bones:blood 31,881,434 Z Renal Clearance (l/h per kg -0.3 ) RC C (31) Toluene (TOL) Central=Richly (RP) and slowly perfused tissues (SP), Peripheral=Fat, Metabolite=undefined Exposure (ppm) C exp 50 (14) RP and SP volume A FV C Fat Liver Fat volume A FV P 0.19 (10) Liver volume (metabolism) A FV M (10) Fat blood flow B BF P 0.05 (24) 0.06 (24) Liver blood flow B BF M (24) 0.16 (24) Blood: air partition coefficient (-) P blood:air 15.6 (32) SP: air partition coefficient (-) P SP:air 27.7 (33) Fat: air partition coefficient (-) P fat:air (33) Michaelis-Menten maximum rate (µmol/h/kg 0.75 ) V MM (10) Michaelis-Menten constant (µmol/l) K MM (10) Fraction of TOL metabolized to hippuric acid (HA)/Fraction of TOL metabolised to o-cresol (-) F 2 /F (10) o-cresol excretion rate constant (l/h per kg -0.3 ) k u,m (34) A Expressed in fraction of body weight. B Expressed in fraction of cardiac output. C ACGIH TLV-TWA. (14) D Simulation of an exposure to 50 µg/m 3, but only 45% of dust is considered to reach the pulmonary alveoli. (26) E Determined according to the following considerations: (1) cadmium half-life in blood is 100 days (25) ; (2) cadmium blood concentration at steady state is about 50 nmol/l. (25) F Determined according to the following considerations: (1) urinary cadmium half-life is 20 years; (25) (2) cadmium half-life in body is 10 years (25).

5 G Deposit rate is supposed equal to 100% because of its small molecular weight H Determined according to the following consideration: the carboxyhemoglobin half-life is 5 hours. (25) I Simulation of an exposure to 50 µg/m 3, but only 15% of smoke is considered to reach the pulmonary alveoli; (26) of this 15%, 60% is considered soluble and distributed in the central compartment directly, and the other 40% was taken to be insoluble and distributed with a half-life of 120 days, (35) which means an approximate constant flow of 0.15 µmol/hour. J Determined according to the following considerations, (1) kidney clearance is calculated from glomerular filtration; (2) the half-life of urinary elimination is 7 hours. (25) K Determined according to the following consideration: the slow half-life of central compartment is 30 hours. (25) L Determined according to the following consideration: the half-life of the peripheral compartment is 3 years. (25) M Workers are exposed to 50 µg/m 3, but only 30% of mixed dust and smoke lay down on pulmonary alveoli. (26) N Determined according to the following considerations: (1) the half-life of transfer between the central compartment and the peripheral compartment is 12 hours; (25) (2) cobalt blood concentration at steady state is about 40 nmol/l. (25) O Determined according to the following consideration: the cobalt half-life in richly perfused tissues is 2 years. (25) P Determined according to the following considerations: the urinary and blood cobalt half-life in RP tissue is 3 days. (25) Q Simulation of an exposure to 2.5 mg/m 3, but only 45% of dust is considered to reach the pulmonary alveoli. (26) R Determined according to the following considerations: (1) kidney clearance is equal to the glomerular filtration; (14) (2) fluorides half-life in TBW is 6 hours; (25) (3) 50% of fluorides are quickly eliminated and the other 50% accumulate in bones. (25) S Determined according to the following consideration: the fluorides half-life in bones is 18 days. (25) T Fluorides clearance is equal to the glomerular filtration. (31) U Determined according to following considerations: (1) at steady state, 90% of the total body burden is found in the kidney; (36) (2) the half-life of Hg in blood is 3 days; (31) (3) the half-life of Hg in kidney is 60 days; (31) (4) at steady state, 58% is excreted in urine. (36) V Determined according to following considerations: (1) elimination by exhalation represents about 10% of the absorbed dose; (2) urinary elimination represents 0.04% of the absorbed dose; (3) elimination by metabolism represents the rest of the absorbed dose. (30) W Value chosen by default in this study for solvents. X Determined according to the following considerations: (1) elimination percentages of free and combined PCP in urine are 12 and 74 % respectively; (37) (2) the rest is eliminated in the expired air; (3) free PCP clearance is l/hour; (37) and (4) plasmatic concentration at the end of shiftwork is next to 19 µmol/l. (25) Y Determined according to the half-life of Ph in the whole body hours. (14) Z Determined according to the half-life of Pb in blood, 37.5 days, and in the skeleton, 20 years. (31)

6 TABLE AII. Symbol Nomenclature Used in Table AI Symbol Definition Units BF i Fraction of cardiac output in the compartment i C exp Exposure dose µg/m 3 or ppm F 2 /F 1 Fraction differentiation between metabolite 1 and 2 FV i Volume of compartment i expressed as fraction of body weight k f,i Feces excretion rate constant for compartment i l/h per kg -0.3 K Mi Michaelis-Menten constant for metabolite i µmol/l or l/h per kg -0.3 k u,i Urine excretion rate constant for compartment i l/h per kg -0.3 P i:j Affinity or partition coefficient between media i and media j P Mi Permeability of metabolite compartment P p Permeability of peripheral compartment RC i Renal clearance from compartment i l/h per kg -0.3 V Mi Michaelis-Menten maximum rate for metabolite i µmol/h per kg 0.75