Supplementary Material
SCREENING OF CHEMICALS FOR HUMAN BIOACCUMULATIVE POTENTIAL WITH A PHYSIOLOGICALLY BASED TOXICOKINETIC MODEL
Arnaud Tonnelier, Sandra Coeckeand José-Manuel Zaldívar
Table of Contents
1) Simulated conditions with Simcyp.
2) Assessment of PBTK model results.
3) Derivation of the simplified bioaccumulation mapping.
4) Distance to the virtual trap PBTK model.
5) Table 1.List of compounds and parameters.
6) Table 2.Ranking based on the estimated human bioconcentration factor.
7) Table 3.Ranking based on the estimated bioaccumulation half-life (top twenty).
8) Table 4. Ranking based on the distance to the virtual trap PBTK model (top twenty).
9) Table 5. List of compounds and CAS numbers
1) Simulated conditions with Simcyp
The Simcyp minimal PBTK model had two routes of elimination: renal excretion and metabolism. As in (Rotroff et al. 2010), the rate of renal excretion was calculated by multiplying the measured unbounded fraction by the standard glomerular filtration rate (6.7 l h-1) (Rule et al. 2004). The rate of metabolic clearance in the liver obtained from in vitro kinetic studies with hepatocytes was input into the software application. For compounds from ECVAM/ICCVAM the free fraction of compound in the microsomal preparation, fumic, was used for the metabolic rate correction. The plasma protein binding is taken from ToxCast Phase I chemical library or is obtained using the predictive method implemented in Simcyp based on the equations published in (Lobell and Sivarajah 2003). The physico-chemical parameters of each compound were input to the software and used by the simulator to predict the volume of distribution according to the mechanism-based approach developed in (Poulin and Theil 2002).
Simulations were performed using a low constant dose of 0.01 mg with a low dose interval 0.1 h with a representative healthy individual. A first-order absorption model was used with a rate constant of 2 h-1. Moreover we assumed that the absorption (the fraction that reaches the body) is total and that there is a complete intestinal availability of the substrate (100% of gastrointestinal absorption).
2) Assessment of PBTK model results
To evaluate the performance of the PBTK modelling approach and to the assess the validity of our predictions, the results of the model were compared with published data. Following Rotroff et al. (2010) the model was run for 2,4-Dichlorophenoxyacetic acid, Oxytetracycline dehydrate, Triclosan, Bisphenol A and Parathion to calculate the average concentration at steady state for 1 mg kg-1d-1 dose. These values were compared with published data (Gentry et al. 2002; Kohli et al. 1974; Sauerhoff et al. 1977; Völkel et al. 2002), being the main difference the overprediction in the average steady state concentration for Oxytetracycline dehydrate. Furthermore, we also used different literature data for Thioridazine (Muusze and Vanderheeren 1977), Warfarin (Black et al. 1996) DDT (Verner et al. 2009), PCBs (Verner et al. 2009; Ritter et al. 2011) and PFOS (Loccisano et al. 2011; Olsen et al. 2007) on plasma elimination half-life times; and for Cloropyrifos (Timchalk et al. 2002) and Propanolol (Kiriyama et al. 2008) on the maximum plasma concentration Cmax reached after oral dose.
3) Derivation of the simplified bioaccumulation mapping.
A three compartments physiologically based model equivalent to the minimal Simcyp model (Simcyp Limited, Sheffield, UK) is considered. The absorption of the substance is assumed to occur at different times, ti, at a small dose, noted D, and the elimination occurs through renal filtration and liver metabolism. The toxicokinetics of each substance is described by a system of differential equations of the following form:
[1]
where, and are the concentrations of the compound in the portal vein, liver and systemic circulation, respectively; and are the volumes of portal vein blood and liver, respectively, is the volume of distribution of substrate; and are the blood flows in the portal vein and hepatic artery; is the fraction of the compound absorbed into the enterocytes; is the intestinal availability of the substrate; is the first-order absorption rate constant; H is the Heaviside step function; is the hepatic clearance and is the renal clearance. We considered here a complete absorption, , and a full intestinal availability . The rate of renal excretion is estimated by multiplying the percent of unbound chemical by the normal adult glomerular filtration rate (=6.7l/h) (Rule et al., 2004; Rotroff et al., 2010). The hepatic clearance is based on the whole-blood toxicant concentration and is derived from the experimentally measured intrinsic metabolic clearance (), based on unbound drug concentration. The commonly used "well-stirred" liver model (Rowland et al., 1973) provides an estimation of the hepatic clearance:
.[2]
It is convenient for simulation purposes and for analytic treatments to rewrite the uptake that appears in the portal vein compartment (see Equation [1]) using a supplementary compartment, leading to the autonomous system of differential equations:
[3]
With at where A(t) is the amount of compound in the absorption compartment.
For a chronic exposure, where is the time elapses between two successive exposures, averaging techniques (Sanders et al. 2007) allow us to replace the time-dependent absorbed amount, A(t), by its average value: . Calculations give .
Therefore, we derive the following averaged-PBTK model
[4]
that describes the mean behaviour of the model (see Figure 1, right). Note that the route of exposure does not appear explicitly in the averaged model and the amount of compound, , could be seen as the result of the sum of different uptake routes (oral and dermal for instance). After a transient, the averaged model stabilizes on a steady state from which we calculate the human bioconcentration factor as
.[5].
The concentration in the systemic compartment is used to measure to which extent a compound accumulates in the body and is compared with a theoretical concentration of compound in the portal vein, assuming a complete absorption of the dose D. The term D/VPV reflects the concentration of the compound in the portal vein where the volume of portal vein is used as a reference. This choice stems from the occurrence of the dose D in the kinetics equation of the portal vein where the dose D occurs through the rate flow D/T. The quantity t in Equation [5] is a time that we set to one hour. Therefore, the factor VPV /t is a normalizing factor that provides a dimensionless bioaccumulation factor.
The steady-state is reached when the time-variations of the concentrations vanish and it is straightforward to calculate from [4] by equating to zero all the rate of change in the different compartments (left-hand side of system [4]). From [5], we find the approximated value of hBCF
[6]
where we used . Note that neither the dose D nor the duration T occur in the analytical expression [6] and therefore the proposed metric for bioaccumulation assessment (Expression [5]) is, on average, independent of the exposure scenario used to compute it. To evaluate the relevance of the approximation derived for hBCF (Equation [6]), we plotted (Figure 3) the value as a function of fu and CLuint using the following parameter values: , , , .
4) Distance to the virtual trap PBTK model.
The vast majority of PBTKmodels retains only the linear kinetic processes and therefore can be written in a generic form as:
[7]
where is a vector describing the time profile of the concentration in the different compartments of the model, the matrix describes all the linear kinetic processes and is obtained from the mass-balance equations for the different compartments: storage tissues, the blood compartment and the liver. The vector described the uptake with possibly different routes of absorption.
We proposed a new metric for the ranking of bioaccumulation potential of compounds based on the singular value decomposition of the pharmacokinetics matrix M. The singular value decomposition (SVD) of is written where and are orthogonal and is diagonal with . It is well known that the smallest value is the distance from to the singular matrix (Demmel, 1992). This value is expected to play a significant role in the prediction of the extent to which a compound accumulates. In fact, the description of the kinetics processes can be split into two independent contributions,, one contribution () is the result of the mass flux inside the body describing the internal transport in blood and the corresponding model is referred to as the virtual trap PBTK model. The virtual trap PBTK model is a theoretical model of the absorption and the distribution of the compound that does not incorporate clearance processes and corresponds to a specific instance of outflow-closed compartmental system (Jacquez and Simon, 1993). This implies that is a singular matrix due to the conservation of mass in the outflow-closed system. The other contribution () describes the loss of mass outside the system by metabolism/elimination. Therefore the distance to the singular matrix reflects the distance of M to M1 and is expected to be a reliable measure of the balance between distribution and elimination. The ranking obtained with the distance to the virtual trap PBTK model is shown Table 4 and is compared with the two previously derived rankings, the hBCF based ranking and the Tacc based ranking.
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5) Supplementary Material, Table 1.List of the compounds and parameters.
Name / Type / MW (g/mol) / log KOW / pKa1 / pKa2 / Fu / Vd(l/kg) / CLint(HEP) (**) / fumic / CLR (renal) (l/h) / C*sys(mg/l) / τsys(h)Abamectin / Insecticide / 819.01 / 4.48 / - / - / 0.02860 / 15.76 / 1.31E+01 / 0.190 / 1.92E-01 / 4.00E-03 / 111.03
Acetamiprid / Pesticide / 222.07 / 2.55 / 3.10 / - / 0.57600 / 4.77 / 0.00E+00 / 1.000 / 3.86E+00 / 2.28E-02 / 113.01
Acetochlor / Herbicide / 269.12 / 3.03 / - / - / 0.14740 / 4.15 / 6.60E+01 / 1.000 / 9.89E-01 / 7.91E-04 / 11.39
Aflatoxin / Mycotoxin / 312.28 / 1.23 / - / - / 0.45800 / 0.56 / 3.49E+00 / 0.600 / 3.07E+00 / 2.51E-03 / 2.16
Alachlor / Herbicide / 269.77 / 3.52 / - / - / 0.14100 / 9.48 / 5.09E+01 / 1.000 / 9.45E-01 / 1.07E-03 / 30.62
Aminoglutethimide / Antisteroid / 232.28 / 0.82 / 10.42 / 3.73 / 0.56300 / 0.48 / 7.23E-01 / 0.300 / 3.78E+00 / 4.31E-03 / 2.66
Aminopterin / Antineoplastic / 440.42 / -1.82 / 3.10 / 4.42 / 0.75000 / 0.44 / 0.00E+00 / 1.000 / 5.03E+00 / 1.75E-02 / 6.49
Amitriptyline / Antidepressant / 277.41 / 4.92 / 9.21 / - / 0.06100 / 5.89 / 7.23E-01 / 0.270 / 4.10E-01 / 3.95E-02 / 216.54
Amphetamine / Psycostimulant / 135.21 / 1.76 / - / - / 0.32820 / 0.83 / 5.11E-01 / 0.610 / 2.20E+00 / 1.62E-02 / 13.01
Antipyrine / Analgesic / 188.23 / 0.38 / - / - / 0.67000 / 0.46 / 0.00E+00 / 1.000 / 5.50E+00 / 1.96E-02 / 7.54
Atrazine / Herbicide / 269.77 / 2.61 / 2.50 / - / 0.11200 / 1.55 / 3.34E+00 / 1.000 / 7.50E-01 / 1.78E-02 / 28.43
Atropine / Alkaloid / 289.38 / 1.83 / 9.07 / - / 0.63360 / 1.03 / 4.96E-01 / 0.810 / 4.25E+00 / 9.71E-03 / 8.57
Bensulide / Herbicide / 397.50 / 4.20 / 5.97 / - / 0.00300 / 0.98 / 1.69E+02 / 1.000 / 2.00E-02 / 1.57E-02 / 13.00
Bentazone / Pesticide / 240.28 / 2.34 / 5.67 / - / 0.02070 / 0.33 / 0.00E+00 / 1.000 / 1.39E-01 / 6.33E-01 / 155.75
BisphenolA / IndChem / 228.29 / 3.32 / 10.36 / 9.59 / 0.16260 / 7.42 / 2.22E+01 / 1.000 / 1.09E+00 / 2.09E-03 / 31.94
Bromacil / Herbicide / 261.12 / 2.11 / 8.71 / - / 0.09910 / 0.63 / 0.00E+00 / 1.000 / 6.65E-01 / 1.33E-01 / 71.47
Buprofezin / Insecticide / 305.44 / 4.30 / 7.69 / - / 0.00020 / 2.98 / 1.50E+01 / 1.000 / 1.30E-03 / 2.55E+00 / 688.16
Busulfan / Pharma / 246.29 / -0.52 / - / - / 0.83800 / 0.46 / 1.39E+00 / 0.940 / 5.62E+00 / 4.08E-03 / 2.37
Caffeine / Stimulant / 194.19 / -0.07 / 1.64 / - / 0.76370 / 0.45 / 1.11E-01 / 0.910 / 5.11E+00 / 1.40E-02 / 5.60
Carbamazepine / Anticonvulsant / 236.28 / 2.45 / 11.40 / 0.34 / 0.19330 / 1.75 / 2.64E-01 / 0.840 / 1.30E+00 / 4.43E-02 / 74.46
Carbaryl / Insecticide / 201.23 / 2.36 / 2.16 / 9.60 / 0.75000 / 2.08 / 7.37E+00 / 0.670 / 5.03E+00 / 8.01E-04 / 3.97
Chloramphenicol / Antimicrobial / 323.13 / 1.14 / - / - / 0.48100 / 0.54 / 7.23E-01 / 0.900 / 3.23E+00 / 1.11E-02 / 5.88
Chlorpyrifos / Insecticide / 350.59 / 4.96 / - / - / 0.01760 / 22.42 / 2.60E+00 / 0.005 / 1.18E-01 / 8.66E-04 / 75.48
Clothianidin / Insecticide / 249.68 / 0.64 / 7.54 / 10.29 / 0.51720 / 0.43 / 1.05E+01 / 1.000 / 3.47E+00 / 1.26E-03 / 1.18
Colchicine / NatProd / 399.45 / 1.30 / - / - / 0.44000 / 0.59 / 6.98E-01 / 0.650 / 2.95E+00 / 1.02E-02 / 6.03
Cycloheximide / NatProd / 281.35 / 0.55 / 10.13 / - / 0.62900 / 0.46 / 1.74E+00 / 0.240 / 4.22E+00 / 1.44E-03 / 1.29
Cyprodinil / Fungicide / 225.13 / 4.00 / 3.02 / - / 0.00100 / 0.63 / 1.93E+01 / 1.000 / 7.00E-03 / 3.82E-01 / 218.05
DDT / Insecticide / 354.49 / 6.91 / - / - / 0.01200 / 38.51 / 1.43E+00 / 1.000 / 1.37E-04 / 4.61E-01 / 22500
Dextropropoxyphene / Analgesic / 339.48 / 4.18 / 8.65 / - / 0.12000 / 5.67 / 1.10E+01 / 0.200 / 8.05E-01 / 1.17E-03 / 15.72
Diazepam / Sedative / 284.75 / 2.82 / 2.93 / - / 0.14100 / 2.71 / 1.23E-01 / 0.560 / 9.46E-01 / 6.80E-02 / 182.26
Diazoxon / Insecticide / 288.00 / 2.07 / 4.26 / - / 0.31060 / 1.29 / 5.73E+01 / 1.000 / 2.08E+00 / 4.18E-04 / 2.86
Dibutylphthalate / IndChem / 278.35 / 4.50 / - / - / 0.02800 / 16.03 / 4.25E+01 / 0.005 / 1.88E-01 / 3.33E-05 / 36.19
Dichlorophenoxy / Herbicide / 221.04 / 2.81 / 3.02 / - / 0.04410 / 0.70 / 0.00E+00 / 1.000 / 2.96E-01 / 2.98E-01 / 149.47
Dicrotophos / Insecticide / 237.19 / 0.00 / 0.21 / - / 0.82330 / 0.47 / 9.40E-01 / 1.000 / 5.52E+00 / 5.69E-03 / 3.05
Diethylphthalate / IndChem / 222.24 / 2.47 / - / - / 0.19000 / 1.79 / 4.25E+01 / 0.005 / 1.27E+00 / 4.76E-06 / 3.40
Digoxin / Pharma / 780.96 / 1.26 / - / - / 0.45000 / 0.57 / 0.00E+00 / 1.000 / 3.02E+00 / 2.92E-02 / 14.30
Diphenhydramine / Antihistamine / 255.36 / 3.27 / 8.71 / - / 0.26500 / 3.37 / 4.00E-01 / 0.350 / 1.79E+00 / 1.66E-02 / 47.28
Diphenylhydantoin / Antiepileptic / 252.27 / 2.47 / 6.95 / 11.31 / 0.06790 / 0.66 / 7.23E-01 / 0.590 / 4.56E-01 / 6.35E-02 / 33.42
Disopyramide / Antiarrythmic / 339.48 / 2.58 / 9.64 / 4.28 / 0.44300 / 2.03 / 4.56E-01 / 1.000 / 2.97E+00 / 1.63E-02 / 25.59
Diuron / Herbicide / 233.09 / 2.68 / 11.39 / - / 0.18560 / 2.59 / 6.07E+00 / 1.000 / 1.25E+00 / 6.24E-03 / 20.47
Emamectin / Insecticide / 1008.24 / 5.00 / - / - / 0.00070 / 2.89 / 0.00E+00 / 1.000 / 4.70E-03 / 1.85E+01 / 55360
Etoxazole / Pesticide / 359.41 / 7.21 / 4.84 / - / 0.00500 / 38.47 / 1.70E+01 / 1.000 / 3.36E-02 / 9.04E-02 / 4483
Fenamiphos / Insecticide / 303.11 / 3.23 / 9.64 / - / 0.03570 / 2.03 / 4.62E+01 / 1.000 / 2.40E-01 / 4.75E-03 / 13.53
Fenoxycarb / Insecticide / 301.13 / 4.30 / 11.13 / - / 0.00420 / 3.02 / 1.38E+01 / 1.000 / 2.82E-02 / 1.32E-01 / 413.32
Fenpropathrin / Pesticide / 349.43 / 5.70 / - / - / 0.00830 / 31.23 / 3.17E+00 / 0.005 / 5.57E-02 / 1.52E-03 / 138.07
Fenvalerate / Insecticide / 419.91 / 6.20 / - / - / 0.00500 / 34.84 / 7.66E-01 / 1.000 / 3.33E-02 / 1.15E+00 / 50124
Fipronil / Insecticide / 437.15 / 4.00 / - / - / 0.04610 / 10.10 / 1.62E-01 / 0.300 / 3.09E-01 / 1.50E-01 / 1701
Forchlorfenuron / Pesticide / 247.68 / 3.20 / 11.46 / 11.67 / 0.03665 / 1.97 / 1.34E+01 / 1.000 / 2.46E-01 / 1.54E-02 / 33.18
Gibberellic_acid / Hormone / 346.38 / 0.24 / 4.80 / - / 0.24000 / 0.32 / 0.00E+00 / 0.940 / 1.61E+00 / 5.48E-02 / 13.56
Haloperidol / Antipsychotic / 375.87 / 4.30 / 8.12 / - / 0.09440 / 9.20 / 9.87E-01 / 0.260 / 6.33E-01 / 1.89E-02 / 198.96
Ibuprofen / Antiinflammatory / 206.29 / 3.97 / 4.53 / - / 0.01350 / 1.68 / 3.31E+00 / 0.810 / 9.06E-02 / 1.26E-01 / 151.30
Isoniazide / Antituberculosis / 137.14 / -0.70 / 11.78 / 3.67 / 0.90000 / 0.48 / 1.11E+00 / 0.040 / 6.04E+00 / 2.63E-04 / 0.99
Isoxaben / Herbicide / 332.39 / 3.94 / 9.19 / 0.69 / 0.04300 / 8.63 / 2.06E+00 / 1.000 / 2.89E-01 / 6.92E-02 / 670.21
Isoxaflutole / Pesticide / 359.32 / 2.32 / - / - / 0.00830 / 0.30 / 2.36E+01 / 1.000 / 5.57E-02 / 3.97E-02 / 10.30
Malathion / Insecticide / 330.35 / 2.36 / - / - / 0.20800 / 1.58 / 4.25E+01 / 0.005 / 1.40E+00 / 4.29E-06 / 2.38
Maprotinline / Antidepressant / 277.41 / 4.52 / 9.93 / - / 0.09160 / 4.15 / 7.23E-01 / 0.040 / 6.15E-01 / 4.58E-03 / 20.44
Metalaxyl / Fungicide / 279.34 / 1.65 / - / - / 0.35400 / 0.76 / 4.32E+00 / 0.860 / 2.38E+00 / 3.77E-03 / 3.76
Methadone / Analgesic / 309.46 / 3.93 / 9.13 / - / 0.15600 / 4.12 / 1.34E+00 / 0.340 / 1.05E+00 / 1.09E-02 / 40.86
Methylparathion / Insecticide / 263.21 / 2.86 / - / - / 0.01415 / 0.57 / 1.05E+01 / 1.000 / 9.49E-02 / 5.08E-02 / 26.46
Methylphenidate / Psycostimulant / 233.31 / 2.78 / 8.68 / - / 0.37700 / 2.45 / 2.51E+00 / 0.340 / 2.53E+00 / 2.48E-03 / 7.93
Metribuzin / Herbicide / 214.29 / 1.70 / 2.84 / - / 0.53700 / 1.08 / 5.35E-01 / 1.000 / 3.60E+00 / 1.24E-02 / 13.16
MGK / Pesticide / 275.39 / 3.70 / - / - / 0.00500 / 1.09 / 7.66E+01 / 1.000 / 3.66E-02 / 2.07E-02 / 23.65
Nalidixic_acid / Antibiotic / 232.24 / 1.59 / 5.04 / 2.27 / 0.74900 / 0.87 / 1.10E+00 / 0.920 / 5.03E+00 / 5.38E-03 / 4.76
Nicotine / Alkaloid / 162.24 / 1.17 / 8.60 / 3.39 / 0.76800 / 0.63 / 2.34E+00 / 0.770 / 5.15E+00 / 2.52E-03 / 2.44
Orphenadrine / Anticholinergic / 269.39 / 3.77 / 8.70 / - / 0.17500 / 4.41 / 7.23E-01 / 0.190 / 1.17E+00 / 1.01E-02 / 43.18
Oxytetracycline / Antibiotic / 496.46 / -3.97 / - / - / 0.38480 / 0.35 / 0.00E+00 / 1.000 / 2.58E+00 / 3.41E-02 / 9.48
Paracetamol / Analgesic / 151.17 / 0.46 / 10.02 / 12.30 / 0.65100 / 0.46 / 7.23E-01 / 0.920 / 4.37E+00 / 8.20E-03 / 3.78
Parathion / Insecticide / 291.26 / 3.83 / - / - / 0.00500 / 1.39 / 3.32E+00 / 1.000 / 3.66E-02 / 4.01E-01 / 536.07
PCB136 / IndChem / 360.88 / 7.65 / - / - / 0.00500 / 38.70 / 2.70E-04 / 1.000 / 3.36E-02 / 2.50E+00 / 122351
PCB153 / IndChem / 360.88 / 7.75 / - / - / 0.00500 / 38.70 / 2.72E-06 / 1.000 / 3.60E-03 / 2.51E+00 / 122753
PCB155 / IndChem / 360.88 / 7.55 / - / - / 0.00500 / 38.70 / 9.24E-06 / 1.000 / 3.60E-03 / 2.51E+00 / 122329
PCB77 / IndChem / 291.99 / 6.63 / - / - / 0.00500 / 37.40 / 6.83E-05 / 1.000 / 3.60E-03 / 2.53E+00 / 118970
PCB80 / IndChem / 291.99 / 6.60 / - / - / 0.00500 / 37.30 / 3.33E-05 / 1.000 / 3.60E-03 / 2.53E+00 / 118800
Pentobarbital / Barbituric / 226.28 / 2.10 / - / - / 0.22400 / 1.04 / 7.23E-01 / 0.880 / 1.50E+00 / 2.43E-02 / 23.65
PFOS / IndChem / 500.13 / 6.28 / - / - / 0.02000 / 37.90 / 0.00E+00 / 1.000 / 1.34E-01 / 5.26E+01 / 31190
Phenobarbital / Barbituric / 232.24 / 1.47 / 7.22 / 10.23 / 0.18400 / 0.41 / 0.00E+00 / 1.000 / 1.24E+00 / 7.11E-02 / 22.81
Physostigmine / Pharma / 275.35 / 1.58 / 11.47 / 7.95 / 0.69900 / 0.82 / 1.64E+00 / 0.990 / 4.69E+00 / 4.57E-03 / 4.09
Procainamide / Antiarrythmic / 235.33 / 0.88 / 11.95 / 9.20 / 0.83000 / 0.56 / 7.23E-01 / 0.210 / 5.57E+00 / 2.07E-03 / 1.81
Propanolol / Hypertension / 259.35 / 3.48 / 9.25 / - / 0.23100 / 3.44 / 1.06E+00 / 0.390 / 1.55E+00 / 9.98E-03 / 30.04
Propetamphos / Insecticide / 281.31 / 3.82 / - / - / 0.01590 / 3.37 / 9.77E+00 / 1.000 / 1.07E-01 / 4.83E-02 / 172.00
Propylparaben / Preservative / 180.21 / 3.04 / 8.22 / - / 0.09700 / 2.88 / 4.25E+01 / 0.005 / 6.50E-01 / 9.51E-06 / 5.61
Pyraclostrobin / Fungicide / 387.82 / 5.45 / - / - / 0.00079 / 7.63 / 3.50E+01 / 1.000 / 5.30E-03 / 3.00E-01 / 2410
Pyrithiobac / Herbicide / 384.74 / 2.74 / - / - / 0.02800 / 0.72 / 1.99E+00 / 1.000 / 1.88E-01 / 1.09E-01 / 71.21
Quinidine / Antiarrythmic / 324.43 / 3.44 / 7.62 / 4.20 / 0.16300 / 5.55 / 1.11E+00 / 0.650 / 1.10E+00 / 2.07E-02 / 121.03
Rotenone / Insecticide / 394.43 / 4.10 / 7.62 / 4.20 / 0.04100 / 10.99 / 2.27E+01 / 1.000 / 2.75E-01 / 8.32E-03 / 126.72
Strychnine / Insecticide / 334.42 / 1.93 / 7.45 / 0.29 / 0.45700 / 1.14 / 2.00E+00 / 0.950 / 3.07E+00 / 6.01E-03 / 7.51
Theophyline / Antiasmathic / 180.17 / -0.04 / 10.49 / - / 0.90000 / 0.49 / 0.00E+00 / 0.750 / 6.04E+00 / 1.46E-02 / 6.10
Thiazopyr / Pesticide / 396.38 / 3.89 / 1.18 / - / 0.01100 / 2.90 / 4.12E+01 / 1.000 / 7.41E-02 / 1.73E-02 / 56.52
Thioridazine / Antipsychotic / 370.57 / 5.90 / 8.81 / 0.58 / 0.02170 / 17.23 / 9.15E-01 / 0.500 / 1.46E-01 / 1.50E-01 / 3006
Triadimefon / Fungicide / 293.75 / 2.77 / 2.22 / - / 0.05710 / 1.25 / 1.63E+01 / 1.000 / 3.83E-01 / 8.18E-03 / 11.99
Triclosan / Antibacterial / 289.54 / 4.76 / 7.74 / - / 0.00500 / 6.64 / 8.38E+01 / 1.000 / 3.36E-02 / 1.89E-02 / 147.42
Verapamil / Hypertension / 454.61 / 3.79 / 8.42 / - / 0.16400 / 5.08 / 6.08E+00 / 0.390 / 1.10E+00 / 2.91E-03 / 21.87
Warfarin / Anticoagulant / 308.34 / 2.70 / 5.86 / - / 0.03980 / 0.59 / 7.23E-01 / 0.870 / 2.67E-01 / 1.39E-01 / 59.98
Zoxamide / Fungicide / 336.64 / 4.35 / - / - / 0.00515 / 3.90 / 2.88E+01 / 1.000 / 3.46E-02 / 5.26E-02 / 221.91
(**) Unit : µL/min/106 cells
For all compounds a blood to plasma ratio of 0.55 is used in Simcyp simulations.
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6) Supplementary Material, Table 2.The complete ranking of the compounds based on the estimated human bioconcentration factor, hBCF.
Rank / Compound name / hBCF1 / PFOS / 926.3898
2 / Emamectin / 325.4481
3 / Buprofezin / 44.9365
4 / PCB80 / 44.5421
5 / PCB77 / 44.4666
6 / PCB153 / 44.1723
7 / PCB155 / 44.0903
8 / PCB136 / 44.0591
9 / Fenvalerate / 20.2192
10 / Bentazone / 11.1487
11 / DDT / 8.1101
12 / Parathion / 7.0519
13 / Cyprodinil / 6.7255
14 / Pyraclostrobin / 5.2800
15 / Dichlorophenoxy / 5.2417
16 / Fipronil / 2.6442
17 / Thioridazine / 2.6407
18 / Warfarin / 2.4438
19 / Bromacil / 2.3343
20 / Fenoxycarb / 2.3273
21 / Ibuprofen / 2.2145
22 / Pyrithiobac / 1.9254
23 / Etoxazole / 1.5917
24 / Phenobarbital / 1.2513
25 / Isoxaben / 1.2185
26 / Diazepam / 1.1968
27 / Diphenylhydantoin / 1.1181
28 / Gibberellic-acid / 0.9638
29 / Zoxamide / 0.9264
30 / Methylparathion / 0.8935
31 / Propetamphos / 0.8492
32 / Carbamazepine / 0.7798
33 / Isoxaflutole / 0.6994
34 / Amitriptyline / 0.6956
35 / Oxytetracycline / 0.6002
36 / Digoxin / 0.5139
37 / Pentobarbital / 0.4277
38 / Acetamiprid / 0.4020
39 / MGK / 0.3639
40 / Quinidine / 0.3637
41 / Antipyrine / 0.3449
42 / Haloperidol / 0.3329
43 / Triclosan / 0.3327
44 / Atrazine / 0.3133
45 / Aminopterin / 0.3085
46 / Thiazopyr / 0.3036
47 / Diphenhydramine / 0.2922
48 / Disopyramide / 0.2876
49 / Amphetamine / 0.2857
50 / Bensulide / 0.2769
51 / Forchlorfenuron / 0.2713
52 / Theophylline / 0.2570
53 / Caffeine / 0.2466
54 / Metribuzin / 0.2180
55 / Chloramphenicol / 0.1962
56 / Methadone / 0.1919
57 / Colchicine / 0.1800
58 / Orphenadrine / 0.1770
59 / Propanolol / 0.1757
60 / Atropine / 0.1709
61 / Rotenone / 0.1465
62 / Paracetamol / 0.1443
63 / Triadimefon / 0.1440
64 / Diuron / 0.1098
65 / Strychnine / 0.1058
66 / Dicrotophos / 0.1002
67 / Nalidixic-acid / 0.0947
68 / Fenamiphos / 0.0836
69 / Maprotinline / 0.0807
70 / Physostigmine / 0.0804
71 / Aminoglutethimide / 0.0758
72 / Busulfan / 0.0719
73 / Abamectin / 0.0704
74 / Metalaxyl / 0.0664
75 / Verapamil / 0.0512
76 / Nicotine / 0.0444
77 / Aflatoxin / 0.0441
78 / Methylphenidate / 0.0436
79 / BisphenolA / 0.0368
80 / Procainamide / 0.0365
81 / Fenpropathrin / 0.0268
82 / Cycloheximide / 0.0254
83 / Clothianidin / 0.0223
84 / Dextropropoxyphene / 0.0207
85 / Alachlor / 0.0188
86 / Chlorpyrifos / 0.0152
87 / Carbaryl / 0.0141
88 / Acetochlor / 0.0139
89 / Diazoxon / 0.0074
90 / Isoniazide / 0.0046
91 / Dibutylphthalate / 5.8523e-004
92 / Propylparaben / 1.6738e-004
93 / Diethylphthalate / 8.3827e-005
94 / Malathion / 7.5463e-005
7) Supplementary Material, Table 3. Ranking of the compounds based on the bioaccumulation half-life, Tacc. Only the top twenty compounds are shown.
Compound name / CAS number / Tacc / Main categoryPCB153 / 35065-27-1 / 9.7 years / Industrial Chem.
PCB136 / 38411-22-2 / 9.7 years / Industrial Chem.
PCB155 / 33979-03-2 / 9.7 years / Industrial Chem.
PCB77 / 32598-13-3 / 9.4 years / Industrial Chem.
PCB80 / 33284-52-5 / 9.4 years / Industrial Chem.
Emamectin / 155569-91-8 / 4.4 years / PPP (insecticide)
Fenvalerate / 51630-58-1 / 4.0 years / PPP (insecticide)
PFOS / 1763-23-1 / 2.5 years / Industrial Chem.
DDT / 50-29-3 / 1.8 years / PPP (insecticide)
Etoxazole / 153233-91-1 / 129.5 days / PPP (insecticide)
Thioridazine / 50-52-2 / 86.8 days / Pharmaceutical (antipsychotic)
Pyraclostrobin / 175013-18-0 / 69.6 days / PPP (fungicide)
Fipronil / 120068-37-3 / 49.1 days / PPP (insecticide)
Buprofezin / 69327-76-0 / 20.0 days / PPP (insecticide)
Isoxaben / 82558-50-7 / 19.4 days / PPP (herbicide)
Parathion / 56-38-2 / 15.5 days / PPP (insecticide)
Fenoxycarb / 72490-01-8 / 11.9 days / PPP (insecticide)
Zoxamide / 156052-68-5 / 6.4 days / PPP (fungicide)
Cyprodinil / 121552-61-2 / 6.3 days / PPP (fungicide)
Amitriptyline / 50-48-6 / 6.3 days / Pharmaceutical (antidepressant)
8) Supplementary Material, Table 4.Ranking based on the distance to the virtual trap PBTK model (top twenty) and comparison with the ranking based on hBCF and Tacc.
Compound name / hBCF Rank / Tacc RankPCB153 / 6 / 1
PCB155 / 7 / 3
PCB77 / 5 / 4
PCB80 / 4 / 5
PCB136 / 8 / 2
Emamectin / 2 / 6
Fenvalerate / 9 / 7
PFOS / 1 / 8
DDT / 11 / 9
Buprofezin / 3 / 14
Bentazone / 10 / 24
Etoxazole / 23 / 10
Thioridazine / 17 / 11
Pyraclostrobin / 14 / 12
Fipronil / 16 / 13
Dichlorophenoxy / 15 / 26
Parathion / 12 / 16
Cyprodinil / 13 / 19
Bromacil / 19 / 35
Isoxaben / 25 / 15
8) Supplementary Material, Table 5. List of compounds and CAS numbers
Chemical Name / CAS NumberAbamectin / 65195-55-3
Acetamiprid / 135410-20-7
Acetochlor / 34256-82-1
Aflatoxin / 1162-65-8
Alachlor / 15972-60-8
Aminoglutethimide / 125-84-8
Aminopterin / 54-62-6
Amitriptyline / 50-48-6
Amphetamine / 300-62-9
Antipyrine / 60-80-0
Atrazine / 1912-24-9
Atropine / 000051-55-8
Bensulide / 741-58-2
Bentazone / 25057-89-0
BisphenolA / 80-05-7
Bromacil / 314-40-9
Buprofezin / 69327-76-0
Busulfan / 55-98-1
Caffeine / 58-08-2
Carbamazepine / 298-46-4
Carbaryl / 63-25-2
Chloramphenicol / 56-75-7
Chlorpyrifos / 2921-88-2
Clothianidin / 210880-92-5
Colchicine / 64-86-8
Cycloheximide / 66-81-9
Cyprodinil / 121552-61-2
DDT / 50-29-3
Dextropropoxyphene / 469-62-5
Diazepam / 439-14-5
Diazoxon / 962-58-3
Dibutylphthalate / 84-74-2
Dichlorophenoxy / 94-75-7
Dicrotophos / 141-66-2
Diethylphthalate / 84-66-2
Digoxin / 20830-75-5
Diphenhydramine / 58-73-1
Diphenylhydantoin / 57-41-0
Disopyramide / 3737-09-5
Diuron / 330-54-1
Emamectin / 155569-91-8
Etoxazole / 153233-91-1
Fenamiphos / 22224-92-6
Fenoxycarb / 72490-01-8
Fenpropathrin / 39515-41-8
Fenvalerate / 51630-58-1
Fipronil / 120068-37-3
Forchlorfenuron / 68157-60-8
Gibberellic_acid / 77-06-5
Haloperidol / 52-86-8
Ibuprofen / 15687-27-1
Isoniazide / 54-85-3
Isoxaben / 82558-50-7
Isoxaflutole / 141112-29-0
Malathion / 121-75-5
Maprotinline / 010262-69-8
Metalaxyl / 57837-19-1
Methadone / 76-99-3
Methylparathion / 298-00-0
Methylphenidate / 113-45-1
Metribuzin / 21087-64-9
MGK / 113-48-4
Nalidixic_acid / 389-08-2
Nicotine / 54-11-5
Orphenadrine / 83-98-7
Oxytetracycline / 6153-64-6
Paracetamol / 103-90-2
Parathion / 56-38-2
PCB136 / 38411-22-2
PCB153 / 35065-27-1
PCB155 / 33979-03-2
PCB77 / 32598-13-3
PCB80 / 33284-52-5
Pentobarbital / 76-74-4
PFOS / 1763-23-1
Phenobarbital / 50-06-6
Physostigmine / 57-47-6
Procainamide / 51-06-9
Propanolol / 525-66-6
Propetamphos / 31218-83-4
Propylparaben / 94-13-3
Pyraclostrobin / 175013-18-0
Pyrithiobac / 123343-16-8
Quinidine / 56-54-2
Rotenone / 83-79-4
Strychnine / 57-24-9
Theophyline / 58-55-9
Thiazopyr / 117718-60-2
Thioridazine / 50-52-2
Triadimefon / 43121-43-3
Triclosan / 3380-34-5
Verapamil / 52-53-9
Warfarin / 81-81-2
Zoxamide / 156052-68-5
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