Toxicology Letters 318 (2020) 50–56

Contents lists available at ScienceDirect

Toxicology Letters
journal homepage: www.elsevier.com/locate/toxlet

Generic physiologically based kinetic modelling for farm animals: Part II. T
Predicting tissue concentrations of chemicals in swine, cattle, and sheep
L.S. Lautza,*, S. Hoeksa, R. Oldenkampa, A.J. Hendriksa, J.L.C.M. Dorneb, A.M.J. Ragasa,c
a
Department of Environmental Science, Radboud University Nijmegen, Houtlaan 4, 6525 XZ, Nijmegen, the Netherlands
b
European Food Safety Authority, Via Carlo Magno 1A, 43126, Parma, Italy
c
Department of Science, Faculty of Management, Science &Technology, Open University, 6419 AT, Heerlen, the Netherlands

A R T I C LE I N FO A B S T R A C T

Keywords: The development of three generic multi-compartment physiologically based kinetic (PBK) models is described
Physiologically based kinetic model for farm animal species, i.e. cattle, sheep, and swine. The PBK models allow one to quantitatively link external
Farm animal species dose and internal dose for risk assessment of chemicals relevant to food and feed safety. Model performance is
Global sensitivity analysis illustrated by predicting tissue concentrations of melamine and oxytetracycline and validated through com-
Melamine
parison with measured data. Overall, model predictions were reliable with 71% of predictions within a 3-fold of
Oxytetracycline
the measured data for all three species and only 6% of predictions were outside a 10-fold of the measured data.
Predictions within a 3-fold change were best for cattle, followed by sheep, and swine (82%, 76%, and 63%).
Global sensitivity analysis was performed to identify the most sensitive parameters in the PBK model. The
sensitivity analysis showed that body weight and cardiac output were the most sensitive parameters. Since
interspecies differences in metabolism impact on the fate of a wide range of chemicals, a key step forward is the
introduction of species-specific information on transporters and metabolism including expression and activities.

1. Introduction chemical properties) and the compound’s biochemistry (e.g. Vmax and
Km, metabolic clearance) (Brochot et al., 2007; Reddy et al., 2005).
Animal health risk assessment of chemicals aims to protect a range Model parameters correspond to physiological and biochemical entities
of farm and companion animals from the harmful effects of chemicals specific to the body and compounds, such as affinities of the compounds
present in the feed chain (Alexander et al., 2012; Toutain et al., 2010). for the tissues, or metabolic clearances. PBK models can be refined as
It accounts also for impacts on human health due to transfer of che- chemical-specific, class-specific or generic for a given species or range
micals into the food-chain (Alexander et al., 2012). For a given che- of species and can be applied to a wide range of data poor compounds
mical, inter-species differences in toxicokinetics (TK) and tox- bearing in mind the underlying uncertainties associated with data gaps
icodynamics (TD) can be investigated through the quantification of and poor characterisation of kinetics (Beaudouin et al., 2010; Clewell
inter-species variability in physiology, diet, absorption, metabolism, et al., 2004; Cohen Hubal et al., 2019; Edginton et al., 2006).
distribution and excretion (ADME), target receptors and toxicological In the area of animal health, the use of kinetic information and PBK
sensitivity in different life-stages (Dorne and Fink-Gremmels, 2013). models is currently mostly limited to two main applications. The first
Recently, the European Food Safety Authority (EFSA) recommended one is on therapeutical dosing of veterinary drugs in a given species, the
to further support quantitative risk assessment through a better un- second one is on determining residue levels and transfer of regulated
derstanding of such inter-species differences in TK and TD processes compounds (feed additives, pesticides, veterinary drugs) or con-
and the development of generic biologically-based models (EFSA, taminants (persistent organic pollutants, toxins) in animal products
2014). Such biologically-based models include tools for allometric (e.g. meat, milk, eggs). Such carry over and residue levels can then be
scaling, physiologically based kinetic (PBK) and physiologically based used as occurrence inputs and combined with human consumption
TK-TD (PBTK-TD) models (Huang et al., 2015; Riviere et al., 2016). patterns of animal products for human exposure assessment (Dorne and
Generic PBK models integrate physiological and anatomical features Fink-Gremmels, 2013; Huang et al., 2015; Riviere et al., 2016). A recent
subdivided into body compartments (i.e. organ volumes), connected review assessed the available models in farm animal species and pro-
through blood flow, chemical specific parameters (e.g. physico- posed the future development of generic PBK models in risk assessment

⁎
Corresponding author.
E-mail address: l.lautz@science.ru.nl (L.S. Lautz).

https://doi.org/10.1016/j.toxlet.2019.10.008
Received 7 June 2019; Received in revised form 2 October 2019; Accepted 12 October 2019
Available online 14 October 2019
0378-4274/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
L.S. Lautz, et al. Toxicology Letters 318 (2020) 50–56

(SI, part 1).

2.2. Anatomical and physiological parameter values

An extensive literature search was performed to identify experi-

mental data on anatomical and physiological parameters (e.g. organ
volumes, relative blood flow). Meta-analyses were performed to define
distributions reflecting intra-species variability in these parameters
(Lautz et al., 2019). Data availability for blood flow parameters and
their associated variability for the three species was limited. Data gaps
were filled using allometric scaling (Lindstedt and Schaeffer, 2002) and
a default variability of 30% was allocated as suggested by Clewell and
Clewell (2008). Tissue composition parameters were expressed as
fractions of neutral lipids, polar lipids, proteins and water. These
fractions were reported for humans and assumed applicable to swine,
cattle, and sheep (Schmitt, 2008).

2.3. Case studies

The PBK models were validated by comparing model predictions of

tissue concentrations with experimental data measured in tissues of
cattle, swine, and sheep for two compounds that are eliminated through
renal excretion: melamine as an environmental contaminant and oxy-
tetracycline as an antibiotic. An extensive search of the published lit-
erature in PubMed and Scopus using search terms 'species', 'substance'
and 'tissue' yielded experimental data for these two compounds (see SI,
part 3.1). Papers were included when the experiment was conducted in
healthy animals, a clear descriptions of the exposure was available, and
Fig. 1. Schematic description of the PBK model developed for cattle, sheep, and measured tissue concentration was reported. Papers not fulfilling these
swine. Uptake and excretion sites are presented in the purple and green, re- criteria were excluded. The tissue:blood partition coefficients as well as
spectively. the blood:air partition coefficient were calculated by available QSARs
(Hendriks et al., 2005). The QSAR allowed the calculation of the che-
(Lautz et al., 2019b). In addition, generic models have been recently mical affinity for all tissues based on the octanol/water partition
published for four fish species (fathead minnow, zebrafish, European coefficient and tissue composition through considering the tissues
stickleback, rainbow trout) (Grech et al., 2019). constituents’ lipids (both neutral and polar), proteins and water. For
This manuscript describes the development and application of both compounds, characteristics, kinetic data and data for model eva-
generic multi-compartment models in three farm animal species, luation are presented in Table 1. Model input parameters were pre-
namely swine, cattle, and sheep. Anatomical and physiological para- dicted by allometric scaling or were based on values from peer-re-
meters were collected via meta-analysis and are presented in a related viewed publications that were independent of the values used for model
manuscript (Lautz et al., 2019). Model performance is illustrated in two evaluation (see SI, part 3.2).
case studies, i.e. one on melamine and one on oxytetracycline and a
global sensitivity analysis was performed to identify the most sensitive 2.4. Global sensitivity analysis
model parameters.
Global sensitivity analysis of the model was performed for each
species using the variance-based Sobol method, based on variance de-
2. Materials and methods composition quantifying the relative contribution of each parameter to
the total variance of the model output (Saltelli et al., 2008; Sobol’ et al.,
2.1. PBK model structure 2007). The global sensitivity analysis orders the model inputs by im-
portance so that the main contributors to the variation in the output
The PBK model structure is generic for all three farm animal species (e.g. blood concentration) can be identified. Sensitivity was assessed for
and is presented in Fig. 1. Each model is structured with eleven com- oxytetracycline concentrations in the whole animal, blood, and kidney
partments: arterial blood, venous blood, gastrointestinal tract (GIT), at three different time points, i.e. absorption phase, fast elimination
liver, heart, brain, adipose tissue, muscle, bone, lung, and kidney. phase, and slow elimination phase. Parameter values and exposure
Sheep and cattle have a twelfth compartment i.e. the milk compart- scenarios are described in detail in SI (part 2.1). Uniform distributions
ment. All organs and tissues were modelled as homogenous compart- were used for all physiological parameters to compare model perfor-
ments with a blood-flow limited distribution. mance between species.
The model covers two exposure routes, i.e. oral exposure and in-
travenous injection. The GIT consists of two sub-compartments, the gut 2.5. Software
lumen and the gut tissue, enabling the inclusion of biliary excretion as a
separate process. Absorption from the gut lumen into the gut tissue is The PBK models were implemented in the R software (version 3.3.3)
modelled as a first order process and distribution is modelled (R Core Development Team, 2014). The function “soboljansen” in the
throughout the body via the systemic circulation. Chemical elimination “sensitivity” package was used to carry out the sensitivity analysis
is included through different routes, i.e. renal excretion, hepatic me- (Pujol et al., 2017). The R codes for the PBK models in the three farm
tabolism, exhalation, egestion and accumulation in milk. The differ- animal species are presented in the SI (part 4) and are also available on
ential equations describing the mass balance in each compartment and the EFSA knowledge junction under the DOI [https://doi.org/10.5281/
parameters abbreviations are provided in the supporting information zenodo.3432796].

51
L.S. Lautz, et al. Toxicology Letters 318 (2020) 50–56

Table 1
Compound-specific parameters and data used for PBK model evaluation.
Parameter Unit Parameter values and references

Melamine Oxytetracycline

Class – Contaminant Drug

Molecular weight g/mol 126.12 460.44
Log Kow – −1.37 −0.9
Solubility mg/L 3230 313
Vapour pressure Pa 4.37E-08 1.29E-22
Absorption rate constant min−1 0.0059a 0.0058b
(kabs) 0.032c
Clearance (renal) L/min/kg 0.001d 0.002d
References for model (Battaglia et al., 2010; Cruywagen et al., 2011; (Ahmad et al., 1990; Black and Gentry, 1984; Immelman and Dreyer, 1986; Kumar
evaluation Sun et al., 2011; Tkachenko et al., 2015) and Malik, 1998, 2003; Mevius et al., 1986; Moreno et al., 1998; Nielsen and Gyrd-
Hansen, 1996; Nouws et al., 1985; Phibro Animal Health, 2004; Pijpers et al., 1990,
1991; Sun et al., 2002; Toutain and Raynaud, 1983; Yar et al., 2000)

a
Poapolathep et al. (2015).
b
Absorption rate constant for cattle and sheep (Schifferli et al., 1982).
c
Absorption rate constant for swine (Pijpers et al., 1991).
d
Based on allometric scaling and dependent on the body weight of each species, equations are given in the SI (SI part 3.2).

3. Results From an inter-species perspective, the model predictions showed

relatively low variability with 82%, 76%, and 63% of predictions
3.1. Model evaluation and validation within a 3-FC for cattle, sheep, and swine respectively. Model predic-
tions exceeded 10-FC in only 3% of cases in sheep and cattle and 9% in
For melamine and oxytetracycline, 19 publications were identified swine.
with experimental data and Figs. 2 and 3 illustrate the comparisons
between their measured concentrations in different tissues and organs
and the PBK model predictions. Tables S5, S6, and S7 summarise the 3.2. Global sensitivity analysis
fold-changes (FC) between the measured data and PBK model predic-
tions for melamine and oxytetracycline (SI part 3.3). Globally, 71% of Global sensitivity analysis of the PBK models for cattle, sheep, and
the model predictions were within a 3-FC of the measured data for all swine with oxytetracycline shows that body weight (BW), cardiac
species and only 6% of the PBK predictions were outside a 10-FC. output (CO) and renal blood flow (fCO_kidney) were the main con-
On a compound-specific basis, 40% and 79% of the predictions of tributors to the overall variance of the model output (Fig. 5). However,
the PBK models were within a 3-FC for melamine and oxytetracycline the relative contribution of each of those varied between cattle, sheep
respectively and only 5–6% of the predictions were over- or under- and swine. During the absorption phase, the model output for the blood
predicted by more than a 10-fold. The predicted curves for blood con- concentration was impacted by the intestinal blood flow (fCO_intestine)
centrations were very close to the measured blood concentration-time as well as distribution of the chemical towards other organs such as
data (Fig. 4). For other organs, single time point measurements were muscle and adipose tissue (fBW_adipose, fCO_muscle). In the elimina-
mostly reported from the literature. And at the tissue or organ level, tion phase, renal blood flow was the most sensitive parameter and had a
58–84% of the predictions in blood, kidney, and muscle were within 3- strong influence on model outputs. The results of the global sensitivity
FC, whereas 67% of the predicted concentrations in liver were between analysis for model outputs with regards to whole animal and kidney
3-FC to 10-FC. concentrations were similar to that for blood concentrations (see SI part
2.2).

Fig. 2. Comparison between concentrations measured in var-

ious organs of cattle (CA), sheep (SH), and swine (SW) and
PBK model predictions for melamine. Dotted lines represent
the 3-fold and 10-fold changes. Organs, species, and references
of experimental datasets are indicated in legend: colours and
shapes represent organs and studies, respectively.

52
L.S. Lautz, et al. Toxicology Letters 318 (2020) 50–56

Fig. 3. Comparison between concentrations

measured in various organs of cattle (CA),
sheep (SH), and swine (SW) and PBK model
predictions for oxytetracycline. Dotted lines
represent the 3-fold and 10-fold changes.
Organs, species, and references of experimental
datasets (full references given in Table 1) are
indicated in legend: colours and shapes re-
present organs and studies, respectively.

absorption rates for melamine in the included species were not avail-
able in literature, melamine absorption rates were extrapolated from
chicken, leading to uncertainty in the PBK model inputs for this para-
meter with still reliable predictions in cattle and sheep (Poapolathep
et al., 2015). Overall, literature data on melamine in various tissues of
the included species were very limited, so the quality of the included
papers is of high relevance for the reliability of the model performance.
Milk concentrations were overpredicted by the model in most cases
when only about 2% of ingested melamine has been reported to be
excreted in milk (Cruywagen et al., 2009). Nevertheless, melamine
patterns in milk were dose dependent and variation was based on the
milk yield which differed between studies (Battaglia et al., 2010;
Cruywagen et al., 2009; Sun et al., 2011). This discrepancy might be
due to the modelled blood flow for the mammary gland, which is higher
compared to the renal blood flow. In swine, the organ concentrations in
muscle and liver were overpredicted and showed large variability at
high exposure concentration (1000 mg/kg). The rationale for such
overpredictions are threefold. First, measured melamine tissue con-
centrations in swine showed large variability within the animals tested
Fig. 4. Comparison of model prediction (solid line and 95th confidence interval) as well as between the measured concentrations of laboratories, leading
and observed data (red dots) (Sun et al., 2002) are shown for concentrations of to discrepancies between model prediction and observed data
oxytetracycline in blood from sheep. (Tkachenko et al., 2015). Second, experimental concentrations in swine
were very high compared with those for sheep and cattle (Cruywagen
4. Discussion et al., 2011; Sun et al., 2011; Tkachenko et al., 2015). However, the
calculated clearance using allometric scaling was similar to measured
Generic PBK models have been developed for three farm animal clearance at high dose and steady-state conditions (0.072 vs 0.079 L/h/
species namely, swine, cattle and sheep. The performance of the models kg) (Wang et al., 2010) even though renal clearance may be altered at
was illustrated and validated for melamine and oxytetracycline elimi- high concentrations (Juhlin et al., 2008). Third, due to limited data
nated via renal excretion while comparing measured data and predicted availability of experimental data for tissue: blood partition coefficients,
outputs in these species. Overall, the generic models provided reliable tissue partitioning was estimated with a QSAR for polar chemicals
predictions within 3-fold of the measured data. (Hendriks et al., 2005) which is based on tissue constituents (e.g. polar
For melamine, a data gap for melamine was identified with regards lipids, non-polar lipids, water, protein) and octanol/water partition
to absorption rate in the digestive tract of ruminants (Cruywagen et al., coefficient. This limitation however, did not affect the prediction of
2009, 2011). However, differences between exposure and excreted organ concentrations for sheep and cattle which were reliable.
concentrations in ruminants suggest that the absorption of melamine is For oxytetracycline, a veterinary antibiotic administered orally and
higher than 75%. In monogastric animals, such as swine, the absorption intravenously, absorption is only partial in the swine’ intestine (Pijpers
of melamine is nearly 100% and unchanged melamine is detected in et al., 1991) and was not characterised in adult ruminants, i.e. cattle
urine only (Cruywagen et al., 2011; Dorne et al., 2013). Since and sheep, and may vary compared to monogastric species. For other

53
L.S. Lautz, et al. Toxicology Letters 318 (2020) 50–56

Fig. 5. Sensitivity analysis of the cattle (upper panels), sheep (middle panels) and swine (lower panels) PBK model applied to oxytetracycline. Sobol’s sensitivity
indices were estimated for the blood concentration in the three species at three time points (from left to right): 1.25, 9.5, and 24 h for cattle, 0.5, 6.5, and 21 h for
sheep; 0.5, 5, and 21 h for swine. Estimation of the Sobol' total sensitivity indices (TI) are presented in dark green and estimation of the Sobol' first-order indices (FOI)
in light green. The nine most influencing parameters according to the total sensitivity indices are shown.

substances, such differences in absorption between monogastric and while for sheep, 76% of the predictions were within a 3-FC.
ruminants already have been observed (Ratz et al., 1995). Oxyte-
tracycline undergoes no metabolism and is excreted in urine unchanged 5. Conclusion and recommendations
(Nouws et al., 1985). Overall, measured blood concentrations were
often available in literature, whereas tissue concentrations were scarce Generic PBK models with species-specific physiological parameters
for more than one time point. For oxytetracycline, model predictions were developed for three farm animal species. The models share the
were reliable compared to observed data. However, Nielsen and Gyrd- same structure for all three species with the exception of the milk
Hansen (1996) reported very low blood concentrations after oral ex- compartment, which has been added for cattle and sheep as an extra
posure, leading to overestimation of the model predictions, compared elimination route of high relevance to food and feed safety. The model
to similar studies in swine (Pijpers et al., 1990, 1991). Differences in the performance was illustrated for melamine and oxytetracycline which
measured blood concentrations between the studies cannot be ex- are renally excreted. In this context, further model validation is needed
plained by small changes in the administered dose. Furthermore, through PBK modelling of residues in edible tissues (e.g. muscle,
kidney concentration of oxytetracycline in swine were underestimated kidney, liver) and animal-based products (i.e. milk) from cattle, swine
by the model. These differences might by due to inclusion of the urinary and sheep for a range of compounds However, a range of data gaps and
formation in the kidney in the measured data, while the model predicts recommendations for future work can be highlighted for these three
kidney tissue only (Black and Gentry, 1984). Another explanation may species:
be the underestimation of tissue partitioning of oxytetracycline in the
kidney. In the literature, a cattle and a sheep PBK model for oxyte- 1 Peer-reviewed literature providing tissue residues and milk residues
tracycline were developed to predict concentrations in different organs, for a range of regulated compounds (pesticides, feed additives) and
after intramuscular administration and fitted model parameters based anthropogenic or naturally-occurring contaminants (e.g. persistent
on experimental data (Achenbach, 2000; Craigmill, 2003). Based on organic pollutants, mycotoxins) are still relatively scarce. Extensive
this approach, the predicted concentration were within a 3-FC in 95% literature searches and data collection from pre-market dossiers
of cases (Achenbach, 2000; Craigmill, 2003). With regards to con- should be performed to develop kinetic databases to further explore
centrations, our PBK model provided predictions with slightly lower the predictability of the models for a larger group of compounds.
accurate predicted values for cattle (82% predictions within a 3-FC) 2 Current generic model do not incorporate developmental aspects.

54
L.S. Lautz, et al. Toxicology Letters 318 (2020) 50–56

Further anatomical and physiological parameters should be col- toxsci/kfh109.

lected to test the impact of growth and age on the PBK prediction Clewell, R.A., Clewell, H.J., 2008. Development and specification of physiologically based
pharmacokinetic models for use in risk assessment. Regul. Toxicol. Pharmacol. 50,
and sensitivity. 129–143. https://doi.org/10.1016/j.yrtph.2007.10.012.
3 Chemicals may undergo transport and phase I and/or Phase II me- Cohen Hubal, E.A., Wetmore, B.A., Wambaugh, J.F., El-Masri, H., Sobus, J.R., Bahadori,
tabolism and databases on species-specific information on trans- T., 2019. Advancing internal exposure and physiologically-based toxicokinetic
modeling for 21st-century risk assessments. J. Expo. Sci. Environ. Epidemiol. 29,
porters, enzyme expression and activities are currently not avail- 11–20. https://doi.org/10.1038/s41370-018-0046-9.
able. Enzyme expression and activities for these species may Craigmill, A.L., 2003. A physiologically based pharmacokinetic model for oxytetracycline
therefore be first collected from the literature or generated experi- residues in sheep. J. Vet. Pharmacol. Ther. 26, 55–63. https://doi.org/10.1046/j.
1365-2885.2003.00451.x.
mentally, when data gaps have been identified. Experimentally, a Cruywagen, C.W., Stander, M.A., Adonis, M., Calitz, T., 2009. Hot topic: pathway con-
range of approaches can provide important datasets with regards to firmed for the transmission of melamine from feed to cow’s milk. J. Dairy Sci. 92,
expression levels and activities including 1. OMICs technologies (i.e. 2046–2050. https://doi.org/10.3168/jds.2009-2081.
Cruywagen, C.W., van de Vyver, W.F.J., Stander, M.A., 2011. Quantification of melamine
transcriptomics, proteomics, metabolomics) providing qualitative
absorption, distribution to tissues, and excretion by sheep. J. Anim. Sci. 89,
and quantitative information on expression of enzymes and trans- 2164–2169. https://doi.org/10.2527/jas.2010-3531.
porters. 1. Enzyme activities in liver microsomes and other organs Dorne, J.L., Doerge, D.R., Vandenbroeck, M., Fink-Gremmels, J., Mennes, W., Knutsen,
(kidney, gut etc.) providing kinetic parameters for specific probe H.K., Vernazza, F., Castle, L., Edler, L., Benford, D., 2013. Recent advances in the risk
assessment of melamine and cyanuric acid in animal feed. Toxicol. Appl. Pharmacol.
substrates (phase I, phase metabolism and transporters), regulated 270, 218–229. https://doi.org/10.1016/j.taap.2012.01.012.
compounds and contaminants. In addition, integration of the in vitro Dorne, J.L.C.M., Fink-Gremmels, J., 2013. Human and animal health risk assessments of
metabolism, kinetic data and generic enzymes activities can also chemicals in the food chain: comparative aspects and future perspectives. Toxicol.
Appl. Pharmacol. 270, 187–195. https://doi.org/10.1016/j.taap.2012.03.013.
provide the basis to further develop quantitative in vitro to in vivo Edginton, A.N., Schmitt, W., Willmann, S., 2006. Development and evaluation of a gen-
extrapolation models, which can be implemented in PBK models for eric physiologically based pharmacokinetic model for children. Clin. Pharmacokinet.
animal risk assessment and ultimately limit in vivo testing in farm 45, 1013–1034. https://doi.org/10.2165/00003088-200645100-00005.
EFSA, 2014. Modern methodologies and tools for human hazard assessment of chemicals.
animal species. EFSA J. 12, 3638–3725. https://doi.org/10.2903/j.efsa.2014.3638.
Grech, A., Tebby, C., Brochot, C., Bois, F.Y., Bado-Nilles, A., Dorne, J.-L., Quignot, N.,
Finally, these data gaps and recommendations can be broaden to a Beaudouin, R., 2019. Generic physiologically-based toxicokinetic modelling for fish:
integration of environmental factors and species variability. Sci. Total Environ. 651,
wider range of mammalian and avian animal species of public health 516–531. https://doi.org/10.1016/j.scitotenv.2018.09.163.
and animal health importance. It is foreseen that these research efforts Hendriks, A.J., Traas, T.P., Huijbregts, M.A., 2005. Critical body residues linked to oc-
will lead to open source databases and PBK tools for multiple species tanol-water partitioning, organism composition, and LC50 QSARs: meta-analysis and
model. Environ. Sci. Technol. 39, 3226–3236. https://doi.org/10.1021/es048442o.
and developmental stages and allow the implementation of a ‘One
Huang, Q., Gehring, R., Tell, L.A., Li, M., Riviere, J.E., 2015. Interspecies allometric meta-
health’ approach in chemical risk assessment while integrating species analysis of the comparative pharmacokinetics of 85 drugs across veterinary and la-
differences in chemical kinetics and toxicity. boratory animal species. J. Vet. Pharmacol. Ther. 38, 214–226. https://doi.org/10.
1111/jvp.12174.
Immelman, A., Dreyer, G., 1986. Oxytetracycline concentrations in plasma and semen of
Declaration of Competing Interest rams. J. S. Afr. Vet. Assoc. 57, 103–104.
Juhlin, T., Jonsson, B.A., Hoglund, P., 2008. Renal effects of aspirin are clearly dose-
None. dependent and are of clinical importance from a dose of 160 mg. Eur. J. Heart Fail.
10, 892–898. https://doi.org/10.1016/j.ejheart.2008.06.014.
Kumar, R., Malik, J.K., 1998. Some pharmacokinetic parameters and dosage regimens for
Acknowledgment a long-acting formulation of oxytetracycline in 6- to 8-month-old male calves. Vet.
Res. Commun. 22, 533–544. https://doi.org/10.1023/a:1006193703979.
Kumar, R., Malik, J.K., 2003. Influence of endotoxin on the disposition kinetics and do-
This work was supported by the European Food Safety Authority sage regimens of oxytetracycline in calves. J. Vet. Pharmacol. Ther. 26, 159–164.
(EFSA) [Contract number: EFSA/SCER/2014/06]. https://doi.org/10.1046/j.1365-2885.2003.00474.x.
Lautz, L.S., Dorne, J.L.C.M., Oldenkamp, R., Hendriks, A.J., Ragas, A.M.J., 2019. Generic
physiologically based kinetic modelling for farm animals: part I. Data collection of
Appendix A. Supplementary data
physiological parameters in swine, cattle and sheep. Toxicol. Lett submitted.
Lautz, L.S., Oldenkamp, R., Dorne, J.L., Ragas, A.M.J., 2019b. Physiologically based ki-
Supplementary material related to this article can be found, in the netic models for farm animals: critical review of published models and future per-
spectives for their use in chemical risk assessment. Toxicol. Vitr. 60, 61–70. https://
online version, at doi:https://doi.org/10.1016/j.toxlet.2019.10.008.
doi.org/10.1016/j.tiv.2019.05.002.
Lindstedt, S.L., Schaeffer, P.J., 2002. Use of allometry in predicting anatomical and
References physiological parameters of mammals. Lab. Anim. 36, 1–19. https://doi.org/10.
1258/0023677021911731.
Mevius, D.J., Nouws, J.F., Breukink, H.J., Vree, T.B., Driessens, F., Verkaik, R., 1986.
Achenbach, T.E., 2000. Physiological and Classical Pharmacokinetic Models of Comparative pharmacokinetics, bioavailability and renal clearance of five parenteral
Oxytetarcycline in Cattle. Simon Fraser University, Burnaby, BC, Canada 1-129 pp. oxytetracycline-20% formulations in dairy cows. Vet. Q. 8, 285–294. https://doi.org/
Ahmad, M., Nawaz, M., Zia-Ur-Rahman, 1990. Disposition kinetics and dosage of oxy- 10.1080/01652176.1986.9694057.
tetracycline in sheep and lamb. Vet. Arh. 60, 173–179. Moreno, L., Serrano, J.M., Guimera, M.E., Carceles, C.M., 1998. Pharmacokinetics of
Alexander, J., Benford, D., Boobis, A., Eskola, M., Fink-Gremmels, J., Fürst, P., Heppner, oxytetracycline after intramuscular administration with lidocaine in sheep, compar-
C., Schlatter, J., van Leuuwen, R., 2012. Risk assessment of contaminants in food and ison with a conventional formulation. Res. Vet. Sci. 65, 209–213. https://doi.org/10.
feed. EFSA J. 10, 1004–1015. https://doi.org/10.2903/j.efsa.2012.s1004. 1016/S0034-5288(98)90145-X.
Battaglia, M., Cruywagen, C.W., Bertuzzi, T., Gallo, A., Moschini, M., Piva, G., Masoero, Nielsen, P., Gyrd-Hansen, N., 1996. Bioavailability of oxytetracycline, tetracycline and
F., 2010. Transfer of melamine from feed to milk and from milk to cheese and whey chlortetracycline after oral administration to fed and fasted pigs. J. Vet. Pharmacol.
in lactating dairy cows fed single oral doses. J. Dairy Sci. 93, 5338–5347. https://doi. Ther. 19, 305–311. https://doi.org/10.1111/j.1365-2885.1996.tb00054.x.
org/10.3168/jds.2010-3326. Nouws, J.F., Vree, T.B., Termond, E., Lohuis, J., van Lith, P., Binkhorst, G.J., Breukink,
Beaudouin, R., Micallef, S., Brochot, C., 2010. A stochastic whole-body physiologically H.J., 1985. Pharmacokinetics and renal clearance of oxytetracycline after in-
based pharmacokinetic model to assess the impact of inter-individual variability on travenous and intramuscular administration to dairy cows. Vet. Q. 7, 296–305.
tissue dosimetry over the human lifespan. Regul. Toxicol. Pharmacol. 57, 103–116. https://doi.org/10.1080/01652176.1985.9694003.
https://doi.org/10.1016/j.yrtph.2010.01.005. Phibro Animal Health, 2004. Freedom of Information Summary, Supplemental New
Black, W.D., Gentry, R.D., 1984. The distribution of oxytetracycline in the tissues of Animal Drug Application, NADA 008-804. NADA, pp. 008–804.
Swine following a single oral dose. Can. Vet. J. 25, 158–161. Pijpers, A., Schoevers, E.J., van Gogh, H., van Leengoed, L.A., Visser, I.J., van Miert, A.S.,
Brochot, C., Smith, T.J., Bois, F.Y., 2007. Development of a physiologically based tox- Verheijden, J.H., 1990. The pharmacokinetics of oxytetracycline following in-
icokinetic model for butadiene and four major metabolites in humans: global sensi- travenous administration in healthy and diseased pigs. J. Vet. Pharmacol. Ther. 13,
tivity analysis for experimental design issues. Chem. Biol. Interact. 167, 168–183. 320–326. https://doi.org/10.1111/j.1365-2885.1990.tb00783.x.
https://doi.org/10.1016/j.cbi.2007.02.010. Pijpers, A., Schoevers, E.J., van Gogh, H., van Leengoed, L.A., Visser, I.J., van Miert, A.S.,
Clewell, H.J., Gentry, P.R., Covington, T.R., Sarangapani, R., Teeguarden, J.G., 2004. Verheijden, J.H., 1991. The influence of disease on feed and water consumption and
Evaluation of the potential impact of age- and gender-specific pharmacokinetic dif- on pharmacokinetics of orally administered oxytetracycline in pigs. J. Anim. Sci. 69,
ferences on tissue dosimetry. Toxicol. Sci. 79, 381–393. https://doi.org/10.1093/ 2947–2954. https://doi.org/10.2527/1991.6972947x.

55
L.S. Lautz, et al. Toxicology Letters 318 (2020) 50–56

Poapolathep, S., Klangkaew, N., Arreesrisom, P., Isariyodom, S., Sugita-Konishi, Y., Sobol’, I.M., Tarantola, S., Gatelli, D., Kucherenko, S.S., Mauntz, W., 2007. Estimating the
Kumagai, S., Poapolathep, A., 2015. Toxicokinetics and absolute oral bioavailability approximation error when fixing unessential factors in global sensitivity analysis.
of melamine in broiler chickens. J. Vet. Pharmacol. Ther. 38, 101–104. https://doi. Reliab. Eng. Syst. Saf. 92, 957–960. https://doi.org/10.1016/j.ress.2006.07.001.
org/10.1111/jvp.12145. Sun, P., Wang, J.Q., Shen, J.S., Wei, H.Y., 2011. Residues of melamine and cyanuric acid
Pujol, G., et al., 2017. Sensitivity: Global Sensitiv-ity Analysis of Model Outputs. R in milk and tissues of dairy cows fed different doses of melamine. J. Dairy Sci. 94,
Package Version 1.14.0. 3575–3582. https://doi.org/10.3168/jds.2010-4018.
R Core Development Team, 2014. R: A Language and Environment for Statistical Sun, Y., Peng, Y., Aksornkoae, N., Johnson, J.R., Boring, J.G., Scruggs, D., Cooper, R.C.,
Computing. R Foundation for Statistical Computing, Vienna, Austria. Laizure, S.C., Shukla, A.J., 2002. Controlled release of oxytetracycline in sheep. J.
Ratz, V., Maas, R., Semjén, G., van Miert, A.S., Witkamp, R.F., 1995. Oral bioavailability Control. Release 85, 125–134. https://doi.org/10.1016/S0168-3659(02)00286-9.
of sulphonamides in ruminants: a comparison between sulphamethoxazole, sulpha- Tkachenko, A., Clark, J., Knutson, N., Wallace, B., Bomba, M., Yacopucci, M., Rhodes, B.,
troxazole, and sulphamerazine, using the dwarf goat as animal model. Vet. Q. 17, Nemser, S.M., Guag, J., Reimschuessel, R., 2015. Investigation of melamine and cy-
82–87. https://doi.org/10.1080/01652176.1995.9694538. anuric acid deposition in pig tissues using LC-MS/MS methods. Food Chem. Toxicol.
Reddy, M.B., Clewell, H.J., Andersen, M.E., 2005. Physiology Based Pharmacokinetic 80, 310–318. https://doi.org/10.1016/j.fct.2015.03.007.
Modeling: Science and Applications. John Wiley & Sons, Inc., Hoboken, New Jersey. Toutain, P.L., Ferran, A., Bousquet-Melou, A., 2010. Species differences in pharmacoki-
Riviere, J.E., Gabrielsson, J., Fink, M., Mochel, J., 2016. Mathematical modeling and netics and pharmacodynamics, comparative and veterinary pharmacology.
simulation in animal health. Part I: moving beyond pharmacokinetics. J. Vet. Handbook of Experimental Pharmacology. Springer, Berlin, Heidelberg, pp. 19–48.
Pharmacol. Ther. 39, 213–223. https://doi.org/10.1111/jvp.12278. Toutain, P.L., Raynaud, J.P., 1983. Pharmacokinetics of oxytetracycline in young cattle:
Saltelli, A., Chan, K., Scott, E.M., 2008. Sensitivity Analysis. New York. . comparison of conventional vs long-acting formulations. Am. J. Vet. Res. 44,
Schifferli, D., Galeazzi, R.L., Nicolet, J., Wanner, M., 1982. Pharmacokinetics of oxyte- 1203–1209.
tracycline and therapeutic implications in veal calves. J. Vet. Pharmacol. Ther. 5, Wang, Z., Ma, X., Zhang, L., Yang, W., Gong, L., He, P., Li, Z., 2010. Screening and de-
247–257. termination of melamine residues in tissue and body fluid samples. Anal. Chim. Acta
Schmitt, W., 2008. General approach for the calculation of tissue to plasma partition 662, 69–75. https://doi.org/10.1016/j.aca.2010.01.004.
coefficients. Toxicol. In Vitro 22, 457–467. https://doi.org/10.1016/j.tiv.2007.09. Yar, M., Ahmad, M., Bukhari, N.I., 2000. Pharmacokinetics of oxytetracycline in sheep
010. after various intravenous doses. Turk. J. Vet. Anim. Sci. 24, 135–138.

56