Bayesian analysis of physiologically based toxicokinetic (PBTK) modeling for pentachlorophenol exposure in pregnant women.

Pentachlorophenol (PCP) is a persistent organic compound that is widely present in the environment. The estimation of internal exposure levels for a given external exposure using toxicokinetic models is key to the human health risk assessment of PCP. The present study developed a physiologically based multicompartmental pharmacokinetic (PBTK) model to describe and predict the behavior of pentachlorophenol (PCP) in an organism. The model consists of stomach, intestines, adipose tissue, kidneys and fast- and poorly perfused tissues that are interconnected via blood circulation. We constructed a PBTK model of PCP in rats and extrapolated it to human dietary PCP exposure. The toxicokinetic data of PCP in human tissues and excreta were obtained from the published literature. Based on the collected PCP dietary survey and internal exposure data of pregnant women in Shanghai, Bayesian statistical analysis was performed for the model using Markov chain Monte Carlo (MCMC) simulation. The posterior distributions of the sensitive parameters were estimated, and the model was parameter optimized and validated using the pregnant women's test dataset. The results showed that the root mean square error (RMSE) improved 37.3% compared to the original model, and a systematic literature search revealed that the optimized model achieved acceptable prediction results for other datasets in China. A PCP metabolism model based on the exposure characteristics of pregnant women in China was constructed in the present study. The model provides a theoretical basis for the study of PCP toxicity and risk assessment.

Predicting the in vivo developmental toxicity of fenarimol from in vitro toxicity data using PBTK modelling-facilitated reverse dosimetry approach.

In vitro methods are widely used in modern toxicological testing; however, the data cannot be directly employed for risk assessment. In vivo toxicity of chemicals can be predicted from in vitro data using physiologically based toxicokinetic (PBTK) modelling-facilitated reverse dosimetry (PBTK-RD). In this study, a minimal-PBTK model was constructed to predict the in-vivo kinetic profile of fenarimol (FNL) in rats and humans. The model was verified by comparing the observed and predicted pharmacokinetics of FNL for rats (calibrator) and further applied to humans. Using the PBTK-RD approach, the reported in vitro developmental toxicity data for FNL was translated to in vivo dose-response data to predict the assay equivalent oral dose in rats and humans. The predicted assay equivalent rat oral dose (36.46 mg/kg) was comparable to the literature reported in vivo BMD10 value (22.8 mg/kg). The model was also employed to derive the chemical-specific adjustment factor (CSAF) for interspecies toxicokinetics variability of FNL. Further, Monte Carlo simulations were performed to predict the population variability in the plasma concentration of FNL and to derive CSAF for intersubject human kinetic differences. The comparison of CSAF values for interspecies and intersubject toxicokinetic variability with their respective default values revealed that the applied uncertainty factors were adequately protective.

Physiologically based toxicokinetic modelling of Tri(2-chloroethyl) phosphate (TCEP) in mice accounting for multiple exposure routes.

Exposure routes are important for health risk assessment of chemical risks. The application of physiologically based toxicokinetic (PBTK) models to predict concentrations in vivo can determine the effects of harmful substances and tissue accumulation on the premise of saving experimental costs. In this study, Tri(2-chloroethyl) phosphate (TCEP), an organophosphate ester (OPE), was used as an example to study the PBTK model of mice exposed to different exposure doses by multiple routes. Different routes of exposure (gavage and intradermal injection) can cause differences in the concentration of chemicals in the organs. TCEP that enters the body through the mouth is mainly concentrated in the gastrointestinal tract and liver. However, the concentrations of chemicals that enter the skin into the mice are higher in skin, rest of body, and blood. In addition, TCEP was absorbed and accumulated very rapidly in mice, within half an hour after a single exposure. We have successfully established a mouse PBTK model of the TCEP accounting for multiple exposure Routes and obtained a series of kinetic parameters. The model includes blood, liver, kidney, stomach, intestine, skin, and rest of body compartments. Oral and dermal exposure route was considered for PBTK model. The PBTK model established in this study has a good predictive ability. More than 70% of the predicted values deviated from the measured values by less than 5-fold. In addition, we extrapolated the model to humans. A human PBTK model is built. We performed a health risk assessment for world populations based on human PBTK model. The risk of TCEP in dust is greater through mouth than through skin. The risk of TCEP in food of Chinese population is greater than dust.

Size-dependent vector effect of microplastics on the bioaccumulation of polychlorinated biphenyls in tilapia: A tissue-specific study.

Microplastics play a significant role in interactions between organisms and hydrophobic organic contaminants (HOCs), leading to a joint toxic effect on aquatic organisms. This study extensively investigated the tissue-specific accumulation of polychlorinated biphenyls (PCBs) resulting from different sized microplastics in tilapia (Oreochromis mossambicus) using a passive dosing device. Based on biological feeding behavior considerations, 1 mm and 2 µm polystyrene (PS) microplastics with concentrations of 2 and 5 mg L-1 were investigated. A physiologically based toxicokinetic (PBTK) model was applied to evaluate the exchange kinetics and fluxes among the tissues. Moreover, an in vitro simulation experiment was conducted to theoretically validate the vector effect. The findings demonstrated that the effects caused by HOCs and microplastics on organisms were influenced by multiple factors such as size and surface properties. The mass transfer kinetics of HOCs in specific tissues were closely related to their adsorption capacity and position microplastics could reach. Specifically, although 2 µm microplastics exhibited high adsorption capacity for PCBs, they were only retained in the intestines and did not significantly contribute to the bioaccumulation of PCBs in gills or muscle. While 1 mm microplastics were ingested but just paused in the mouth and subsequently flew through the gills with oral mucus. Their vector effects increased the desorption of microplastic-bound PCB-118 in the gill mucus microcosm, thereby facilitating the mass transfer and accumulation of PCB-118 in gills and muscle. This study sheds new light on how the size-dependent vector generated by microplastics affects the tissue-specific accumulation of HOCs in aquatic organisms.

Relative bioavailability of cadmium in aquatic products and its application on the cadmium exposure risk assessment / 上海预防医学

ObjectiveTo understand the relative bioavailability （RBA） of cadmium in different aquatic products. Based on the consideration of the gender differences and the relative bioavailability of cadmium in different foods， the physiologically based toxicokinetic （PBTK） model of cadmium was further optimized and verified. The correlation between internal and external exposure in quantitative risk assessment of food safety was optimized， and the provisional tolerable daily intake （PTDI） value of cadmium was derived. MethodsThe relative bioavailability of cadmium in different aquatic products was determined in four-week-old Balb/c female mice. The PBTK model of cadmium metabolism was optimized by ABC-MCMC method using combined internal and external exposure data of cadmium in Shanghai residents， and the PTDI was calculated accordingly. ResultsExcept for scallops and squid， the RBA of aquatic samples was less than 1， indicating that the absorption rate of cadmium in aquatic products was lower than that of cadmium chloride. The higher RBA of squid and scallop may be due to the presence of cadmium in the visceral organs， which is conducive to cadmium absorption and its higher concentration of cadmium. Frying at the temperature less than 160 ℃ reduced cadmium absorption but may increase cadmium absorption at the temperature greater than 160 ℃. The optimized model parameters converged well and the model could reasonably estimate urinary cadmium level according to the external exposure of cadmium. The PTDI value was0.466 4 μg·（kg·day）-1 according to the optimized single-chamber model. ConclusionThe relative bioavailability of cadmium in different foods varies greatly， except for squid and scallops， RBA is less than 1， and cooking processing will affect the RBA of food. The construction of the PBTK model did not only consider the effects of gender differences on cadmium metabolism， but also included the relative bioavailability data to optimize and adjust the correlation coefficient of absorption rate. Compared with the model without RBA adjustment， the adjusted model has enhanced the ability to predict urinary cadmium level， which provides a new， more accurate method for the risk assessment of food safety.

Bioconcentration of polycyclic aromatic hydrocarbons in different tissues of zebrafish (Danio rerio) investigated with PBTK model.

Due to the lipophilicity, polycyclic aromatic hydrocarbons (PAHs) are easily accumulated in fish. However, the research on PAH bioaccumulation process in different fish tissues and the relevant effect mechanisms are still deficient. The bioconcentration of PAHs (phenanthrene, anthracene, fluoranthene, and pyrene) in different zebrafish tissues (skin, fish muscle, gill, digestive tract, liver, gonad, and residual) was studied. It was found that there was a difference in the PAH concentrations in different zebrafish tissues. Compared with other tissues, the PAH concentration was highest in the skin and lowest in the fish muscle. For example, the steady-state concentration of phenanthrene in the skin was nearly five times higher than that in the muscle. PAH distribution was related with the lipid contents in different zebrafish tissues; however, the correlation was not significant (p > 0.05), indicating that the lipid content was not the determining factor for the PAH distribution. The distribution was also affected by the bioconcentration kinetics of PAHs in different zebrafish tissues, and the PAH hydrophobic properties. In addition, the physiological based toxicokinetic (PBTK) model showed good performance in predicting PAH internal concentrations, and it may be used to predict the concentrations of PAHs in different fish tissues in future.

Reconstruction of exposure to methylene diphenyl-4,4'-diisocyanate (MDI) aerosol using computational fluid dynamics, physiologically based toxicokinetics and statistical modeling.

OBJECTIVES: This study employed computational fluid dynamics (CFD), physiologically based toxicokinetics (PBTK), and statistical modeling to reconstruct exposure to methylene diphenyl-4,4'-diisocyanate (MDI) aerosol. By utilizing a validated CFD model, human respiratory deposition of MDI aerosol in different workload conditions was investigated, while a PBTK model was calibrated using experimental rat data. Biomonitoring data and Markov Chain Monte Carlo (MCMC) simulation were utilized for exposure assessment. RESULTS: Deposition fraction of MDI in the respiratory tract at the light, moderate, and heavy activity were 0.038, 0.079, and 0.153, respectively. Converged MCMC results as the posterior means and prior values were obtained for several PBTK model parameters. In our study, we calibrated a rat model to investigate the transport, absorption, and elimination of 4,4'-MDI via inhalation exposure. The calibration process successfully captured experimental data in the lungs, liver, blood, and kidneys, allowing for a reasonable representation of MDI distribution within the rat model. Our calibrated model also represents MDI dynamics in the bloodstream, facilitating the assessment of bioavailability. For human exposure, we validated the model for recent and long-term MDI exposure using data from relevant studies. CONCLUSION: Our computational models provide reasonable insights into MDI exposure, contributing to informed risk assessment and the development of effective exposure reduction strategies.

The Application of a Physiologically Based Toxicokinetic Model in Health Risk Assessment.

Toxicokinetics plays a crucial role in the health risk assessments of xenobiotics. Classical compartmental models are limited in their ability to determine chemical concentrations in specific organs or tissues, particularly target organs or tissues, and their limited interspecific and exposure route extrapolation hinders satisfactory health risk assessment. In contrast, physiologically based toxicokinetic (PBTK) models quantitatively describe the absorption, distribution, metabolism, and excretion of chemicals across various exposure routes and doses in organisms, establishing correlations with toxic effects. Consequently, PBTK models serve as potent tools for extrapolation and provide a theoretical foundation for health risk assessment and management. This review outlines the construction and application of PBTK models in health risk assessment while analyzing their limitations and future perspectives.

Extending Regulatory Biokinetic Lead Models towards Food Safety: Evaluation of Consumer Baby Food Contribution to Infant Blood Lead Levels and Variability.

The U.S. Food and Drug Administration released proposed lead (Pb) action levels for foods intended for babies and young children in January 2023 based on the agency's interim reference value of 2.2 µg/day for dietary Pb. Since the 1980s, biokinetic models have estimated blood lead levels (BLLs) associated with environmental contamination, but their use in food safety assessment has been limited. We compared three recent biokinetic models (IEUBK Model, ICRP Model Version 5, and AALM) to develop insights on contributors to variability in potential exposures to Pb in consumer baby food products. While modest variation was observed for babies, the predictions trended to convergence for children aged 3 and older, approaching the U.S. FDA dietary conversion factor of 0.16 µg Pb/dL blood per µg Pb intake/day. We applied the IEUBK model in a probabilistic exposure assessment framework characterizing the distribution of Pb in soil, dust, water, and food intake in the United States. Soil and dust were the primary contributors to variance in infant BLLs, while food and water contributed <15% combined. Thus, reductions in upper-bound soil and dust concentrations will be necessary before achieving appreciable reductions in the frequency of BLLs greater than the BLRV of 3.5 µg/dL.

Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans.

Perfluorooctanoic acid (PFOA) is an environmental toxicant exhibiting a years-long biological half-life (t1/2) in humans and is linked with adverse health effects. However, limited understanding of its toxicokinetics (TK) has obstructed the necessary risk assessment. Here, we constructed the first middle-out physiologically based toxicokinetic (PBTK) model to mechanistically explain the persistence of PFOA in humans. In vitro transporter kinetics were thoroughly characterized and scaled up to in vivo clearances using quantitative proteomics-based in vitro-to-in vivo extrapolation. These data and physicochemical parameters of PFOA were used to parameterize our model. We uncovered a novel uptake transporter for PFOA, highly likely to be monocarboxylate transporter 1 which is ubiquitously expressed in body tissues and may mediate broad tissue penetration. Our model was able to recapitulate clinical data from a phase I dose-escalation trial and divergent half-lives from clinical trial and biomonitoring studies. Simulations and sensitivity analyses confirmed the importance of renal transporters in driving extensive PFOA reabsorption, reducing its clearance and augmenting its t1/2. Crucially, the inclusion of a hypothetical, saturable renal basolateral efflux transporter provided the first unified explanation for the divergent t1/2 of PFOA reported in clinical (116 days) versus biomonitoring studies (1.3-3.9 years). Efforts are underway to build PBTK models for other perfluoroalkyl substances using similar workflows to assess their TK profiles and facilitate risk assessments.

Transfer and toxicokinetic modeling of non-dioxin-like polychlorinated biphenyls (ndl-PCBs) into accidentally exposed dairy cattle and their calves - A case report.

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that accumulate in tissues of exposed animals and humans. This case report refers ton=3 dairy cows accidentally exposed to non-dioxin-like PCBs (ndl-PCBs) of unknown origin on a German farm. At study start they had a cumulative total of 122-643 ng/g fat in milk and 105-591 ng/g fat in blood, consisting mainly of PCBs 138, 153, and 180. Two cows calved during the study and their calves were raised on their mothers' milk, resulting in cumulative exposure until slaughter. A physiologically based toxicokinetic model was developed to describe the fate of ndl-PCBs in the animals. The toxicokinetic behavior of ndl-PCBs was simulated in individual animals, including transfer of contaminants into calves via milk and placenta. Both the simulations and experimental data indicate that contamination via both routes is significant. In addition, the model was used to estimate kinetic parameters for risk assessment.

PBTK modeled perfluoroalkyl acid kinetics in zebrafish eleutheroembryos suggests impacts on bioconcentrations by chorion porosity dynamics.

The zebrafish eleutheroembryo (zfe) is widely used as a model to characterize the toxicity of chemicals. However, analytical methods are still missing to measure organ concentrations. Therefore, physiologically-based toxicokinetic (PBTK) modeling may overcome current limitations to help understand the relationship between toxic effects and internal exposure in various organs. A previous PBTK model has been updated to include the chorionic transport barrier and its permeabilization, hatching dynamics within a zfe population over development, and active mediated transport mechanisms. The zfe PBTK model has been calibrated using measured time-dependent internal concentrations of PFBA, PFHxS, PFOA, and PFOS in a zfe population and evaluated using external datasets from the literature. Calibration was successful with 96% of the predictions falling within a 2-fold range of the observed concentrations. The external dataset was correctly estimated with about 50% of the predictions falling within a factor of 3 of the observed data and 10% of the predictions are out of the 10-fold error. The calibrated model suggested that active mediated transport differs between PFAS with a sulfonic and carboxylic acid functional end groups. This PBTK model predicts well the fate of PFAS with various physicochemical properties in zfe. Therefore, this model may improve the use of zfe as an alternative model in toxicokinetic-toxicodynamic studies and help to refine and reduce zfe-based experiments, while giving insights into the internal kinetics of chemicals.

Estimation of the bio-accessibility of methylmercury from aquatic foods using a PBTK model with an approximate Bayesian computation method in Chinese pregnant women.

BACKGROUND: Fish are the primary source of protein and docosahexaenoic acid (DHA) for pregnant women and children, but methylmercury (MeHg) pollution is the potential hazard of fish consumption. In risk assessments, the bio-accessibility of MeHg is usually assumed to be 100%, which could lead to overestimation of dietary exposure. METHOD: An existing PBTK model was adapted to estimate parameters of the bio-accessibility based on MeHg exposure data from a cohort of 397 Chinese pregnant women. The posterior distributions of parameters were determined by using the ABC - MCMC. RMSEP and Spearman's rank correlation coefficients (Rho) were calculated to determine the goodness of model fitting. The Monte Carlo analysis was performed for the parameter distributions to estimate the model variability. RESULT: The median of daily MeHg intake and maternal MeHg levels were 0.018 µg/kg bw and 3.01 µg/kg in the early and middle terms of pregnancy. The estimated bio-accessibility of freshwater fish, marine fish and others were 46.1, 17.3 and 58.2%, separately. The RMSEP improved from 11.18 to 2.54 and the Rho improved from 0.19 to 0.22 after bio-accessibility optimization. The model variability was estimated to be 2.6. CONCLUSION: The bio-accessibility estimated in this study was comparable to that determined in previous in vitro studies. The optimized model could improve the prediction performance on the MeHg body burden by dietary exposure.

The toxicokinetics of bisphenol A and its metabolites in fish elucidated by a PBTK model.

Bisphenol A (BPA) is a chemical of major concern due to its endocrine disrupting function, high production volume, and persistence in the aquatic environment. Consequently, organisms such as fish are subject to chronic exposure to BPA. However, physiologically-based toxicokinetic (PBTK) models, which are valuable tools to improve the understanding of a chemical's fate in an organism, have never been specifically adapted to model BPA toxicokinetics (TK) in fish. In our work, an existing PBTK developed for four different fish species was modified to model BPA ADME processes (absorption, distribution, metabolization and excretion). The metabolization of BPA into BPA-monoglucuronide (BPA gluc) and BPA-monosulfate (BPA sulf) and their TK in various organs was taking into account in the model. Experiments were performed to generate BPA TK data in a model species commonly used in ecotoxicology, the stickleback. The model structure had to include two sites of metabolization to simulate BPA TK accurately in stickleback organs. Thus, the fish liver may not be the only site of the metabolization of BPA: plasma or gills could also play a role in BPA metabolization. The PBTK model predictive performance evaluated on literature data in zebrafish and rainbow trout concurs with this conclusion. Finally, a calibration mixing data from the three species was compared to the calibration on stickleback data only.

Mapping blood lead levels in French children due to environmental contamination using a modeling approach.

The decrease in levels of lead in air and drinking water over the last 40 years has resulted in an overall decrease in blood lead levels (BLLs). However, there is no known safe level of lead regarding developmental effects in children. This paper maps predicted BLLs of children in France, resulting from a simulated chronic exposure in two steps, with the aim of identifying areas with environmentally overexposed populations. Probabilistic estimates of BLLs based on environmental contamination were obtained and compared to biomonitoring data. First, the contribution of various environmental exposure pathways was estimated using a multimedia exposure model: spatialized data on soil, drinking water and air contamination, together with data on food contamination and ingestion, was joined using geostatistical approaches. In a second step, a Physiologically Based Toxicokinetic (PBTK) model provided estimates of BLLs. Probabilistic estimates of BLLs were obtained by simulating uncertainty and variability of exposure levels, physiological characteristics and lead-specific parameters in the PBTK model. The median and 95th percentile of predicted BLLs in children aged 1 to 11 were compared to recent biomonitoring data obtained in France in young children (SATURNINF study): median predictions were overestimated in infants and in agreement with median observed BLLs in children aged 3 to 6. Upper bounds of predicted BLLs were protective due to uncertainties in exposure estimates. The main source of exposure appeared to be drinking water in children over 2 years old, and vegetal food and milk in children under 2 years old. Although elevated drinking water lead levels were not related to large geographical areas, the relatively fine resolution map also pinpointed geographical areas of concern due to elevated soil lead levels.

A Novel Multispecies Toxicokinetic Modeling Approach in Support of Chemical Risk Assessment.

Standardized laboratory tests with a limited number of model species are a key component of chemical risk assessments. These surrogate species cannot represent the entire diversity of native species, but there are practical and ethical objections against testing chemicals in a large variety of species. In previous research, we have developed a multispecies toxicokinetic model to extrapolate chemical bioconcentration across species by combining single-species physiologically based toxicokinetic (PBTK) models. This "top-down" approach was limited, however, by the availability of fully parameterized single-species models. Here, we present a "bottom-up" multispecies PBTK model based on available data from 69 freshwater fishes found in Canada. Monte Carlo-like simulations were performed using statistical distributions of model parameters derived from these data to predict steady-state bioconcentration factors (BCFs) for a set of well-studied chemicals. The distributions of predicted BCFs for 1,4-dichlorobenzene and dichlorodiphenyltrichloroethane largely overlapped those of empirical data, although a tendency existed toward overestimation of measured values. When expressed as means, predicted BCFs for 26 of 34 chemicals (82%) deviated by less than 10-fold from measured data, indicating an accuracy similar to that of previously published single-species models. This new model potentially enables more environmentally relevant predictions of bioconcentration in support of chemical risk assessments.

PBPK Modeling of Slightly Soluble Silver Nanomaterials and Regulatory Acceptance.

International efforts to promote predictive toxicology incorporate some form of modeling based on the regularities, insights, and hypotheses gained from analyzing laboratory studies compiled in databases. While there has been a broad commentary on definitions, metadata, and test methodologies, all necessary to establishing data repositories, there has been less on translating the resulting insights into computational models. The recent use of a computational model to support a recommended exposure limit for nanoparticulate silver is an opportunity to examine physiologically based toxicokinetics in terms of data availability, model verification and validation, and regulatory acceptance. The resulting suggestions align with findings from the EU-US Roadmap Nanoinformatics 2030 and the 2018 acceptance of a computational model by the European Food Safety Authority.

A generic PBTK model implemented in the MCRA platform: Predictive performance and uses in risk assessment of chemicals.

Physiologically-based toxicokinetic (PBTK) models are important tools for in vitro to in vivo or inter-species extrapolations in health risk assessment of foodborne and non-foodborne chemicals. Here we present a generic PBTK model implemented in the EuroMix toolbox, MCRA 9 and predict internal kinetics of nine chemicals (three endocrine disrupters, three liver steatosis inducers, and three developmental toxicants), in data-rich and data-poor conditions, when increasingly complex levels of parametrization are applied. At the first stage, only QSAR models were used to determine substance-specific parameters, then some parameter values were refined by estimates from substance-specific or high-throughput in vitro experiments. At the last stage, elimination or absorption parameters were calibrated based on available in vivo kinetic data. The results illustrate that parametrization plays a capital role in the output of the PBTK model, as it can change how chemicals are prioritized based on internal concentration factors. In data-poor situations, estimates can be far from observed values. In many cases of chronic exposure, the PBTK model can be summarized by an external to internal dose factor, and interspecies concentration factors can be used to perform interspecies extrapolation. We finally discuss the implementation and use of the model in the MCRA risk assessment platform.

Physiologically based toxicokinetic models and in silico predicted partition coefficients to estimate tetrachlorodibenzo-p-dioxin transfer from feed into growing pigs.

Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous, toxic, persistent and bioaccumulative organic pollutant. TCDD can potentially enter the food chain through contaminated food of animal origin as a consequence of feed contamination. Prediction of the TCDD transfer from feed into animal products is thus important for human health risk assessment. Here, we develop several physiologically based toxicokinetic (PBTK) models of TCDD transfer from contaminated feed into growing pigs (Sus scrofa) exposed to doses ranging from 24.52 to 3269.25 ng of TCDD. We test the consequences of explicit dose-dependent absorption (DDA) versus the indirect effects of a self-induced liver metabolism (SIM). The DDA and SIM models showed similar fit to experimental data, although currently it is not possible to unequivocally make statement on a mechanistic preference. The performance of both toxicokinetic models was successfully evaluated using the 1999 Belgian case of contaminated fats for feeding. In combination with toxicokinetic models of other dioxin congeners, they can be used to formulate maximum allowance levels of dioxins in feedstuffs for pigs. Additionally, the implementation of in silico-predicted partition coefficients was explored as a useful alternative to predict TCDD tissue distribution in low-dose scenarios without recurring to animal experiments.

Investigating the interaction between melamine and cyanuric acid using a Physiologically-Based Toxicokinetic model in rainbow trout.

Following outbreaks of feed and food adulterations with a melamine and cyanuric acid mixture in 2007 and melamine in 2008 respectively, the kinetics and toxicodynamics of the mixture have been investigated particularly in sensitive species such as the rainbow trout. Tissue concentrations and intensity of the adverse effect, melamine-cyanurate crystal formation in kidney, were reported in similar experimental conditions. Here, a recent PBTK model for rainbow trout has been applied to model the kinetics of both single compounds based on residue levels in tissues. Both PBTK models for the single compounds were combined and a model of crystal formation for the mixture melamine-cyanuric acid was also added to predict the intensity of crystal formation under the assumptions that crystals formed either in urine or in kidney tissue. Modelling the kinetics of melamine and cyanuric acid provided a better understanding and prediction of intensity of crystal formation in case of sequential exposures with varying intensity or co-exposure. This study demonstrates, for the first time, how fish PBTK models can play a key role in the understanding and prediction of toxicokinetics and toxicodynamics of mixtures. This study also illustrates how adverse effects may potentially occur even when the compounds are not administered together as a mixture.