Toxicokinetic Model Research Articles

A workflow to build PBTK models for novel species

Physiology-based pharmacokinetic and toxicokinetic (PBPK/TK) models allow us to simulate the concentration of xenobiotica in the plasma and different tissues of an organism. PBPK/TK models are therefore routinely used in many fields of life sciences to simulate the physiological concentration of exogenous compounds in plasma and tissues. The application of PBTK models in ecotoxicology, however, is currently hampered by the limited availability of models for focal species. Here, we present a best practice workflow that describes how to build PBTK models for novel species. To this end, we extrapolated eight previously established rabbit models for several drugs to six additional mammalian species (human, beagle, rat, monkey, mouse, and minipig). We used established PBTK models for these species to account for the species-specific physiology. The parameter sensitivity in the resulting 56 PBTK models was systematically assessed to rank the relevance of the parameters on overall model performance. Interestingly, more than 80% of the 609 considered model parameters showed a negligible sensitivity throughout all models. Only approximately 5% of all parameters had a high sensitivity in at least one of the PBTK models. This approach allowed us to rank the relevance of the various parameters on overall model performance. We used this information to formulate a best practice guideline for the efficient development of PBTK models for novel animal species. We believe that the workflow proposed in this study will significantly support the development of PBTK models for new animal species in the future.

Estimating human exposure to pyrethroids’ mixtures from biomonitoring data using physiologically based pharmacokinetic modeling

Human biomonitoring data provide evidence to exposure of environmental chemicals. Physiologically based pharmacokinetic (PBPK) modelling together with an adequate exposure scenario allows to transpose measured concentrations of chemicals or their metabolites into exposure levels, as daily intakes. In France, high levels of urinary pyrethroids metabolites have been measured in populations. Our work aims at estimating the exposure of the French ENNS cohort to mixtures of four pyrethroids (deltamethrin, permethrin, cypermethrin, and cyfluthrin) from the urinary concentrations of five pyrethroids' metabolites commonly measured in biomonitoring studies. We developed a modelling approach based on a global toxicokinetic model that accounts for the cumulative exposure to pyrethroids as some of the metabolites can be shared by several parent compounds and for human inter-individual variability in metabolism. The median of the individual daily intakes was estimated to 8.1 ng/kg bw/day for permethrin, 17.7 ng/kg bw/day for cypermethrin, 20.4 ng/kg bw/day for cyfluthrin and 34.3 ng/kg bw/day for deltamethrin leading to similar weights for the pair permethrin and cypermethrin (36%), cyfluthrin (31%) and deltamethrin (33%) to the cumulative exposure. Accounting for human variability enabled to explain some of the variations in the metabolites' levels within the cohort. The cumulative exposure was then weighted by their toxicities towards three neurotoxic effects to calculate margins of exposure (MOE). Low MOE values were always associated with high measured concentrations of metabolites in urine and the lowest MOEs were observed for the autonomic division. No risks associated with reconstructed mixtures of pyrethroids were expected for the ENNS cohort. Our approach is an asset to analyse the biomarkers of exposure to pyrethroids simultaneously and could be easily adapted to any local or national specificities in pyrethroids’ exposure or populations.

Tutorial: Understanding the transport, deposition, and translocation of particles in human respiratory systems using Computational Fluid-Particle Dynamics and Physiologically Based Toxicokinetic models

Dynamic modeling of how particulate matter (PM) transport, deposit, and translocate from human respiratory systems to systemic regions subject to indoor and outdoor exposures are essential for case-specific lung dosimetry predictions and occupational health risk assessments. Because of the invasive nature and imaging resolution limitations of existing in vitro and in vivo methods, Computational Fluid-Particle Dynamics plus Physiologically Based Pharmacokinetic/Toxicokinetic (CFPD-PBPK/TK) models have been employed to predict the fate of the respirable aerosols for decades. This paper presents a guide on how to use the multiscale CFPD-PBPK/TK models to predict lung dosimetry and systemic translocations quantitatively with 3D subject-specific human respiratory systems. The tutorial aims to clarify possibly ambiguous concepts. The step-by-step modeling procedure should help researchers set up the CFPD-PBPK/TK model accurately, following the standard model validation and verification (V&V) processes, and to bring the lung dosimetry predictions to health endpoints. Starting from the fundamentals of CFPD and PBPK/TK governing equations, the tutorial covers the problem identification, pre-processing, solving, and post-processing steps to perform a computational lung aerosol dynamics simulations, emphasizing on (a) the importance of correct reconstruction and mesh generation of the pulmonary airways; (b) the significance of choosing the appropriate turbulence model to predict the laminar-to-turbulence pulmonary airflow regimes; and (c) the standard (V&V) procedures of submodels in the CFPD-PBPK/TK modeling framework. The tutorial also highlights the deficiencies of current CFPD-PBPK/TK models, clarifies the missing biomechanisms and aerosol dynamics in the respiratory systems that need to be considered to build the next-generation virtual human whole-lung models.

Bioaccumulation, Biotransformation, and Multicompartmental Toxicokinetic Model of Antibiotics in Sea Cucumber (Apostichopus japonicus).

Extensive application of antibiotics leads to their ubiquitous occurrence in coastal aquatic environments. However, it remains largely unknown whether antibiotics can be bioaccumulated and biotransformed in major mariculture organisms such as sea cucumbers and toxicokinetic models for Echinodermata are lacking. In this study, laboratory exposure experiments on juvenile sea cucumber (Apostichopus japonicus) were performed for seven antibiotics (sulfadiazine, sulfamethoxazole, trimethoprim, enrofloxacin, ofloxacin, clarithromycin, and azithromycin). Field sea cucumber and surrounding seawater samples were also analyzed. Results show that the sea cucumbers tend to accumulate high concentrations of the antibiotics with kinetic bioconcentration factors (BCFs) up to 1719.7 L·kg-1 for ofloxacin. The BCFs determined in the laboratory agree well with those estimated from the field measurements. Seven biotransformation products (BTPs) of the antibiotics were identified, four of which were not reported previously in aquatic organisms. The BTPs were mainly found in the digestive tract, indicating its high capacity in the biotransformation. A multicompartmental toxicokinetic model based on the principles of passive diffusion was developed, which can successfully predict time-course concentrations of the antibiotics in different compartments of the juvenile sea cucumbers. The findings may offer a scientific basis for assessing health risks and guiding healthy mariculture of sea cucumbers.

In vitro-in vivo and cross-life stage extrapolation of uptake and biotransformation of benzo[a]pyrene in the fathead minnow (Pimephales promelas)

Understanding internal dose metrics is integral to adequately assess effects environmental contaminants might have on aquatic wildlife, including fish. In silico toxicokinetic (TK) models are a leading approach for quantifying internal exposure metrics for fishes; however, they often do not adequately consider chemicals that are actively biotransformed and have not been validated against early-life stages (ELS) that are often considered the most sensitive to the exposure to contaminants. To address these uncertainties, TK models were parameterized for the rapidly biotransformed chemical benzo[a]pyrene (B[a]P) in embryo-larval and adult life stages of fathead minnows. Biotransformation of B[a]P was determined through measurements of in vitro clearance. Using in vitro-in vivo extrapolation, in vitro clearance was integrated into a multi-compartment TK model for adult fish and a one-compartment model for ELS. Model predictions were validated using measurements of B[a]P metabolites from in vivo flow-through exposures to graded concentrations of water-borne B[a]P. Significantly greater amounts of B[a]P metabolites were observed with exposure to greater concentrations of parent compound in both life stages. However, when assessing biotransformation capacity, no differences in phase I or phase II biotransformation were observed with greater exposures to B[a]P. Results of modelling suggested that biotransformation of B[a]P can be successfully implemented into in silico models to accurately predict life stage-specific abundances of B[a]P metabolites in either whole-body larvae or the bile of adult fish. Models developed increase the scope of applications in which TK models can be used to support environmental risk assessments.

Dietary bioaccumulation of persistent organic pollutants in the common sole Solea solea in the context of global change. Part 1: Revisiting parameterisation and calibration of a DEB model to consider inter-individual variability in experimental and natural conditions.

Studying adverse effects of chemical pressure on aquatic ecosystems needs a comprehensive knowledge of bioaccumulation mechanisms of pollutants in biota to predict internal concentrations, especially for Persistent Organic Pollutants (POPs). However, the large variability of responses in measured POP concentrations requires explicit consideration of both individual variability and environmental influences. Dynamic Energy Budget (DEB) theory provides a rigorous and generic conceptual framework for tackling these questions in a relevant mechanistic way. In the present study, parameterisation and calibration of previous DEB models for Solea solea were revisited in order to accurately represent the full life cycle with an original emphasis on larval stage, metamorphosis, reproduction rules and sexual differences. We first improved calibration thanks to the use of the estimation procedure developed by the DEB network coupled with a broad compilation of data from literature. Then, we validated this set of parameter estimates on independent datasets of i) individual monitoring of larval growth in controlled food conditions from a novel experiment, and ii) juvenile and adult growth, and female fecundity, from a natural population. Finally, we combined the DEB model developed in the present paper with we used a simple toxicokinetic (TK) model from literature. This TK model was also combined to a previous DEB model and was used to reproduce the mean trajectories of a growth and contamination dataset. We applied the same TK model with our DEB model considering inter-individual variability in food availability. This application highlighted the need to accurately consider inter-individual variability in ingestion to correctly estimate growth and contamination variability. The present work is the first step in the development of a mechanistic TK model that will be used in a companion paper for investigations of juvenile sole sensitivity to warming, nursery quality and prey contamination, in highly fluctuating estuarine environments.

Impact of dietary guidelines on lifetime exposure to chemical contaminants: Divergent conclusions for two bioaccumulative substances

Food based dietary guidelines (FBDGs) are developed to promote appropriate nutrients intake. However, FBDGs may trigger higher exposure to some food chemical contaminants while recommending the consumption of specific food groups that are more contaminated than others. In some cases, the balance between benefits and risks is difficult to achieve.In the present article, we describe the long-term impact of some FBDGs on the exposure to food contaminants. Two examples of bioaccumulative substances were studied: cadmium and PCBs. To this aim, lifetime dietary exposure trajectories were simulated for two populations: the first representing the general French population, the second generated using virtual individuals following national FBDGs during their entire life. Exposure trajectories were then converted into lifetime cadmium and PCB internal concentrations using physiologically based toxicokinetic models. Finally, trajectories were compared with reference values to assess the health risk related to dietary exposures to cadmium and PCBs, for both simulated populations.This work highlights that FBDGs may have a major impact on PCB dietary exposures and lead to significantly higher PCB plasma concentrations than those observed in the general population. In contrast, cadmium exposure is only slightly impacted when FBDGs are followed. This underscores the relevance of taking into account lifetime exposures when establishing FBDGs.

Dietary bioaccumulation of persistent organic pollutants in the common sole Solea solea in the context of global change. Part 2: Sensitivity of juvenile growth and contamination to toxicokinetic parameters uncertainty and environmental conditions variability in estuaries

The amount of potentially toxic chemicals in a fish depends on various environmental factors, such as temperature and feeding ecology, which can be affected by Global Changes (GC). The main objective of the present work was to study the relative influence of temperature, food quality and food availability on the growth and contamination of juveniles of common sole (Solea solea), a marine flatfish species known to be a relevant indicator of the nursery quality. It focuses on two Persistent Organic Pollutants (CB153 and L-PFOS) of legacy and emerging concern, respectively. To achieve this, we used a toxicokinetic (TK) model in which toxicant flows are mechanistically predicted using a bioenergetic model based on the Dynamic Energy Budget (DEB) theory. This modelling framework was applied to juvenile sole from the Gironde estuary (SW France) and allows accounting for the influence of environmental conditions on fish biological processes involved in toxicant fluxes. To compare their respective influence on model predictions of age, length, and contamination at puberty, we included in a global sensitivity analysis: (1) environmental variability gathered from literature for this particular estuary and (2) TK parameters (i.e. assimilation efficiency AE and elimination rate k˙e) variability and uncertainty gathered from literature about each contaminant but for different fish species and experimental conditions. Then, model predictions were confronted to fish contamination measurements from the Gironde Estuary with different combinations of TK parameter values from literature. Results highlighted a key role of diet composition on fish contamination and growth while water temperature only affected growth. It stressed the need to focus on GC impact on benthic communities and their consequences on juvenile fish diet for future work on GC scenarios. Furthermore, for both chemical, the range of variability of TK parameters from experiments led to underestimated fish contaminations. The best model fits were obtained using TK parameter values from model applications: from Mounier et al. (n.d.) for CB153 (Solea solea, experiment, AE=0.8 and k˙e=0 d−1) and from de Vos et al. (2008) for PFOS (food chain of the Western Scheldt estuary, The Netherlands, AE=0.8 and k˙e=0.8 10−2.d−1).

Transfer kinetics of fipronil into chicken (Gallus gallus domesticus) eggs

In 2017–2018, a fipronil contamination occurred in the European chicken egg supply chain due to its illegal use as insecticide to control red lice infestations. Fipronil has the potential to be transferred into eggs of laying hens, thereby entering the food chain. Here, we present a toxicokinetic model to predict the transfer of fipronil in laying hens as a tool for risk assessors and managers. Data from two studies documenting fipronil transfer to eggs were used as a basis to model its kinetic properties. We obtained estimates for fundamental kinetic parameters: the fraction of absorbed fipronil available for transfer 0.44 (CI95 0.41–0.50), the excretion into eggs half-life 11.3 d (CI95 9.9–13.8 d) and the delay of excretion after oral intake. We also calculated the transfer factor at steady state. The parametrized model was evaluated against an independent dataset, showing good correspondence upon visual inspection. The model can be of use in risk assessment and management of fipronil contamination events (repeated exposure) in the egg supply chain and as a starting point for more complex models, i.e. multiple compartments models, which could take in consideration the dynamics of egg-laying.

A Simple Toxicokinetic Model Exhibiting Complex Dynamics and Nonlinear Exposure Response.

Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose-dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low-dose exposure response in chronic exposure. A simple one-compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up- or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.

Toxicokinetic Studies in Piglets Reveal Age-Related Differences in Systemic Exposure to Zearalenone, Zearalenone-14-Glucoside, and Zearalenone-14-Sulfate.

Juveniles are considered as one of the most vulnerable population groups concerning mycotoxins and their modified forms. The weaning stage is a particularly vulnerable period in the life of mammals, reflected in intestinal and immune dysfunction. The current study investigated the toxicokinetic (TK) characteristics of zearalenone (ZEN), zearalenone-14-glucoside (ZEN14G), and zearalenone-14-sulfate (ZEN14S) in weaned (4-week-old) piglets, by means of oral and intravenous administration of equimolar doses, i.e., 331, 500, and 415 μg/kg bodyweight, respectively. Plasma and urine were sampled pre- and post-administration and were quantitatively analyzed for ZEN, ZEN14G, ZEN14S, and in vivo metabolites by liquid chromatography-high-resolution mass spectrometry. Tailor-made TK models were elaborated to process data. A statistical comparison of the results was performed with TK data obtained in a previously reported study in pigs of 8 weeks of age. Additionally, porcine plasma protein binding was determined to support TK findings. The TK results for ZEN, ZEN14G, and ZEN14S, obtained in 4- and 8-week-old pigs, revealed significant age-related differences, based on differences in intestinal permeability, body fat content, gastrointestinal transit time, and biotransformation, with a special emphasis on an increased absorbed fraction of ZEN14G, i.e., 94 vs 61% in 4- compared to 8-week-old pigs. Since the growing pig has been reported to be a suitable pediatric animal model for humans concerning TK processes, these results may contribute to refine the risk assessment concerning modified ZEN forms in juvenile animals and humans.

Toxicokinetics of Hydrolyzed Fumonisin B1 after Single Oral or Intravenous Bolus to Broiler Chickens Fed a Control or a Fumonisins-Contaminated Diet

The toxicokinetics (TK) of hydrolyzed fumonisin B1 (HFB1) were evaluated in 16 broiler chickens after being fed either a control or a fumonisins-contaminated diet (10.8 mg fumonisin B1, 3.3 mg B2 and 1.5 mg B3/kg feed) for two weeks, followed by a single oral (PO) or intravenous (IV) dose of 1.25 mg/kg bodyweight (BW) of HFB1. Fumonisin B1 (FB1), its partially hydrolyzed metabolites pHFB1a and pHFB1b, and fully hydrolyzed metabolite HFB1, were determined in chicken plasma using a validated ultra-performance liquid chromatography–tandem mass spectrometry method. None of the broiler chicken showed clinical symptoms of fumonisins (FBs) or HFB1 toxicity during the trial, nor was an aberration in body weight observed between the animals fed the FBs-contaminated diet and those fed the control diet. HFB1 was shown to follow a two-compartmental pharmacokinetic model with first order elimination in broiler chickens after IV administration. Toxicokinetic parameters of HFB1 demonstrated a total body clearance of 16.39 L/kg·h and an intercompartmental flow of 8.34 L/kg·h. Low levels of FB1 and traces of pHFB1b were found in plasma of chickens fed the FBs-contaminated diet. Due to plasma concentrations being under the limit of quantification (LOQ) after oral administration of HFB1, no toxicokinetic modelling could be performed in broiler chickens after oral administration of HFB1. Moreover, no phase II metabolites, nor N-acyl-metabolites of HFB1 could be detected in this study.

Development and evaluation of a high throughput inhalation model for organic chemicals.

Currently it is difficult to prospectively estimate human toxicokinetics (particularly for novel chemicals) in a high-throughput manner. The R software package httk has been developed, in part, to address this deficiency, and the aim of this investigation was to develop a generalized inhalation model for httk. The structure of the inhalation model was developed from two previously published physiologically-based models from Jongeneelen et al. (2011) and Clewell et al. (2001) while calculated physicochemical data was obtained from EPA’s CompTox Chemicals Dashboard. In total, 142 exposure scenarios across 41 volatile organic chemicals were modeled and compared to published data. The slope of the regression line of best fit between log-transformed simulated and observed combined measured plasma and blood concentrations was 0.46 with an r2= 0.45 and a Root Mean Square Error (RMSE) of direct comparison between the log-transformed simulated and observed values of 1.11.. Approximately 5.1% (n = 108) of the data points analyzed were > 2 orders of magnitude different than expected. The volatile organic chemicals examined in this investigation represent small, generally lipophilic molecules. Ultimately this paper details a generalized inhalation component that integrates with the httk physiologically-based toxicokinetic model to provide high-throughput estimates of inhalation chemical exposures.

Predicting copper toxicity in zebrafish larvae under complex water chemistry conditions by using a toxicokinetic–toxicodynamic model

Multiple water chemistry parameters influence metal toxicity in natural waters and accurate quantification of those influences may accelerate the development of site-specific water quality criteria (WQC) and further execute metal risk assessment for better protection of aquatic biota. Here, we investigated the effects of water chemistry parameters on copper (Cu) toxicity of larval zebrafish (Danio rerio) and then incorporated the effects of key parameters in a Toxicokinetic and Toxicodynamic (TK-TD) model. Further, the proposed TK-TD model was used to predict Cu toxicity in laboratory artificial waters as well as natural water samples. The predictive performance of the TK-TD model was evaluated in comparison to the biotic ligand model (BLM). The results showed that increasing Ca, Mg, pH, and fulvic acid (FA) levels significantly mitigated Cu toxicity in larvae, while K and Na levels had no significant effect on Cu toxicity. A predictive TK-TD model based on these data described 91 % of Cu accumulation and 87 % of survival of larvae exposed to Cu under 0, 2.5, 5, 10 mg/L FA. Compared with BLM, TK-TD model predicted better Cu accumulation and toxicity for an independent dataset in low DOC concentration (<10.95 mg L−1) of 9 sites in Haihe river (Tianjin, China) media during 96 h exposure. The BLM under-predicted the acute Cu toxicity to larvae when compared with observed values. In high DOC concentration (13.12–17.78 mg L−1) among three field sites, BLM and TK-TD model both under-predicted the acute Cu toxicity to larvae when compared with observed values. Our research provides a TK-TD approach for predicting Cu toxicity under complex water chemistry conditions and deriving Cu-WQC in different scenarios where there exist limits for using the BLM.

Temperature effect on perfluorooctane sulfonate toxicokinetics in rainbow trout (Oncorhynchus mykiss): Exploration via a physiologically based toxicokinetic model

Salmonids are poikilotherms, which means that their internal temperature varies with that of water. Water temperature thus controls many of their lifecycle processes and physiological functions, which could influence the mechanisms of absorption, distribution, metabolism and excretion (ADME) of many substances, including perfluorinated alkyl acids (PFAAs). However, the processes governing the fate of PFAAs are still poorly understood in fish. Here we developed a physiologically-based toxicokinetic (PBTK) model for rainbow trout (Oncorhynchus mykiss) to study changes in physiological functions and PFAA ADME at different temperatures. The model was calibrated using experimental data from dietary exposure to perfluorooctane sulfonate at 7 °C and 19 °C. Predictions of PFOS concentrations were globally satisfactory at both temperatures, when accounting for the influence of temperature on growth, ventilation rate, cardiac output, clearances, and absorption rates. Accounting for the influence of temperature on tissue–plasma partition coefficients significantly improved predicted in-organ PFOS concentrations.

High inter-species differences of 12378-polychlorinated dibenzo-p-dioxin between humans and mice

Although huge interspecies differences in the response to dioxins have been acknowledged, toxic equivalency factors derived from rodent studies are often used to assess human health risk. To determine interspecies differences, we first developed a toxicokinetic model in humans by measuring dioxin concentrations in environmental and biomonitoring samples from Southern China. Significant positive correlations between dioxin concentrations in blood and age were observed for seven dioxin congeners, indicating an age-dependent elimination rate. Based on toxicokinetic models in humans, the half-lives of 15 dioxin congeners were estimated to be 1.60–28.55 years. In consideration that the highest contribution to total toxic equivalency in blood samples was by 12378-polychlorinated dibenzo-p-dioxin (P5CDD), this study developed a physiologically based pharmacokinetic (PBPK) model of 12378-P5CDD levels in the liver, kidney, and fat of C57/6J mice exposed to a single oral dose, and the half-life was estimated to be 26.1 days. Based on estimated half-lives in humans and mice, we determined that the interspecies difference of 12378-P5CDD was 71, much higher than the default usually used in risk assessment. These results could reduce the uncertainty human risk assessment of 12378-P5CDD, and our approach could be used to estimate the interspecies differences of other dioxin congeners.

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.

Cancer risk and disease burden of dietary cadmium exposure changes in Shanghai residents from 1988 to 2018

Cadmium (Cd) is a widely distributed toxic metal, which is mainly exposed to humans through diet. The impact of dietary guidelines on the Chinese diet structure has indirectly led to changes in dietary Cd exposure. The Chinese Dietary Guidelines were issued in 1997 and revised in 2007. Based on the time between issuance and revision, this study examined the Cd contamination levels in Shanghai foods from 1988 to 2018 and evaluated cancer risk and disease burden of dietary Cd exposure accordingly. Over the time periods of 1988–1997, 1998–2007, and 2008–2018, it was found that Cd dietary exposure of Shanghai residents showed a trend of increasing and then decreasing (39.7, 44.7, and 36.4 μg/day, respectively). In contrast to cereals, the contribution rates of meat and vegetables to Cd exposure have gradually increased over time, and aquatic foods have become the main source of Cd exposure (40.6%). Although the non-cancer risk hazard quotients of dietary Cd exposure and the excess lifetime cancer risks (ELCR) are relatively low (HQ < 1, ELCR < 10−4), 26.6% of Shanghai residents had a potential risk of kidney injury calculated by toxicokinetic model (TK model), and the disability adjusted life years (DALYs) have been rising (from 41.6 to 58.2). Results indicated that in the past three decades, changes of Cd contamination in food due to both limit standards and changes in dietary structure have influenced cancer risk and disease burden from Cd exposure in Shanghai residents. In summary, our study suggested that while regulating the contamination in foods, attention should also be paid to the potential impacts of dietary structure and guidelines on the exposure of pollutants.

Estimated postnatal p,p\u2019-DDT and p,p\u2019-DDE levels and body mass index at 42\u2009months of age in a longitudinal study of Japanese children

BackgroundChildren are exposed to p,p’-dichlorodiphenyltrichloroethane (p,p’-DDT) and p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE) through placental and lactational transfer. Some studies have suggested that early-life exposure to these compounds could lead to increased body mass index (BMI) during childhood. Our aim was to assess whether children’s exposure during the first 2 years of life is associated with BMI z-score in Japanese children at 42 months of age.MethodsWe used data from a birth cohort (n = 290) of the Tohoku Study of Child Development. p,p’-DDT and p,p’-DDE levels were measured in breast milk samples collected 1 month after birth, and levels in children were estimated using a toxicokinetic model for three exposure periods (0–6 months, 6–12 months, 12–24 months). Associations between exposure estimates and BMI z-score at 42 months of age were assessed using multivariate linear regression models.ResultsWe found no significant association between levels of p,p’-DDT measured in breast milk or estimated in children and BMI z-score. However, we observed associations between estimated p,p’-DDE levels in girls during all postnatal exposure periods and BMI z-score; for each log increase in the estimated p,p’-DDE levels, BMI z-score increased by 0.23 (C.I. 95%: 0.01, 0.45) for the 0–6 months exposure period, 0.26 (C.I. 95%: 0.06, 0.47) for the 6–12 months exposure period, and 0.24 (C.I. 95%: 0.05, 0.43) for the 12–24 months exposure period.ConclusionIn this study of Japanese children, estimated postnatal p,p’-DDE levels were associated with increased BMI z-score at 42 months of age, mostly in girls. These results are in line with previous studies supporting that early-life exposure to p,p’-DDE may be associated with higher BMI during childhood.

Are pigs a suitable animal model for in vivo metabolism studies of new psychoactive substances? A comparison study using different in vitro/in vivo tools and U-47700 as model drug

Being highly potent, New Synthetic Opioids (NSO) have become a public health concern. Little is known though about the metabolism and toxicokinetics (TK) of many of the non fentanyl NSO such as U-47700. Obtaining such data in humans is challenging and so we investigated if pigs were a suitable model species as TK model for U-47700. The metabolic fate of U-47700 was elucidated after intravenous administration to one pig in vivo and results were compared to metabolic patterns formed by different other in vitro systems (human and pig liver microsomes, human liver S9 fraction) and compared to rat and human in vivo data. Furthermore, monooxygenase isozymes responsible for the major metabolic steps were elucidated.In total, 12 phase I and 8 phase II metabolites of U-47700 could be identified. The predominant reactions were N-demethylation, hydroxylation, and combination of them followed by glucuronidation or sulfation. The most predominant monooxygenase catalyzed conversions were N-demethylation, and hydroxylation by CYP3A4 and 2B6, and FMO3 catalyzed N-oxidation. Similar main phase I metabolites were found in vitro as compared to in vivo (pig/human). The metabolic pattern elucidated in the pig was comparable to human in vivo data. Thus, pigs seem to be a suitable animal model for metabolism and further TK of U-47700.