PBPK and population modelling to interpret urine cadmium concentrations of the French population.

As cadmium accumulates mainly in kidney, urinary concentrations are considered as relevant data to assess the risk related to cadmium. The French Nutrition and Health Survey (ENNS) recorded the concentration of cadmium in the urine of the French population. However, as with all biomonitoring data, it needs to be linked to external exposure for it to be interpreted in term of sources of exposure and for risk management purposes. The objective of this work is thus to interpret the cadmium biomonitoring data of the French population in terms of dietary and cigarette smoke exposures. Dietary and smoking habits recorded in the ENNS study were combined with contamination levels in food and cigarettes to assess individual exposures. A PBPK model was used in a Bayesian population model to link this external exposure with the measured urinary concentrations. In this model, the level of the past exposure was corrected thanks to a scaling function which account for a trend in the French dietary exposure. It resulted in a modelling which was able to explain the current urinary concentrations measured in the French population through current and past exposure levels. Risk related to cadmium exposure in the general French population was then assessed from external and internal critical values corresponding to kidney effects. The model was also applied to predict the possible urinary concentrations of the French population in 2030 assuming there will be no more changes in the exposures levels. This scenario leads to significantly lower concentrations and consequently lower related risk.

An integrative risk assessment approach for persistent chemicals: a case study on dioxins, furans and dioxin-like PCBs in France.

For persistent chemicals slowly eliminated from the body, the accumulated concentration (body burden), rather than the daily exposure, is considered the proper starting point for the risk assessment. This work introduces an integrative approach for persistent chemical risk assessment by means of a dynamic body burden approach. To reach this goal a Kinetic Dietary Exposure Model (KDEM) was extended with the long term time trend in the exposure (historic exposure) and the comparison of bioaccumulation with body burden references for toxicity. The usefulness of the model was illustrated on the dietary exposure to PolyChlorinatedDibenzo-p-Dioxins (PCDDs), PolyChlorinatedDibenzoFurans (PCDFs) and PolyChlorinated Biphenyls (PCBs) in France. Firstly the dietary exposure to these compounds was determined in 2009 and combined with its long term time trend. In order to take differences between the kinetics of PCDD/F and dl-PCBs into account, three groups of congeners were considered i.e. PCDD/Fs, PCB 126 and remaining dl-PCBs. The body burden was compared with reference body burdens corresponding to reproductive, hepatic and thyroid toxicity. In the case of thyroid toxicity this comparison indicated that in 2009 the probability of the body burden to exceed its reference ranged from 2.8% (95% CI: 1.5-4.9%) up to 3.9% (95% CI: 2.7-7.1%) (18-29 vs. 60-79year olds). Notwithstanding the decreasing long-term time trend of the dietary dioxin exposure in France, this probability still is expected to be 1.5% (95% CI: 0.3-2.5%) in 2030 in 60-79 olds. In the case of reproductive toxicity the probability of the 2009 body burden to exceed its reference ranged from 3.1% (95% CI: 1.4-5.0%) (18-29year olds) to 3.5% (95% CI: 2.2-5.2%) (30-44year olds). In 2030 this probability is negligible in 18-29year olds, however small though significant in 30-44year olds (0.7%, 95% CI: 0-1.6%). In the case of hepatic toxicity the probability in 2009 even in 60-79year olds already was negligible. In conclusion this approach indicates that in France dioxin levels in food form a declining, though still present, future health risk with respect to thyroid and reproductive toxicity.

Impact of sociodemographic profile, generation and bioaccumulation on lifetime dietary and internal exposures to PCBs.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants triggering numerous adverse effects. Because they are present in various food, dietary exposure of the population to these contaminants must be estimated to assess the related health risk. However, the classical risk assessment approach allows only short-term estimates of exposure and does not account for dietary changes, evolution of food contaminations and bioaccumulation of PCBs through life. The approach presented here assesses lifetime PCB exposure trajectories according to birth year and individual sociodemographic profiles. Moreover, a physiologically based toxicokinetic model was developed to simulate lifetime PCB plasma concentrations, while considering physiological changes with age. A focus on the long-term impact of breastfeeding is also presented in order to consider the risk related to PCBs and due to the mother-to-child transfer. For example, the exposure of an individual born in 1972 exceeds the critical value of 20 ng PCB/kg bw/day half as often as an individual born in 1932 throughout their lifetime but 13 times more often than an individual born in 2012, according to our simulations. In addition, even if breastfeeding clearly leads to much higher dietary exposures than formula feeding, the long-term impact on PCB body burden remains negligible. Risk assessment related to PCB lifetime trajectories is described and discussed.

Human variability in glutathione-S-transferase activities, tissue distribution and major polymorphic variants: Meta-analysis and implication for chemical risk assessment.

The input into the QIVIVE and Physiologically-Based kinetic and dynamic models of drug metabolising enzymes performance and their inter-individual differences significantly improve the modelling performance, supporting the development and integration of alternative approaches to animal testing. Bayesian meta-analyses allow generating and integrating statistical distributions with human in vitro metabolism data for quantitative in vitro-in vivo extrapolation. Such data are lacking on glutathione-S-transferases (GSTs). This paper reports for the first time results on the human variability of GST activities in healthy individuals, their tissue localisation and the frequencies of their major polymorphic variants by means of extensive literature search, data collection, data base creation and meta-analysis. A limited number of papers focussed on in vivo GST inter-individual differences in humans. Ex-vivo total GST activity without discriminating amongst isozymes is generally reported, resulting in a high inter-individual variability. The highest levels of cytosolic GSTs in humans are measured in the kidney, liver, adrenal glands and blood. The frequencies of GST polymorphisms for cytosolic isozymes in populations of different geographical ancestry were also presented. Bayesian meta-analyses to derive GST-related uncertainty factors provided uncertain estimates, due to the limited database. Considering the relevance of GST activities and their pivotal role in cellular adaptive response mechanisms to chemical stressors, further studies are needed to identify GST probe substrates for specific isozymes and quantify inter-individual differences.

Dietary risk assessment methodology: how to deal with changes through life.

Chemicals are present in food and numerous methods have been developed to assess dietary risk associated with these substances, but mainly by studying short periods of exposure. Usually, consumption data used to assess the risk are collected over a short period-of-time. The aim of this paper was to compile existing methods to assess dietary risk and identify their limitations in terms of lifetime risk assessment. To this end, we reviewed the different methods currently used at each step of risk assessment (i.e. methods to collect consumption data, to compute dietary exposures, and then to interpret these exposures in terms of risk for the consumer). Numerous methodologies exist to collect consumption data, contamination data collection, as well as for data treatment and interpretation. These methods consider different hypotheses and therefore lead to numerous uncertainties and discrepancies in the estimation of the exposure. Moreover, changes in eating habits through life, evolutions of food contamination, as well as health risk induced by fluctuating exposures, are rarely studied. A scientific consensus on the current risk assessment approaches is needed between national regulatory authorities. Moreover, additional research activities appear needed to take the evolution of consumption and contamination through time into account and to be able to assess the dietary health risk over the entire life.

A method to assess lifetime dietary risk: Example of cadmium exposure.

Usually health risk related to food contaminants is assessed based on consumption data collected on a few days. Consequently, this approach considers neither the evolution of exposures over time nor the potential accumulation of the substance. The aim of the present study was to develop a method to assess lifetime dietary risk due to cadmium exposure. Three methods were compared, respectively based on age, dietary pattern and sociodemographic characteristics. Additionally, exposure trajectories were converted into cadmium body burden trajectories using a PBTK-TD model ultimately predicting the occurrence of renal effects. It was shown that dietary exposures to cadmium, as well as exceedances of health based guidance values, greatly vary with age and individual profiles. The developed methods allowed identifying parameters affecting dietary exposure to cadmium and distinguishing at-risk subpopulations. Furthermore, this study demonstrated that it is necessary to consider individual changes through life and kinetic of the substance to assess risk properly.

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.

Improving dietary exposure models by imputing biomonitoring data through ABC methods.

New data are available in the field of risk assessment: the biomonitoring data which is measurement of the chemical dose in a human tissue (e.g. blood or urine). These data are original because they represent direct measurements of the dose of chemical substances really taken up from the environment, whereas exposure is usually assessed from contamination levels of the different exposure media (e.g. food, air, water, etc.) and statistical models. However, considered alone, these data provide little help from the perspective of Public Health guidance. The objective of this paper is to propose a method to exploit the information provided by human biomonitoring in order to improve the modeling of exposure. This method is based on the Kinetic Dietary Exposure Model which takes into account the pharmacokinetic elimination and the accumulation phenomenon inside the human body. This model is corrected to account for any possible temporal evolution in exposure by adding a scaling function which describes this evolution. Approximate Bayesian Computation is used to fit this exposure model from the biomonitoring data available. Specific summary statistics and appropriate distances between simulated and observed statistical distributions are proposed and discussed in the light of risk assessment. The promoted method is then applied to measurements of blood concentration of dioxins in a group of French fishermen families. The outputs of the model are an estimation of the body burden distribution from observed dietary intakes and the evolution of dietary exposure to dioxins in France between 1930 and today. This model successfully fit to dioxins data can also be used with other biomonitoring data to improve the risk assessment to many other contaminants.

Identification of pesticide mixtures and connection between combined exposure and diet.

The identification of the major associations of pesticides to which the population is exposed is the first step for the risk assessment of mixtures. Moreover, the interpretation of the mixtures through the individuals' diet and the characterization of potentially high-risk populations constitute a useful tool for risk management. This paper proposes a method based on Non-Negative Matrix Factorization which allows the identification of the major mixtures to which the French population is exposed and the connection between this exposure and the diet. Exposure data of the French population are provided by the Second French Total Diet Study. The NMF is implemented on consumption data to extract consumption systems which are combined with the residue levels to link dietary behavior with exposure to mixtures of pesticides. A clustering of the individuals is achieved in order to highlight clusters of individuals with similar exposure to pesticides/consumption habits. The model provides 6 main consumption systems, 6 associated mixtures of pesticides and the description of the population which is most exposed to each mixture. Two different ways to estimate the matrix providing the mixtures of pesticides to which the population is exposed are suggested. Their advantages in different contexts of risk assessment are discussed.