Nathalie Bonvallot

Metabolomics Tools for Describing Complex Pesticide Exposure in Pregnant Women in Brittany (France)

Background The use of pesticides and the related environmental contaminations can lead to human exposure to various molecules. In early-life, such exposures could be responsible for adverse developmental effects. However, human health risks associated with exposure to complex mixtures are currently under-explored. Objective This project aims at answering the following questions: What is the influence of exposures to multiple pesticides on the metabolome? What mechanistic pathways could be involved in the metabolic changes observed? Methods Based on the PELAGIE cohort (Brittany, France), 83 pregnant women who provided a urine sample in early pregnancy, were classified in 3 groups according to the surface of land dedicated to agricultural cereal activities in their town of residence. Nuclear magnetic resonance-based metabolomics analyses were performed on urine samples. Partial Least Squares Regression-Discriminant Analysis (PLS-DA) and polytomous regressions were used to separate the urinary metabolic profiles from the 3 exposure groups after adjusting for potential confounders. Results The 3 groups of exposure were correctly separated with a PLS-DA model after implementing an orthogonal signal correction with pareto standardizations (R2u200a=u200a90.7% and Q2u200a=u200a0.53). After adjusting for maternal age, parity, body mass index and smoking habits, the most statistically significant changes were observed for glycine, threonine, lactate and glycerophosphocholine (upward trend), and for citrate (downward trend). Conclusion This work suggests that an exposure to complex pesticide mixtures induces modifications of metabolic fingerprints. It can be hypothesized from identified discriminating metabolites that the pesticide mixtures could increase oxidative stress and disturb energy metabolism.

An exposure-based framework for grouping pollutants for a cumulative risk assessment approach: case study of indoor semi-volatile organic compounds.

Humans are exposed to a large number of contaminants, many of which may have similar health effects. This paper presents a framework for identifying pollutants to be included in a cumulative risk assessment approach. To account for the possibility of simultaneous exposure to chemicals with common toxic modes of action, the first step of the traditional risk assessment process, i.e. hazard identification, is structured in three sub-steps: (1a) Identification of pollutants people are exposed to, (1b) identification of effects and mechanisms of action of these pollutants, (1c) grouping of pollutants according to similarity of their mechanism of action and health effects. Based on this exposure-based grouping we can derive multi-pollutant toxicity reference values, in the dose-response assessment step. The approach proposed in this work is original in that it is based on real exposures instead of a limited number of pollutants from a unique chemical family, as traditionally performed. This framework is illustrated by the case study of semi-volatile organic compounds in French dwellings, providing insights into practical considerations regarding the accuracy of the available toxicological information. This case study illustrates the value of the exposure-based approach as opposed to the traditional cumulative framework, in which chemicals with similar health effects were not always included in the same chemical class.

Childhood exposure to polybrominated diphenyl ethers and neurodevelopment at six years of age.

Mixtures of polybrominated diphenyl ethers (PBDEs) are present in indoor environments. Studies of the developmental effects of exposure to these chemicals in large prospective mother-child cohorts are required, with data on prenatal exposure and long-term follow-up of the children. We aimed to investigate the relationship between prenatal and childhood exposure to PBDEs and neurodevelopment at the age of six years. We determined the levels of PBDEs and other neurotoxicants in cord blood and dust collected from the homes of children for 246 families included in the PELAGIE mother-child cohort in France. We assessed two cognitive domains of the six-year-old children using the Wechsler Intelligence Scale for Children-IV. Verbal comprehension scores were lower in children from homes with higher concentrations of BDE99 (βDetects<median_vs_NonDetects=-1.6; 95% CI: -6.1, 2.9; βDetects≥median_vs_NonDetects=-5.4; -9.9, -1.0; p trend=0.02) and of BDE209 (β2nd_vs_1st_tertile=-1.8; 95% CI: -6.1, 2.5; β3rd_vs_1st_tertile=-3.2; -7.5, 1.2; p trend=0.15) in dust, particularly for boys (p trend=0.02 and 0.04, respectively). Working memory scores seemed to be lower in children with higher BDE99 concentrations in dust (p trend=0.10). No association was observed with cord blood levels of BDE209. Our findings are in agreement with those of four previous studies suggesting adverse cognitive outcomes among children associated with early-life exposure to penta-BDE mixtures, and provide new evidence for the potential neurotoxicity of BDE209. Several countries are in the process of banning the use of PBDE mixtures as flame-retardants. However, these compounds are likely to remain present in the environment for a long time to come.

Semi-volatile organic compounds in the air and dust of 30 French schools: a pilot study.

The contamination of indoor environments with chemical compounds released by materials and furniture, such as semi-volatile organic compounds (SVOCs), is less documented in schools than in dwellings-yet children spend 16% of their time in schools, where they can also be exposed. This study is one of the first to describe the contamination of the air and dust of 90 classrooms from 30 nursery and primary schools by 55xa0SVOCs, including pesticides, phosphoric esters, musks, polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyls (PCBs), phthalates, and polybromodiphenylethers (PBDEs). Air samples were collected using an active sampling method, and dust samples were collected via two sampling methods (wiping and vacuum cleaning). In air, the highest concentrations (median >100xa0ng/m3 ) were measured for diisobutyl phthalate (DiBP), dibutyl phthalate (DBP), diethyl phthalate (DEP), bis(2-ethylhexyl) phthalate (DEHP), and galaxolide. In dust, the highest concentrations (median >30xa0μg/g) were found for DEHP, diisononyl phthalate (DiNP), DiBP, and DBP. An attempt to compare two floor dust sampling methods using a single unit (ng/m²) was carried out. SVOC concentrations were higher in wiped dust, but frequencies of quantification were greater in vacuumed dust.

Transfluthrin indoor air concentration and inhalation exposure during application of electric vaporizers.

Different household insecticide applications via two electric vaporizers emitting transfluthrin were realized in a full-scale experimental room under controlled air exchange rate conditions. On-line high-time resolved measurements of the gas-phase concentrations of the active substance during and immediately after the spreading periods were performed with a High Sensitivity Proton-Transfer-Reaction Mass Spectrometer (HS-PTR-MS). Experimental and modelled data from the ConsExpo 4.0 software were also compared to evaluate the sources of differences. Different application scenarios were also compared. Averaged inhaled concentrations over 1h, 1week, and 5months were estimated to be 8.3, 1.8, and 1.8μg.m(-3), respectively. Corresponding margins of exposures range from 1000 to 10,000, claiming for the absence of effect. Dermal and dust ingestion pathways, although roughly estimated, seems being non-negligible. This claims for a more in-depth integrated risk assessment.

Haber's rule duration adjustments should not be used systematically for risk assessment in public health decision-making.

Human health risk assessment can be used to support decisions for public health regulations and actions. Characterizing the hazards of inhaled toxicants generally includes extrapolation from observations on experimental animals, subjected to intermittent or subchronic exposures, to a human environmental context with exposure that is usually continuous and long-term. The extrapolation is usually based on a simple linear relationship derived from Habers rule which assumes that, for a given chemical compound, multiplying the same concentration by the same duration of exposure will yield the same biological response. This study assessed the reliability of this assumption. The p-power in the equation C×t(p)=k was calculated for 21 chemicals, based on a comparison of LOAELs for subacute, subchronic and chronic durations. A bibliographic survey was then carried out to study the reliability of the intermittent-to-continuous exposure adjustment factors currently used in risk assessment. The results showed that the value of p, assumed to be 1 in risk assessment methodology, was not in fact equal to 1 for any of the selected chemicals. Moreover, in the case of respiratory tract irritation, the value of p varied from 0 to 0.44, as confirmed by experimental studies. These results suggest that a more in-depth and case-by-case approach is required for regulatory toxicology, based on toxicokinetics and toxicodynamic data analysis for each toxicant before applying a temporal-adjustment factor.

Dermal absorption of semivolatile organic compounds from the gas phase: Sensitivity of exposure assessment by steady state modeling to key parameters

Recent research has demonstrated the importance of dermal exposure for some semivolatile organic compounds (SVOCs) present in the gas phase of indoor air. Though models for estimating dermal intake from gaseous SVOCs exist, their predictions can be subject to variations in input parameters, which can lead to large variation in exposure estimations. In this sensitivity analysis for a steady state model, we aimed to assess these variations and their determinants using probabilistic Monte Carlo sampling for 8 SVOCs from different chemical families: phthalates, bisphenols, polycyclic aromatic hydrocarbons (PAHs), organophosphorus (OPs), organochlorines (OCs), synthetic musks, polychlorinated biphenyls (PCBs) and polybromodiphenylethers (PBDEs). Indoor SVOC concentrations were found to be the most influential parameters. Both Henrys law constant (H) and octanol/water partition coefficient (Kow) uncertainty also had significant influence. While exposure media properties such as volume fraction of organic matter in the particle phase (fom-part), particle density (ρpart), concentration ([TSP]) and transport coefficient (ɣd) had a slight influence for some compounds, human parameters such as body weight (W), body surface area (A) and daily exposure (t) make a marginal or null contribution to the variance of dermal intake for a given age group. Inclusion of a parameter sensitivity analysis appears essential to reporting uncertainties in dermal exposure assessment.

Indoor residential exposure to semivolatile organic compounds in France

Multiple chemicals are emitted in residential accommodation. Aggregate Daily Doses (ADD) (ng/kg-bw/d) were estimated for 32 semivolatile organic compounds (SVOCs) of different chemical families that are frequently detected in French dwellings in both air and settled dust. Daily doses were determined using steady-state models for the population, categorized into 11 age groups covering birth to age 30. Three routes of exposure were taken into account: dust ingestion, inhalation (gaseous and particulate phases) and dermal contact with the gaseous phase of air. Contamination levels were preferentially retrieved from large, nationwide representative datasets. A two-dimensional probabilistic approach was used to assess parametric uncertainty and identify the most influential factors. For children aged 2 to 3years, ADD estimates spanned orders of magnitude, with median values ranging from 8.7pg/kg-bw/d for 2,2,3,4,4-pentabromodiphenylether (BDE 85) to 1.3μg/kg-bw/d for di-isobutyl phthalate (DiBP). Inhalation, ingestion and dermal pathway contributed at varying levels, and depending on compound, air was the dominant medium for 28 of the 32 compounds (either by inhalation or dermal contact). Indoor exposure estimate variance was mainly driven by indoor contamination variability, and secondarily by uncertainty in physical and chemical parameters. These findings lend support to the call for cumulative risk assessment of indoor SVOCs.

Bioaccessibility and bioavailability of environmental semi-volatile organic compounds via inhalation: A review of methods and models

Semi-volatile organic compounds (SVOCs) present in indoor environments are known to cause adverse health effects through multiple routes of exposure. To assess the aggregate exposure, the bioaccessibility and bioavailability of SVOCs need to be determined. In this review, we discussed measurements of the bioaccessibility and bioavailability of SVOCs after inhalation. Published literature related to this issue is available for 2,3,7,8-tetrachlorodibenzo-p-dioxin and a few polycyclic aromatic hydrocarbons, such as benzo[a]pyrene and phenanthrene. Then, we reviewed common modeling approaches for the characterization of the gas- and particle-phase partitioning of SVOCs during inhalation. The models are based on mass transfer mechanisms as well as the structure of the respiratory system, using common computational techniques, such as computational fluid dynamics. However, the existing models are restricted to special conditions and cannot predict SVOC bioaccessibility and bioavailability in the whole respiratory system. The present review notes two main challenges for the estimation of SVOC bioaccessibility and bioavailability via inhalation in humans. First, in vitro and in vivo methods need to be developed and validated for a wide range of SVOCs. The in vitro methods should be validated with in vivo tests to evaluate human exposures to SVOCs in airborne particles. Second, modeling approaches for SVOCs need to consider the whole respiratory system. Alterations of the respiratory cycle period and human biological variability may be considered in future studies.

Relative toxicity for indoor semi volatile organic compounds based on neuronal death

BACKGROUNDnSemi Volatile Organic Compounds (SVOCs) are contaminants commonly found in dwellings as a result of their use as plasticizers, flame retardants, or pesticides in building materials and consumer products. Many SVOCs are suspected of being neurotoxic, based on mammal experimentation (impairment of locomotor activity, spatial learning/memory or behavioral changes), raising the question of cumulative risk assessment. The aim of this work is to estimate the relative toxicity of such SVOCs, based on neuronal death.nnnMETHODnSVOCs fulfilling the following conditions were included: detection frequency >10% in dwellings, availability of data on effects or mechanism of action for neurotoxicity, and availability of dose-response relationships based on cell viability assays as a proxy of neuronal death. Benchmark concentration values (BMC) were estimated using a Hill model, and compared to assess relative toxicity.nnnRESULTSnOf the 58 SVOCs selected, 28 were suspected of being neurotoxic in mammals, and 21 have been documented as inducing a decrease in cell viability in vitro. 13 have at least one dose-response relationship that can be used to derive a BMC based on a 10% fall in neuronal viability. Based on this in vitro endpoint, PCB-153 appeared to be the most toxic compound, having the lowest BMC10 (0.072μM) and diazinon the least toxic compound, having the highest BMC10 (94.35μM). We showed that experimental designs (in particular choice of cell lines) had a significant influence on BMC calculation.nnnCONCLUSIONnFor the first time, the relative in vitro toxicity of 13 indoor contaminants belonging to different chemical families has been assessed on the basis of neuronal cell viability. Lack of comparable toxicity datasets limits the number of SVOCs that can be included. More standardized protocols in terms of cell lines, species and exposure duration should be developed with a view to cumulative risk assessment.