Laurent Bodin

A Pragmatic Approach to Assess the Exposure of the Honey Bee (Apis mellifera) When Subjected to Pesticide Spray

Plant protection spray treatments may expose non-target organisms to pesticides. In the pesticide registration procedure, the honey bee represents one of the non-target model species for which the risk posed by pesticides must be assessed on the basis of the hazard quotient (HQ). The HQ is defined as the ratio between environmental exposure and toxicity. For the honey bee, the HQ calculation is not consistent because it corresponds to the ratio between the pesticide field rate (in mass of pesticide/ha) and LD50 (in mass of pesticide/bee). Thus, in contrast to all other species, the HQ can only be interpreted empirically because it corresponds to a number of bees/ha. This type of HQ calculation is due to the difficulty in transforming pesticide field rates into doses to which bees are exposed. In this study, we used a pragmatic approach to determine the apparent exposure surface area of honey bees submitted to pesticide treatments by spraying with a Potter-type tower. The doses received by the bees were quantified by very efficient chemical analyses, which enabled us to determine an apparent surface area of 1.05 cm2/bee. The apparent surface area was used to calculate the exposure levels of bees submitted to pesticide sprays and then to revisit the HQ ratios with a calculation mode similar to that used for all other living species. X-tomography was used to assess the physical surface area of a bee, which was 3.27 cm2/bee, and showed that the apparent exposure surface was not overestimated. The control experiments showed that the toxicity induced by doses calculated with the exposure surface area was similar to that induced by treatments according to the European testing procedure. This new approach to measure risk is more accurate and could become a tool to aid the decision-making process in the risk assessment of pesticides.

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.

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.

Probabilistic assessment method of the non-monotonic dose-responses-Part I: Methodological approach

More and more studies aim to characterize non-monotonic dose response curves (NMDRCs). The greatest difficulty is to assess the statistical plausibility of NMDRCs from previously conducted dose response studies. This difficulty is linked to the fact that these studies present (i) few doses tested, (ii) a low sample size per dose, and (iii) the absence of any raw data. In this study, we propose a new methodological approach to probabilistically characterize NMDRCs. The methodology is composed of three main steps: (i) sampling from summary data to cover all the possibilities that may be presented by the responses measured by dose and to obtain a new raw database, (ii) statistical analysis of each sampled dose-response curve to characterize the slopes and their signs, and (iii) characterization of these dose-response curves according to the variation of the sign in the slope. This method allows characterizing all types of dose-response curves and can be applied both to continuous data and to discrete data. The aim of this study is to present the general principle of this probabilistic method which allows to assess the non-monotonic dose responses curves, and to present some results.

Evaluating the evidence for non-monotonic dose-response relationships: A systematic literature review and (re-)analysis of in vivo toxicity data in the area of food safety

&NA; This study aims to evaluate the evidence for the existence of non‐monotonic dose‐responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR. In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose‐response analysis. These studies contained 179 in vivo dose‐response datasets with at least five dose groups (and a control group) as fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose‐response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. While these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non‐monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non‐monotonicity. HighlightsThe systematic review methodology was used to assess the plausibility of NMDR.Quality of relevant in vivo data for substances in the area of food was assessed.Six specific checkpoints were developped to evaluate the evidence of NMDR.Among 179 in vivo assays, 10 fulfill all checkpoints and provide evidence for NMDR.

Aggregate exposure of the adult French population to pyrethroids

ABSTRACT The French Nutrition and Health Survey (ENNS) reported higher biomarker levels of exposure to pyrethroids than those observed in North American and German biomonitoring studies. The authors therefore investigated aggregate exposure to permethrin as an initial case study because this compound is one of the most widely‐used pyrethroid insecticides. We assessed several contamination sources—such as indoor and outdoor air, settled dust and diet—and several pathways, including oral, inhalation and dermal routes. We used permethrin exposure level estimations (computed from ENNS data) and a PBPK model calibrated with human kinetic data (from 6 individuals) to simulate an internal dose of cis‐ and trans‐3‐(2,2 dichlorovinyl)‐2,2‐dimethyl‐(1‐cyclopropane) carboxylic acid (cis‐ or trans‐DCCA) in a population of 219 individuals. The urinary concentrations of cis‐ and trans ‐DCCA predicted by the PBPK model according to three permethrin exposure scenarios (“lower”, “intermediate”, and “upper”), were compared to the urinary levels measured in the ENNS study. The ENNS levels were between the levels simulated according to permethrin exposure scenarios “lower” and “intermediate”. The “upper” scenario led to an overestimation of the predicted urinary concentration levels of cis ‐ and trans ‐DCCA compared to those measured in the ENNS study. The most realistic scenario was the “lower” one (permethrin concentration of left‐censored data considered as 0). Using PBPK modeling, we estimated the contribution of each pathway and source to the internal dose. The main route of permethrin exposure was oral (98%), diet being the major source (87%) followed by dust (11%) then the dermal route (1.5%) and finally inhalation (0.5%). HIGHLIGHTSAssessment of the adult French populations aggregate exposure to permethrinAdjustment of a PBPK model of permethrin to predict urinary concentrations of DCCAEstimation of the contributions of each source and pathway to permethrin exposure

Opinion of the scientific committee on consumer safety (SCCS) – Final opinion on Polyaminopropyl Biguanide (PHMB) in cosmetic products - Submission III

• The SCCS considers the use of the Polyaminopropyl Biguanide not safe up to maximal concentration of 0.3% as preservative.

Probabilistic assessment method of the non-monotonic dose-responses-Part II: Robustness assessment

In a previous study, we presented a new method that uses a large-scale sampling system to probabilistically assess non-monotonic dose-response curves. The statistical plausibility of the characterization was governed by the probability of the dominant category, but gave no information about the specific robustness of the curve. In this paper we propose an improvement to the method by integrating a scoring system based on 4 criteria which can be used to assess the slope robustness of each of the 10,000 sampled curves. The distribution criterion which assesses the number of doses forming a slope, the intensity criterion which assesses the amplitude of the response, and the minimum and maximum confirmation criteria which increase the certainty that the response is present. The probabilistic method was tested on 294 dose-response curves taken from 2 databases and 2 other methodologies currently proposed. A total of 544 dose-response curves have been processed. The developed method offers a concrete and probabilistic characterization of the type of curve analyzed. It evaluates its statistical plausibility and its robustness according to its sampling curves. This method is applicable to all types of data (continuous and discrete) and all experimental curves starting from theoretically 3 doses at least.

Développement de séquences d’événements aboutissant à l’hépatotoxicité et modèles in vitro associés

En accord avec les recommandations du National Research Council [NRC (2007)] relatives a la recherche de nouvelles pistes susceptibles d’aider a la determination du mode d’action des agents environnementaux responsable de leur toxicite, l’objectif de ce travail est d’evaluer la possibilite d’application de telles preconisations et d’estimer en quoi leur prise en compte conduirait a revoir ou completer les pratiques actuelles en termes d’identification des dangers lors de l’evaluation de risque sanitaire. Une meilleure connaissance des mecanismes d’action tant au niveau cellulaire que moleculaire devrait permettre de definir les reponses precoces associees a une batterie de tests (in vitro) et a certains types de biomarqueurs. Ceci serait en particulier rendu possible par le developpement de modeles tels que des cellules humaines in vitro ou des approches in silico. Cette nouvelle approche est ici illustree par un organe cible, le foie, en recensant des pathologies et cartographiant le mode d’action de polluants environnementaux. Cette methodologie pourrait ainsi permettre de decrire les voies pertinentes de l’hepatotoxicite en lien avec une exposition a des xenobiotiques et en particulier les manifestations precoces predictives des differents types d’atteintes lesionnelles.