Valeurs toxicologiques de référence : comment choisir ?

National audienceAccurate toxicity reference values are needed to conduct health risk assessments. Often, however, risk assessors must make a choice among several toxicity reference values (TR values) recommended by different toxicological agencies for the same substance with the same exposure route and effect. Some French agencies (DGS and InVS), working with other organizations, have developed pragmatic criteria to help risk assessors make this choice, but as far as we know no scientifically rigorous methodology has been proposed for national harmonization. Accordingly, risk assessors tend to select the most conservative value. Our objectives here are to suggest both an in-depth methodology to evaluate the scientific quality of TR values and appropriate pragmatic criteria to help risk assessors choose accurate TR values. This paper itemizes and discusses several key points to be considered in assessing the scientific quality of TR values: consistency of scientific data, critical effect, critical dose or concentration, uncertainty factors, exposure scenarios and mathematical models. At the same time, attention should be paid to the key studies and to any peer review process used by agencies to select their TR values.Dans le cadre des évaluations de risque sanitaire, pour une substance chimique considérée, plusieurs valeurs toxicologiques de référence (VTR) peuvent être élaborées par des organismes reconnus, pour une voie d'exposition, un temps d'exposition et un type d'effet donnés (effet " à seuil de dose " et effet " sans seuil de dose "). Dans ce cas, un choix doit être réalisé parmi les différentes VTR existantes. Certains organismes tels que la Direction générale de la Santé (DGS), l'Institut de veille sanitaire (InVS) et certains bureaux d'études ont réfléchi aux différents critères permettant de faire un choix rapide et pragmatique destiné le plus souvent aux évaluateurs de risque, mais à notre connaissance aucune méthodologie harmonisée de choix des VTR en fonction de la qualité scientifique de leur élaboration n'a été proposée au plan national. Par défaut, ou par peur de ne pas réaliser un choix adéquat en utilisant des critères pragmatiques, les évaluateurs de risque retiennent, le plus souvent, la valeur la plus précautionneuse. Cet article propose des critères pragmatiques, destinés aux évaluateurs de risque afin de réaliser un choix rapide de VTR, mais également une méthodologie approfondie permettant d'évaluer la qualité scientifique de l'élaboration des VTR. Des critères scientifiques auxquels doivent répondre les études clés pour s'assurer de leur qualité scientifique et de leur pertinence dans l'élaboration d'une VTR ont été recherchés et indiqués pour les études expérimentales et épidémiologiques. Les points clés sur lesquels il est important de se focaliser ont été également mentionnés et discutés, en particulier la cohérence des données scientifiques, l'effet critique, la dose ou la concentration critique, les facteurs d'incertitude, le scénario d'exposition et le modèle mathématique

IMPACT DES PARTICULES DIESEL ET DES ACARIENS SUR LES CELLULES EPITHELIALES BRONCHIQUES HUMAINES (ALTERATION DES INTERACTIONS CELLULE-MATRICE EXTRACELLULAIRE)

PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Analyse et proposition de méthodes d'évaluation de la relation dose-réponse des effets cancérigènes induits par un mélange d'hydrocarbures aromatiques polycycliques

National audienc

Proposition d'une méthode empirique de construction de valeurs toxicologiques de référence pour des effets sensibilisants après une exposition cutanée

National audienceThe dermal exposure route is not taken into account in most health risk assessments conducted in France today for the protection of the general population. No dermal value is proposed by any of the 6 organizations that establish recognized health toxicity reference values (HTRV). Similarly, no method has been developed to quantify effects after dermal exposure in the workplace. Only a "skin notation" gives information on possible cutaneous absorption of the agent. It thus appears useful to explore methods for taking the dermal exposure route into account and particularly to develop a method for deriving HTRVs for dermal exposure. A review of the literature focused on empirical approaches (by determining adjustment factors, modelling excluded) to the dermal route is highly complex and many factors influence it. The quantification of sensitising effects after skin exposure has been studied, however, in the field of cosmetics. The method we propose to derive HTRVs for sensitising effects induced by skin exposure is based on 2 studies of cosmetics. It provides only an initial approach, because it concerns only one type of effect and skin exposure. Because of the complexity of the dermal route and the influence of numerous factors, the choice of uncertainty factors remains difficult and will require further discussion as knowledge progresses, especially data provided by the increasing number of modelling approaches. As part of the implementation of the REACH regulations, new cutaneous tests will be developed, and new substances will be tested, thus providing new data and expanding the method proposed to several other effects induced by dermal exposure.Actuellement, en France, l'exposition cutanée n'est généralement pas prise en compte dans les évaluations du risque sanitaire pour protéger la population générale. Parmi les six organismes reconnus pour élaborer des valeurs toxicologiques de référence (VTR), aucun n'en propose pour une exposition cutanée. De même, dans le milieu professionnel, aucune méthode n'est vraiment développée pour quantifier les effets induits après une exposition cutanée. Seule la " notation peau " est utilisée \; elle renseigne sur le potentiel d'absorption de la substance. Ainsi, il apparaît intéressant de travailler sur la prise en compte de la voie cutanée dans les évaluations de risque sanitaire et particulièrement sur l'élaboration d'une méthode de construction de VTR pour une exposition cutanée. Un travail de revue bibliographique portant spécifiquement sur les approches empiriques par détermination de facteurs d'ajustement a permis de mettre en évidence la complexité et le nombre important desdits facteurs influençant la voie cutanée. En revanche, l'existence de travaux menés dans le milieu de la cosmétique et ayant pour sujet la quantification des effets sensibilisants après une exposition cutanée permet d'ores et déjà un travail sur l'élaboration d'une méthode de construction de VTR ad hoc. La méthode ainsi proposée est une première approche car elle ne concerne qu'un type d'effet et l'exposition de la peau. De plus, en raison de l'ensemble des éléments influençant la réponse cutanée et la complexité de cette voie, le choix des facteurs d'incertitude reste délicat et sera, sans doute, à rediscuter au fur et à mesure de l'évolution des connaissances, en particulier celles relatives aux approches par modélisation qui se multiplient. Enfin, dans le cadre de la réglementation REACH (Registration, Evaluation and Authorization of Chemicals), de nouveaux tests cutanés seront développés et menés sur de nouvelles substances, ce qui permettra d'obtenir de nouvelles données et d'élargir la méthode proposée aux autres effets induits par la voie cutanée

On the Strength and Validity of Hazard Banding

Hazard Banding (HB) is a process of allocating chemical substances in bands of increasing health hazard based on their hazard classifications. Recent Control Banding (CB) tools use the classifications of the United Nations Global Harmonized System (UN GHS) or the European Union Classifications, Labelling and Packaging (EU CLP) which are grouped over 5 HBs. The use of CB is growing worldwide for the risk control of substances without an Occupational Exposure Limit Value (OELV). Well-known CB-tools like HSE-COSHH Essentials, BAuA-Einfaches Maßnahmenkonzept Gefahrstoffe (EMKG), and DGUV-IFA-Spaltenmodell (IFA) use however different GHS/CLP groupings which may lead to dissimilar HBs and control regimes for individual substances. And as the choice for a CB tool seems to be determined by geography and/or local status these differences may hamper a global, aligned HSE approach. Therefore, the HB-engines of the three public CBs and an in-company (Solvay) CB called ‘Occupational Exposure Banding’ (S-OEB) were compared mutually and ranked in their relation with the OELV as the ‘de facto’ standard. This was investigated graphically and using a 5 strength indicator, statistical method. A data set of 229 substances with high-quality GHS/CLP classifications and OELVs was used. HB concentration ranges, as linked to S-OEB and COSHH, were validated against the corresponding OELV distributions. The four HB-engines allocate between 23 and 64% of the 229 substances in the same bands. The remaining substances differ at least one band, with IFA placing more substances in a higher hazard band, EMKG doing the opposite and COSHH and S-OEB in between. The overall strength scores of S-OEB, IFA, and EMGK HB-engines are higher than COSHH, with S-OEB having the highest overall strength score. The lower ends of the concentration ranges defined for the 3 ‘highest’ hazard bands of S-OEB were in good agreement with the 10(th) percentiles of the corresponding OELV distributions obtained from the substance data set. The lower ends of the COSHH concentration ranges comply with the 10(th) percentiles of the COSHH OELV distributions for dust/aerosol but not for vapour/gas substances. Both the S-OEB and COSHH concentration ranges underestimate the overall width of the OELV distributions that can span 2–3 orders of magnitude. As the performance of the S-OEB HB-engine meets our criteria of being at least as good as the public engines, it will be used as a standard within Solvay’s global operations. In addition, the method described here to evaluate the strength of HB-engines and the validity of their corresponding concentration ranges is a useful tool enabling further developments and worldwide alignment of HB

The French approach for deriving toxicity references values: the example with reprotoxic effects

International audienceFollowing the French health and environment action plan, the French Agency for Environmental and Occupational Health and Safety set up a workgroup to standardise a method of deriving toxicity reference values (TRVs). Over the last few decades, there has been increasing concern about the effect of exposure to chemicals on reproductive function, leading the group to take an interest in reprotoxic effects. This article presents the recommendations of the workgroup regarding specific reprotoxic effects. Abnormal development of foetuses and infants, together with impairment of reproduction were considered to be critical effects. Where critical windows of exposure were concerned, quantitative analysis suggested the need for several types of toxicity reference value, as a function of exposure duration: reprotoxic effects may result from acute or chronic exposure at any time of life, whilst developmental effects may occur after exposure during the pregnancy or during the lactation period. The choice of a critical study is based on epidemiological or toxicological quality criteria. The working group recommends the use of the benchmark dose approach in estimating the critical dose. Finally, the working group considered the application of uncertainty factors typically used to take into account the variability between animal and human, between different individuals, and the availability of the data

Development of French Indoor Air Quality Guidelines. Method and example for Formaldehyde

International audienceIndoor air quality (IAQ) guidelines provide safe levels of indoor pollutant concentrations below which adverse health effects are not expected to occur in general population, including sensitive subgroups. The French Agency for environmental and occupational health safety (AFSSET) and the French Scientific and technical centre for building (CSTB) have been leading a working group in charge of development of IAQ guidelines based on human toxicological criteria. First, a list of substances of concern was established. Then for each pollutant of concern, existing health effect-based IAQ guidelines recommended by international groups or by other countries are collected. Available human toxicological values from US-Environmental Protection Agency, Agency for Toxic Substances and Disease Registry, Office of Environmental Health Hazard Assessment, Health Canada and Dutch Agency for environmental health are listed as well. After a critical analysis of these values, IAQ guidelines are proposed. Elaboration of IAQ guidelines for formaldehyde is presented