Retrospective analysis of the Draize test for serious eye damage/eye irritation: importance of understanding the in vivo endpoints under UN GHS/EU CLP for the development and evaluation of in vitro test methods

For more than two decades, scientists have been trying to replace the regulatory in vivo Draize eye test by in vitro methods, but so far only partial replacement has been achieved. In order to better understand the reasons for this, historical in vivo rabbit data were analysed in detail and resampled with the purpose of (1) revealing which of the in vivo endpoints are most important in driving United Nations Globally Harmonized System/European Union Regulation on Classification, Labelling and Packaging (UN GHS/EU CLP) classification for serious eye damage/eye irritation and (2) evaluating the method’s within-test variability for proposing acceptable and justifiable target values of sensitivity and specificity for alternative methods and their combinations in testing strategies. Among the Cat 1 chemicals evaluated, 36–65 % (depending on the database) were classified based only on persistence of effects, with the remaining being classified mostly based on severe corneal effects. Iritis was found to rarely drive the classification (<4 % of both Cat 1 and Cat 2 chemicals). The two most important endpoints driving Cat 2 classification are conjunctiva redness (75–81 %) and corneal opacity (54–75 %). The resampling analyses demonstrated an overall probability of at least 11 % that chemicals classified as Cat 1 by the Draize eye test could be equally identified as Cat 2 and of about 12 % for Cat 2 chemicals to be equally identified as No Cat. On the other hand, the over-classification error for No Cat and Cat 2 was negligible (<1 %), which strongly suggests a high over-predictive power of the Draize eye test. Moreover, our analyses of the classification drivers suggest a critical revision of the UN GHS/EU CLP decision criteria for the classification of chemicals based on Draize eye test data, in particular Cat 1 based only on persistence of conjunctiva effects or corneal opacity scores of 4. In order to successfully replace the regulatory in vivo Draize eye test, it will be important to recognise these uncertainties and to have in vitro tools to address the most important in vivo endpoints identified in this paper.JRC.I.5-Systems Toxicolog

t4 Workshop Report: Integrated Testing Strategies (ITS) for Safety Assessment

Integrated testing strategies (ITS), as opposed to single definitive tests or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and “Good ITS Practices”.JRC.I.5-Systems Toxicolog

CATMoS: Collaborative Acute Toxicity Modeling Suite.

BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495

L' allaitement maternel, une pratique à promouvoir (état des lieux et élaboration d'un livret d'information et de soutien à destination des mamans allaitantes)

L allaitement maternel gagnerait à être promu en France. La progression des chiffres du taux d allaitement brut à la naissance est encourageante (52.5% en 1998 et 62.6% en 2003), mais il reste encore une large marge de progression si on regarde les résultats des autres pays du monde. Les mamans françaises arrêtent trop précocement leur allaitement, surtout dans les 3 premiers mois, par manque d aide adéquate. Pourtant les bénéfices pour la santé de l enfant et de la mère ainsi que les bénéfices économiques individuels et communautaires du lait maternel sont bien démontrés. Les pouvoirs publics en France, sous la bonne influence des instances internationales, se mobilisent. Ils font une place plus confortable aux mamans allaitantes, notamment par rapport à la reprise du travail. Mais les freins à l allaitement sont encore nombreux et le biberon tient à sa place. Un soutien efficace du choix d allaiter doit être maintenu tout au long de la grossesse, lors de l accouchement, lors du séjour à la maternité et au retour à domicile. C est dans cette dernière phase qu il semble le plus faire défaut, c est pourtant le moment où le lien entre la maman et son choix de l allaitement au sein est extrêmement fragile. Ce constat a sous-tendu l idée de la création d un livret d information et de soutien pour la femme allaitante dans le service de gynécologique obstétrique de Senlis (Oise)AMIENS-BU Santé (800212102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

La nutrithérapie dans la prévention de l'ostéoporose (rôle du pharmacien)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Enquête prospective sur la prise en charge de la douleur aiguë en pré-hospitalier auprès des hôpitaux périphériques du Languedoc-Roussillon

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Integrated pre-concentrator gas sensor system for improved trace gas sensing performance

An integrated gas measurement system is presented which combines MEMS gas sensors with a micro gas pre-concentration device. Designed to increase gas sensor selectivity and sensitivity, the pre-concentrator samples gases and releases them by thermal desorption. Simulations show that the design works very well for volatile organic compounds in the ppb concentration range, which would be the target gases in indoor air quality monitoring. A gas concentration increase of a factor of 27 was achieved in the presented setup of the simulation. In test measurements with benzene, the successful operation of the integrated system is demonstrated for concentrations down to 10 ppb. The height of the sensor response was nearly doubled during pre-concentrator gas desorption