Integrating toxicokinetics into toxicology studies and the human health risk assessment process for chemicals: Reduced uncertainty, better health protection.

The database of practical examples where toxicokinetic (TK) data has benefitted all stages of the human health risk assessment process are increasingly being published and accepted. This review aimed to highlight and summarise notable examples and to describe the "state of the art" in this field. The overall recommendation is that for any in vivo animal study conducted, measurements of TK should be very carefully considered for inclusion as the numerous benefits this brings continues to grow, particularly during the current march towards animal free toxicology testing and ambitions to eventually conduct human health risk assessments entirely based upon non-animal methods.

Telephonic Medical Toxicology Service in a Low-Resource Setting: Setup, Challenges, and Opportunities.

Poisoning and envenomation are a global health problem for which the mortality burden is shouldered heavily by middle- and low-income countries that often lack poison prevention programs and medical toxicology expertise. Although telehealth or teleconsult services have been used to bridge the expertise gap between countries for multiple specialties, the use of medical toxicology teleconsult services across borders has been limited. We aim to describe the use of a United States-based medical toxicology teleconsult service to support patient care at a hospital in a middle-income country that lacks this expertise. This report outlines the logistics involved in setting up such a service, including the challenges and opportunities that emerged from establishing medical toxicology teleconsult service in a low-resource setting.

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience.

In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.

Contemporary Activities of Toxicologic Pathology Societies.

Educational activities and training opportunities in toxicologic pathology are major goals of 9 formally established Toxicologic Pathology Societies and the International Academy of Toxicologic Pathology. Some Toxicologic Pathology Societies have examination-based certification programs while others accept certification or registration by veterinary pathology organizations including the American College of Veterinary Pathologists, the European College of Veterinary Pathologists. We summarize here the membership numbers and current activities of formally established Toxicologic Pathology Socities.

A Multidisciplinary Toxicity Team for Cancer Immunotherapy-Related Adverse Events.

BACKGROUND: Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs). Methods to obtain real-time multidisciplinary input for irAEs that require subspecialist care are unknown. This study aimed to determine whether a virtual multidisciplinary immune-related toxicity (IR-tox) team of oncology and medicine subspecialists would be feasible to implement, be used by oncology providers, and identify patients for whom multidisciplinary input is sought. PATIENTS AND METHODS: Patients treated with ICIs and referred to the IR-tox team in August 2017 through March 2018 were identified. Feasibility was defined as receipt of electronic referrals and provision of recommendations within 24 hours of referral. Use was defined as the proportion of referring providers who used the team's recommendations, which was determined through a postpilot survey. Demographics and tumor, treatment, and referral data were collected. Patient features and irAE associations were analyzed. RESULTS: The IR-tox team was found to be feasible and used: 117 referrals from 102 patients were received in 8 months, all providers received recommendations within 24 hours, 100% of surveyed providers used the recommendations, and 74% changed patient management based on IR-tox team recommendations. Referrals were for suspected irAEs (n=106; 91%) and suitability to treat with ICIs (n=11; 10%). In referred patients, median age was 64 years, 54% were men, 13% had prior autoimmunity, and 46% received ICI combinations versus monotherapy (54%). The most commonly referred toxicities were pneumonitis (23%), arthritis (16%), and dermatitis (15%); 15% of patients had multisystem toxicities. Multiple referrals were more common in those treated with combination ICIs (odds ratio [OR], 6.0; P=.035) or with multisystem toxicities (OR, 8.1; P=.005). The IR-tox team provided a new multidisciplinary forum to assist providers in diagnosing and managing complex irAEs. This model identifies educational and service needs, and patients with irAEs for whom multidisciplinary care is most sought. CONCLUSIONS: A virtual multidisciplinary toxicity team for irAEs was a feasible and used service, and facilitated toxicity identification and management.

[Accreditation of the toxicological screening: recommendations of the SFBC-SFTA group]. / Accréditation du criblage toxicologique : recommandations du groupe SFBC-SFTA.

Toxicological screening is a specific approach to analytical toxicology that uses analytical tools such as GC-MS, LC-UV (diode array) or LC-MS. Toxicological screening allows the detection and simultaneous identification of a large number of compounds. The results may be based on the use of one or more techniques. As part of the accreditation process for medical biology examinations according to standard NF EN ISO 15189, the group from SFTA and SFBC recommends an approach to accredit toxicological screening. Indeed, the complexity of the accreditation of this analysis comes in particular from the high number of compounds that can be detected. Validation parameters are discussed in the specific context of toxicological screening by considering two distinct approaches: the simple identification of compounds, or the identification and estimation of a range of concentration related to clinical outcomes.

The impact of the introduction of a toxicology service on the intensive care unit.

Objective: To examine the impact of a clinical toxicology service on toxicology patients admitted to an intensive care department Methods: The authors performed a retrospective chart audit of all patients presenting to Cairns Emergency Department (ED) over a five-year period from 2011 to 2016 with a toxicology diagnosis requiring Intensive Care Unit (ICU) admission. They were divided into two groups: pre-toxicology (1 April 2011 to 30 September 2012), and post-toxicology service (1 October 2012 to 31 of March 2016) introduction. Patients were identified using ED and ICU databases. Patient charts were manually searched, and data entered on a preformatted data extraction tool. The data were statistically compared pre- versus post-toxicology service introduction using univariate (t-tests and Pearson's Chi Square) and multivariate modelling. Where appropriate, continuous variables were log transformed to enable parametric analyses. Results: There were 37 patients in the pre-toxicology and 102 in the post-toxicology group, with an increased median APACHE III J score in the post toxicology group (39 vs. 49). The introduction of a toxicology service was associated with statistically significant reductions in median ICU length of stay (LOS) (32.9 vs. 20.6 h), median duration of mechanical ventilation (29.1 vs. 20.6 h) and median time to psychiatry review (19.4 vs. 6.7 h). The reduction in ICU LOS remained statistically significant (p = 0.036) when adjusted by sex, age and duration of mechanical ventilation. There was neither increase in mortality, nor readmissions from EDSSU to ICU. Conclusions: This study has demonstrated that the introduction of a toxicology service was associated with a reduction in median ICU LOS, duration of mechanical ventilation and time to psychiatric review in patients with a toxicology diagnosis admitted to our ICU.

Protocolo del Sistema Nacional de Vigilancia Epidemiológica: intoxicaciones por plaguicidas, lesiones de causa externa y conducta suicida. No. 10 / Protocol of the National Epidemiological Surveillance System: pesticide poisonings, external cause injuries and suicidal behavior. No. 10

Estos protocolos están dirigido a personal médico, paramédico y otros profesionales que realizan acciones gerenciales y operativas de vigilancia epidemiológica en los servicios de salud del país, y están divididos en varios tomos para dar a conocer y actualizar la identificación y medidas de control para diversos padecimientos a fin de continuar con el mejoramiento de las capacidades técnicas de los trabajadores de salud, que permita planificar la prestación de servicios con decisiones partiendo de un enfoque epidemiológico comprobado, para responder a los cambios de tendencias epidemiológicas y con ello contribuir al fortalecimiento de prácticas asertivas de la salud pública de nuestro país.

NTP/NIEHS Global Contributions to Toxicologic Pathology.

National Toxicology Program (NTP) pathologists are engaged in important initiatives that have significant global impact. These initiatives build on its leadership in pathology peer review and publications in the areas of toxicologic pathology, clinical pathology, and laboratory animal medicine. Over the past decade, NTP/National Institute of Environmental Health Sciences research initiatives have focused on cancer and noncancer hazard identification, with the goal of understanding cellular and molecular mechanisms of disease. New initiatives of significant global impact include the web-based nonneoplastic lesion atlas and an NTP partnership with international scientists to investigate molecular mechanisms at the whole genome level, which will be used to inform potential mechanisms of environmental exposures in human cancers. Also, we are dedicated to contributing to pathology and toxicology organizations through service on executive committees and editorial boards, participating in international projects and symposiums, and providing training for future leaders in toxicologic pathology. Herein, we provide highlights of our global contributions.

The need for strategic development of safety sciences.

The practice of risk assessment and regulation of substances has largely developed as a patchwork of circumstantial additions to a nowadays more or less shared international toolbox. The dominant drivers from the US and Europe have pursued remarkably different approaches in the use of these tools for regulation, i.e., a more risk-based approach in the US and a more precautionary approach in Europe. We argue that there is need for scientific developments not only for the tools but also for their application, i.e., a need for Regulatory Science or, perhaps better, Safety Science. While some of this is emerging on the US side as strategic reports, e.g., from the National Academies, the NIH and the regulatory agencies, especially the EPA and the FDA, such strategic developments beyond technological developments are largely lacking in Europe or have started only recently at EFSA, ECHA or within the flagship project EU-ToxRisk. This article provides a rationale for the creation of a European Safety Sciences Institute (ESSI) based on regulatory and scientific needs, political context and current EU missions. Moreover, the possible modus operandi of ESSI will be described along with possible working formats as well as anticipated main tasks and duties. This mirrors the triple alliance on the American side (US EPA, NIH and FDA) in revamping regulatory sciences. Moreover, this could fit the political agenda of the European Commission for better implementation of existing EU legislation rather than creating new laws.

History and development of The Journal of Toxicological Sciences.

The Journal of Toxicological Sciences, published by The Japanese Society of Toxicology (JSOT), is an international scientific journal covering the entire field of toxicology. This article reviews the history of The Journal of Toxicological Sciences as well as actions taken by the Editorial Committee to improve the journal and the results of these initiatives.

History of Japanese Society of Toxicology.

Founded in 1981, the Japanese Society of Toxicology (JSOT) has grown into an organization of nearly 3,000 members working together to advance the nation's scientific knowledge and understanding of toxicology through the implementation of planning that ensures a systematic and efficient expenditure of energies and resources, and is closely aligned with a strategy for accomplishing the Society's long-range plans. To promote public education in toxicology, the Society organizes public lectures during each year's annual meeting. Other activities include hosting scientific conferences, promoting continuing education, and facilitating international collaboration. Internally, the JSOT operates five standing committees: General Affairs, Educational, Editorial, Finance, and Science and Publicity to handle its necessary relationships. To bestow official recognition, the Society established its Toxicologist Certification Program in 1997, and has certified 536 members as Diplomat Toxicologists (DJSOT) as of May 1, 2016. Furthermore, on the same date, 43 JSOT members were certified as Emeritus Diplomats of the JSOT (EDJSOT). The Society has launched two official journals, the "Journal of Toxicological Sciences (JTS)" in 1981 and "Fundamental Toxicological Sciences (Fundam. Toxicol. Sci.)" in 2014. As for participation in the international organizations, the JSOT (then known as the Toxicological Research Group) joined the International Union of Toxicology as a charter member in 1980, and became a founding member of the Asian Society of Toxicology at its inauguration in 1994. Into the future, the JSOT will continue working diligently to advance knowledge and understanding of toxicology and secure its place among the interdisciplinary fields of science, humane studies, and ethics.

La vigilancia de las intoxicaciones en Argentina y en América Latina. Notificación, análisis y gestión de eventos / Surveillance of poisoning in Argentina and Latin America. Reporting, analysis and event management

La vigilancia de las intoxicaciones, o toxicovigilancia, es una herramienta fundamental de la evaluación de riesgos para la salud y de la valoración de los efectos de las medidas regulatorias que hacen a la seguridad de los productos químicos. Existen numerosas experiencias latinoamericanas desde los Sistemas Nacionales de Vigilancia Epidemiológica donde muchas intoxicaciones han sido incluidas en los listados de enfermedades de notificación obligatoria, tales como las intoxicaciones por plaguicidas, por metales y por hidrocarburos, el botulismo, los envenenamientos por animales ponzoñosos, las intoxicaciones medicamentosas o por drogas de abuso. En este campo se observan también diferencias en los listados nacionales y regionales, destacándose, por ejemplo, la notificación de las intoxicaciones por alcohol adulterado con metanol o por glifosato en Colombia, la intoxicación paralizante por mariscos en países del Cono Sur, las intoxicaciones por plaguicidas en Centroamérica y su relación con la enfermedad renal crónica. También hay peculiaridades en las definiciones de brote y las alertas epidemiológicas, así como en la urgencia o periodicidad requerida para la notificación. Los Centros de Información y Asesoramiento Toxicológicos y los Laboratorios de Análisis Clínicos Toxicológicos también cumplen una importante función al respecto, siendo los efectores más especializados en el diagnóstico y donde se puede obtener información de mayor calidad. Importante ha sido la implementación de la toxicovigilancia en convenios internacionales de Seguridad Química, tales como el de Rotterdam y el de Estocolmo, y los esfuerzos realizados por las Naciones Unidas para armonizar los registros y los informes nacionales.

Surveillance of poisoning, or toxicovigilance, is a fundamental tool for the assessment of health risks and the assessment of the effects of regulatory measures that make the safety of chemicals. There are many Latin American experiences from the National Epidemiological Surveillance where many poisonings have been included in the lists of notifiable diseases such as pesticide poisoning, metals and oil, botulism poisonings venomous animals, poisoning drug or drugs of abuse. In this field also differences are observed in national and regional listings, highlighting, for example, notification of poisoning by adulterated alcohol with methanol or glyphosate in Colombia, paralytic shellfish poisoning in Southern Cone countries, pesticide poisoning in Central America and its relationship to chronic kidney disease. There are also peculiarities in the definitions of outbreak and epidemiological alerts, as well as the urgency or frequency required for notification. Information Centers and Toxicological Consulting and Clinical Toxicology Laboratories Analysis also play an important role in this regard, the most specialized effectors in the diagnosis and where you can get better information. Important has been the implementation of international conventions toxicovigilance Chemical Safety such as Rotterdam and Stockholm, and efforts by the United Nations to harmonize national records and reports.