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Molecules ; 29(8)2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38675645


In the realm of predictive toxicology for small molecules, the applicability domain of QSAR models is often limited by the coverage of the chemical space in the training set. Consequently, classical models fail to provide reliable predictions for wide classes of molecules. However, the emergence of innovative data collection methods such as intensive hackathons have promise to quickly expand the available chemical space for model construction. Combined with algorithmic refinement methods, these tools can address the challenges of toxicity prediction, enhancing both the robustness and applicability of the corresponding models. This study aimed to investigate the roles of gradient boosting and strategic data aggregation in enhancing the predictivity ability of models for the toxicity of small organic molecules. We focused on evaluating the impact of incorporating fragment features and expanding the chemical space, facilitated by a comprehensive dataset procured in an open hackathon. We used gradient boosting techniques, accounting for critical features such as the structural fragments or functional groups often associated with manifestations of toxicity.

Algoritmos , Relação Quantitativa Estrutura-Atividade , Toxicologia/métodos , Humanos
Int J Toxicol ; 43(4): 355-356, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38575143

Toxicologia , Humanos
Int J Toxicol ; 43(4): 377-386, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38606470


The inclusion of recovery animals in nonclinical safety studies that support clinical trials is undertaken with a wide diversity of approaches even while operating under harmonized regulatory guidance. While empirical evaluation of reversibility may enhance the overall nonclinical risk assessment, there are often overlooked opportunities to reduce recovery animal use by leveraging robust scientific and regulatory information. In the past, there were several attempts to benchmark recovery practices; however, recommendations have not been consistently applied across the pharmaceutical industry. A working group (WG) sponsored by the 3Rs Translational and Predictive Sciences Leadership Group of the IQ Consortium conducted a survey of current industry practice related to the evaluation of reversibility/recovery in repeat dose toxicity studies. Discussion among the WG representatives included member company strategies and case studies that highlight challenges and opportunities for continuous refinements in the use of recovery animals. The case studies presented in this paper demonstrate increasing alignment with the Society of Toxicologic Pathology recommendations (2013) towards (1) excluding recovery phase cohorts by default (include only when scientifically justified), (2) minimizing the number of recovery groups (e.g., control and one dose level), and (3) excluding controls in the recovery cohort by leveraging external and/or dosing phase data. Recovery group exclusion and decisions regarding the timing of reversibility evaluation may be driven by indication, modality, and/or other scientific or strategic factors using a weight of evidence approach. The results and recommendations discussed present opportunities to further decrease animal use without impacting the quality of human risk assessment.

Testes de Toxicidade , Animais , Medição de Risco , Toxicologia/normas , Toxicologia/métodos , Humanos
J Anal Toxicol ; 48(5): 1, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38581660

Toxicologia , Humanos
Regul Toxicol Pharmacol ; 150: 105632, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38679316


The replacement of a proportion of concurrent controls by virtual controls in nonclinical safety studies has gained traction over the last few years. This is supported by foundational work, encouraged by regulators, and aligned with societal expectations regarding the use of animals in research. This paper provides an overview of the points to consider for any institution on the verge of implementing this concept, with emphasis given on database creation, risks, and discipline-specific perspectives.

Testes de Toxicidade , Toxicologia , Animais , Toxicologia/métodos , Testes de Toxicidade/métodos , Humanos , Bases de Dados Factuais , Medição de Risco
Arch Toxicol ; 98(7): 2047-2063, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38689008


The ongoing transition from chemical hazard and risk assessment based on animal studies to assessment relying mostly on non-animal data, requires a multitude of novel experimental methods, and this means that guidance on the validation and standardisation of test methods intended for international applicability and acceptance, needs to be updated. These so-called new approach methodologies (NAMs) must be applicable to the chemical regulatory domain and provide reliable data which are relevant to hazard and risk assessment. Confidence in and use of NAMs will depend on their reliability and relevance, and both are thoroughly assessed by validation. Validation is, however, a time- and resource-demanding process. As updates on validation guidance are conducted, the valuable components must be kept: Reliable data are and will remain fundamental. In 2016, the scientific community was made aware of the general crisis in scientific reproducibility-validated methods must not fall into this. In this commentary, we emphasize the central importance of ring trials in the validation of experimental methods. Ring trials are sometimes considered to be a major hold-up with little value added to the validation. Here, we clarify that ring trials are indispensable to demonstrate the robustness and reproducibility of a new method. Further, that methods do fail in method transfer and ring trials due to different stumbling blocks, but these provide learnings to ensure the robustness of new methods. At the same time, we identify what it would take to perform ring trials more efficiently, and how ring trials fit into the much-needed update to the guidance on the validation of NAMs.

Toxicologia , Reprodutibilidade dos Testes , Medição de Risco/métodos , Animais , Toxicologia/métodos , Toxicologia/normas , Testes de Toxicidade/métodos , Humanos , Estudos de Validação como Assunto , Projetos de Pesquisa/normas , Alternativas aos Testes com Animais/métodos
Br J Clin Pharmacol ; 90(5): 1357-1364, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38439145


To prepare medical students appropriately for the management of toxicological emergencies, we have developed a simulation-based medical education (SBME) training in acute clinical toxicology. Our aim is to report on the feasibility, evaluation and lessons learned of this training. Since 2019, each year approximately 180 fifth-year medical students are invited to participate in the SBME training. The training consists of an interactive lecture and two SBME stations. For each station, a team of students had to perform the primary assessment and management of an intoxicated patient. After the training, the students completed a questionnaire about their experiences and confidence in clinical toxicology. Overall, the vast majority of students agreed that the training provided a fun, interactive and stimulating way to teach about clinical toxicology. Additionally, they felt more confident regarding their skills in this area. Our pilot study shows that SBME training was well-evaluated and feasible over a longer period.

Competência Clínica , Estudos de Viabilidade , Estudantes de Medicina , Toxicologia , Humanos , Estudantes de Medicina/psicologia , Projetos Piloto , Toxicologia/educação , Treinamento com Simulação de Alta Fidelidade/métodos , Inquéritos e Questionários , Educação de Graduação em Medicina/métodos , Treinamento por Simulação/métodos
J Med Toxicol ; 20(2): 77-78, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38446354
Clin Toxicol (Phila) ; 62(3): 164-167, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38525861


BACKGROUND: Paracetamol overdose is the most common cause of acute liver failure in the United States. Administration of acetylcysteine is the standard of care for this intoxication. Laboratory values and clinical criteria are used to guide treatment duration, but decision-making is nuanced and often complex and difficult. The purpose of this study was to evaluate the effect of the introduction of a medical toxicology service on the rate of errors in the management of paracetamol overdose. METHODS: This was a single center, retrospective, cohort evaluation. Patients with suspected paracetamol overdose were divided into two groups: those attending in the 1 year period before and those in the 1 year after the introduction of the medical toxicology service. The primary outcome was the frequency of deviations from the established management of paracetamol intoxication, using international guidelines as a reference. RESULTS: Fifty-four patients were eligible for the study (20 pre-toxicology-service, 34 post-toxicology-service). The frequency of incorrect therapeutic decisions was significantly lower in the post-toxicology service implementation versus the pre-implementation group (P = 0.005). DISCUSSION: Our study suggests that a medical toxicology service reduces the incidence of management errors, including the number of missed acetylcysteine doses in patients with paracetamol overdose. The limitations include the retrospective study design and that the study was conducted at a single center, which may limit generalizability. CONCLUSIONS: The implementation of a medical toxicology service was associated with a decrease in the number of errors in the management of paracetamol overdose.

Acetaminofen , Acetilcisteína , Overdose de Drogas , Centros de Atenção Terciária , Humanos , Acetaminofen/intoxicação , Estudos Retrospectivos , Overdose de Drogas/terapia , Overdose de Drogas/tratamento farmacológico , Feminino , Masculino , Adulto , Acetilcisteína/uso terapêutico , Pessoa de Meia-Idade , Analgésicos não Narcóticos/intoxicação , Antídotos/uso terapêutico , Toxicologia/métodos , Adulto Jovem
Clin Toxicol (Phila) ; 62(2): 76-81, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38465693


INTRODUCTION: Scientific societies aim to provide a collective voice and unified stance on important issues. The Clinical Toxicology Recommendations Collaborative was formed in 2016 to develop evidence- and consensus-based recommendations for the management of patients exposed to common and/or serious poisonings for which the management is unclear or controversial. ORGANIZATION: The Clinical Toxicology Recommendations Collaborative is led jointly by the American Academy of Clinical Toxicology, the Asia Pacific Association of Medical Toxicology, and the European Association of Poison Centres and Clinical Toxicologists. The Governance Committee is chaired by a Past-President of one of these Societies and comprised of the six Presidents and Immediate Past-Presidents of the three Societies. A Steering Committee oversees the process of each project workgroup. METHODOLOGY: The overall process is guided by standards set forth by the Institute of Medicine for developing trustworthy guidelines and the Appraisal of Guidelines for Research and Evaluation Instrument. Systematic reviews are produced using the framework set in the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Workgroup members jointly review the evidence and prepare statements on which they vote anonymously using a 9-point Likert scale. A two-round modified Delphi method is used to reach a consensus on clinical recommendations using the RAND/UCLA Appropriateness Method. Final recommendations are approved by unanimous consent of the workgroup and are expressed as both levels of evidence and strength of recommendations. LIMITATIONS: The major limitations of the Clinical Toxicology Recommendations Collaborative process centre around the amount and quality of evidence, the assessment of that evidence, and the voting of the panel. CONCLUSIONS: By using a transparent evidence- and consensus-based approach to produce systematic reviews and clinical recommendations, the Clinical Toxicology Recommendations Collaborative aims to create an international framework for clinical toxicology education and decision-making and foster positive change for the benefit of poisoned patients.

Toxicologia , Humanos , Consenso , Toxicologia/organização & administração , Medicina Baseada em Evidências , Guias como Assunto
Arch Toxicol ; 98(6): 1727-1740, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38555325


The first step in the hazard or risk assessment of chemicals should be to formulate the problem through a systematic and iterative process aimed at identifying and defining factors critical to the assessment. However, no general agreement exists on what components an in silico toxicology problem formulation (PF) should include. The present work aims to develop a PF framework relevant to the application of in silico models for chemical toxicity prediction. We modified and applied a PF framework from the general risk assessment literature to peer reviewed papers describing PFs associated with in silico toxicology models. Important gaps between the general risk assessment literature and the analyzed PF literature associated with in silico toxicology methods were identified. While the former emphasizes the need for PFs to address higher-level conceptual questions, the latter does not. There is also little consistency in the latter regarding the PF components addressed, reinforcing the need for a PF framework that enable users of in silico toxicology models to answer the central conceptual questions aimed at defining components critical to the model application. Using the developed framework, we highlight potential areas of uncertainty manifestation in in silico toxicology PF in instances where particular components are missing or implicitly described. The framework represents the next step in standardizing in silico toxicology PF component. The framework can also be used to improve the understanding of how uncertainty is apparent in an in silico toxicology PF, thus facilitating ways to address uncertainty.

Simulação por Computador , Toxicologia , Medição de Risco/métodos , Toxicologia/métodos , Humanos , Incerteza , Animais , Testes de Toxicidade/métodos
Toxicol Sci ; 199(1): 29-39, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38374304


To avoid adverse events in humans, toxicity studies in nonclinical species have been the foundation of safety evaluation in the pharmaceutical industry. However, it is recognized that working with animals in research is a privilege, and conscientious use should always respect the 3Rs: replacement, reduction, and refinement. In the wake of the shortages in routine nonrodent species and considering that nonanimal methods are not yet sufficiently mature, the value of the rabbit as a nonrodent species is worth exploring. Historically used in vaccine, cosmetic, and medical device testing, the rabbit is seldom used today as a second species in pharmaceutical development, except for embryo-fetal development studies, ophthalmic therapeutics, some medical devices and implants, and vaccines. Although several factors affect the decision of species selection, including pharmacological relevance, pharmacokinetics, and ADME considerations, there are no perfect animal models. In this forum article, we bring together experts from veterinary medicine, industry, contract research organizations, and government to explore the pros and cons, residual concerns, and data gaps regarding the use of the rabbit for general toxicity testing.

Testes de Toxicidade , Coelhos , Animais , Especificidade da Espécie , Modelos Animais , Alternativas aos Testes com Animais , Humanos , Toxicologia/métodos
ALTEX ; 41(2): 273-281, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38215352


Both because of the shortcomings of existing risk assessment methodologies, as well as newly available tools to predict hazard and risk with machine learning approaches, there has been an emerging emphasis on probabilistic risk assessment. Increasingly sophisticated AI models can be applied to a plethora of exposure and hazard data to obtain not only predictions for particular endpoints but also to estimate the uncertainty of the risk assessment outcome. This provides the basis for a shift from deterministic to more probabilistic approaches but comes at the cost of an increased complexity of the process as it requires more resources and human expertise. There are still challenges to overcome before a probabilistic paradigm is fully embraced by regulators. Based on an earlier white paper (Maertens et al., 2022), a workshop discussed the prospects, challenges and path forward for implementing such AI-based probabilistic hazard assessment. Moving forward, we will see the transition from categorized into probabilistic and dose-dependent hazard outcomes, the application of internal thresholds of toxicological concern for data-poor substances, the acknowledgement of user-friendly open-source software, a rise in the expertise of toxicologists required to understand and interpret artificial intelligence models, and the honest communication of uncertainty in risk assessment to the public.

Probabilistic risk assessment, initially from engineering, is applied in toxicology to understand chemical-related hazards and their consequences. In toxicology, uncertainties abound ­ unclear molecular events, varied proposed outcomes, and population-level assessments for issues like neurodevelopmental disorders. Establishing links between chemical exposures and diseases, especially rare events like birth defects, often demands extensive studies. Existing methods struggle with subtle effects or those affecting specific groups. Future risk assessments must address developmental disease origins, presenting challenges beyond current capabilities. The intricate nature of many toxicological processes, lack of consensus on mechanisms and outcomes, and the need for nuanced population-level assessments highlight the complexities in understanding and quantifying risks associated with chemical exposures in the field of toxicology.

Inteligência Artificial , Toxicologia , Animais , Humanos , Alternativas aos Testes com Animais , Medição de Risco/métodos , Incerteza , Toxicologia/métodos