Empirical analysis of lead neurotoxicity mode of action and its application in health risk assessment.

The mode of action (MOA) framework is proposed to inform a biological link between chemical exposures and adverse health effects. Despite a significant increase in knowledge and awareness, the application of MOA in human health risk assessment (RA) remains limited. This study aims to discuss the adoption of MOA for health RA within a regulatory context, taking our previously proposed but not yet validated MOA for lead neurotoxicity as an example. We first conducted a quantitative weight of evidence (qWOE) assessment, which revealed that the MOA has a moderate confidence. Then, targeted bioassays were performed within an in vitro blood-brain barrier (BBB) model to quantitatively validate the scientific validity of key events (KEs) in terms of essentiality and concordance of empirical support (dose/temporal concordance), which increases confidence in utilizing the MOA for RA. Building upon the quantitative validation data, we further conducted benchmark dose (BMD) analysis to map dose-response relationships for the critical toxicity pathways, and the lower limit of BMD at a 5% response (BMDL5) was identified as the point of departure (POD) value for adverse health effects. Notably, perturbation of the Aryl Hydrocarbon Receptor (AHR) signaling pathway exhibited the lowest POD value, measured at 0.0062 µM. Considering bioavailability, we further calculated a provisional health-based guidance value (HBGV) for children's lead intake, determining it to be 2.56 µg/day. Finally, the health risk associated with the HBGV was assessed using the hazard quotient (HQ) approach, which indicated that the HBGV established in this study is a relative safe reference value for lead intake. In summary, our study described the procedure for utilizing MOA in health RA and set an example for MOA-based human health risk regulation.

Assessment of Developmental Neurotoxicity Using Semi-automatic Behavior Analysis System for Zebrafish.

Traditionally, morphological, conventional, and toxicological approaches have been used to demonstrate neurotoxicity; however, there has been a growing interest in animal behavioral methods for assessing neurotoxicity, both at the scientific and regulatory levels. Zebrafish (Danio rerio) is a small tropical freshwater fish currently recognized as a suitable model organism for investigating developmental neurotoxicity. There are many animal-tracking software programms used for behavioral analysis in biomedical research. Some of these software programms require a fee, which may exceed the laboratory budget and require detailed technical equipment. As a solution, freely available programs can be used. However, animal tracking may not be possible due to the glare from the aquatic environment of fish, and the small size of zebrafish embryos makes animal tracking difficult. In our laboratory, we developed a semi-automatic system to overcome these difficulties by using three different software available for free. This chapter explains the system for zebrafish embryos and adult zebrafish.

Eastern Mediterranean Health Journal [2023; Vol.29, Issue 8]

Eastern Mediterranean Health Journal is the official health journal published by the Eastern Mediterranean Regional Office of the World Health Organization. It is a forum for the presentation and promotion of new policies and initiatives in health services; and for the exchange of ideas concepts epidemiological data research findings and other information with special reference to the Eastern Mediterranean Region. It addresses all members of the health profession medical and other health educational institutes interested NGOs WHO Collaborating Centres and individuals within and outside the Region

المجلة الصحية لشرق المتوسط هى المجلة الرسمية التى تصدرعن المكتب الاقليمى لشرق المتوسط بمنظمة الصحة العالمية. وهى منبر لتقديم السياسات والمبادرات الجديدة فى الصحة العامة والخدمات الصحية والترويج لها، و لتبادل الاراء و المفاهيم والمعطيات الوبائية ونتائج الابحاث وغير ذلك من المعلومات، و خاصة ما يتعلق منها باقليم شرق المتوسط. وهى موجهة الى كل اعضاء المهن الصحية، والكليات الطبية وسائر المعاهد التعليمية، و كذا المنظمات غير الحكومية المعنية، والمراكز المتعاونة مع منظمة الصحة العالمية والافراد المهتمين بالصحة فى الاقليم و خارجه

La Revue de Santé de la Méditerranée Orientale est une revue de santé officielle publiée par le Bureau régional de l’Organisation mondiale de la Santé pour la Méditerranée orientale. Elle offre une tribune pour la présentation et la promotion de nouvelles politiques et initiatives dans le domaine de la santé publique et des services de santé ainsi qu’à l’échange d’idées de concepts de données épidémiologiques de résultats de recherches et d’autres informations se rapportant plus particulièrement à la Région de la Méditerranée orientale. Elle s’adresse à tous les professionnels de la santé aux membres des instituts médicaux et autres instituts de formation médico-sanitaire aux ONG Centres collaborateurs de l’OMS et personnes concernés au sein et hors de la Région

Non-disclosure of developmental neurotoxicity studies obstructs the safety assessment of pesticides in the European Union.

BACKGROUND: In the European Union (EU), the safety assessment of plant protection products relies to a large extent on toxicity studies commissioned by the companies producing them. By law, all performed studies must be included in the dossier submitted to authorities when applying for approval or renewal of the active substance. METHODS: For one type of toxicity, i.e. developmental neurotoxicity (DNT), we evaluated if studies submitted to the U.S. Environmental Protection Agency (EPA) had also been disclosed to EU authorities. RESULTS: We identified 35 DNT studies submitted to the U.S. EPA and with the corresponding EU dossiers available. Of these, 9 DNT studies (26%) were not disclosed by the pesticide company to EU authorities. For 7 of these studies, we have identified an actual or potential regulatory impact. CONCLUSIONS: We conclude that (1) non-disclosure of DNT studies to EU authorities, in spite of clear legal requirements, seems to be a recurring phenomenon, (2) the non-disclosure may introduce a bias in the regulatory risk assessment, and (3) without full access to all performed toxicity studies, there can be no reliable safety evaluation of pesticides by EU authorities. We suggest that EU authorities should cross-check their data sets with their counterparts in other jurisdictions. In addition, applications for pesticide approval should be cross-checked against lists of studies performed at test facilities operating under Good Laboratory Practice (GLP), to ensure that all studies have been submitted to authorities. Furthermore, rules should be amended so that future studies should be commissioned by authorities rather than companies. This ensures the authorities' knowledge of existing studies and prevents the economic interest of the company from influencing the design, performance, reporting and dissemination of studies. The rules or practices should also be revised to ensure that non-disclosure of toxicity studies carries a significant legal risk for pesticide companies.

Framework to leverage physical therapists for the assessment and treatment of chemotherapy-induced peripheral neurotoxicity (CIPN).

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a highly prevalent, dose-limiting, costly, and tough-to-treat adverse effect of several chemotherapy agents, presenting as sensory and motor dysfunction in the distal extremities. Due to limited effective treatments, CIPN can permanently reduce patient function, independence, and quality of life. One of the most promising interventions for CIPN is physical therapy which includes exercise, stretching, balance, and manual therapy interventions. Currently, there are no physical therapy guidelines for CIPN, thus limiting its uptake and potential effectiveness. METHODS: Utilizing the authors' collective expertise spanning physical therapy, symptom management research, oncology, neurology, and treating patients with CIPN, we propose a comprehensive clinical workflow for physical therapists to assess and treat CIPN. This workflow is based on (1) physical therapy guidelines for treating neurologic symptoms like those of CIPN, (2) results of clinical research on physical therapy and exercise, and (3) physical therapy clinical judgement. RESULTS: We present detailed tables of pertinent physical therapy assessment and treatment methods that can be used in clinical settings. CIPN assessment should include detailed sensory assessment, objective strength assessments of involved extremities, and validated physical performance measures incorporating static and dynamic balance, gait, and functional mobility components. CIPN treatment should involve sensorimotor, strength, balance, and endurance-focused interventions, alongside a home-based exercise prescription that includes aerobic training. We conclude with action items for oncology teams, physical therapists, patients, and researchers to best apply this framework to address CIPN. CONCLUSIONS: Physical therapists are in a unique position to help assess, prevent, and treat CIPN given their training and prevalence, yet there are no physical therapy clinical practice guidelines for CIPN. Our preliminary suggestions for CIPN assessments and treatments can catalyze the development of guidelines to assess and treat CIPN. We urge oncology teams, physical therapists, patients, and researchers to develop, adapt, and disseminate this framework to help alleviate the burden of chemotherapy on patients with cancer.

Risk assessment of combined exposure to lead, cadmium, and total mercury among the elderly in Shanghai, China.

Lead (Pb), cadmium (Cd) and total mercury (THg) are toxic heavy metals (THMs) that are widely present in the environment and can cause substantial health problems. However, previous risk assessment studies have rarely focused on the elderly population and have usually targeted a single heavy metal, which might underestimate the long-term accumulative and synergistic effects of THMs in humans. Based on the food frequency questionnaire and inductively coupled plasma mass spectrometry, this study assessed external and internal exposures to Pb, Cd and THg in 1747 elderly people in Shanghai. Probabilistic risk assessment with the relative potential factor (RPF) model was used to assess the neurotoxicity and nephrotoxicity risks of combined THMs exposures. The mean external exposures of Pb, Cd and THg in Shanghai elderly were 46.8, 27.2 and 4.9 µg/day, respectively. Plant-based foods are the main source of Pb and THg exposure, while Cd is mainly from animal-based foods. The mean concentrations of Pb, Cd and THg were 23.3, 1.1 and 2.3 µg/L in the whole blood, and 6.2, 1.0 and 2.0 µg/L in the morning urine, respectively. Combined exposure to THMs leading to 10.0 % and 7.1 % of Shanghai elderly at risk of neurotoxicity and nephrotoxicity. The results of this study have important implications for understanding the profiles of Pb, Cd and THg exposure in the elderly living in Shanghai and provide data support for risk assessment and control of nephrotoxicity and neurotoxicity from combined THMs exposure in the elderly.

CAR t-cell therapy in BOlogNa-NEUrotoxicity TReatment and Assessment in Lymphoma (CARBON-NEUTRAL): proposed protocol and results from an Italian study.

OBJECTIVE: To investigate neurotoxicity clinical and instrumental features, incidence, risk factors, and early and long-term prognosis in lymphoma patients who received CAR T-cell therapy. METHODS: In this prospective study, consecutive refractory B-cell non-Hodgkin lymphoma patients who received CAR T-cell therapy were included. Patients were comprehensively evaluated (neurological examination, EEG, brain MRI, and neuropsychological test) before and after (two and twelve months) CAR T-cells. From the day of CAR T-cells infusion, patients underwent daily neurological examinations to monitor the development of neurotoxicity. RESULTS: Forty-six patients were included in the study. The median age was 56.5 years, and 13 (28%) were females. Seventeen patients (37%) developed neurotoxicity, characterized by encephalopathy frequently associated with language disturbances (65%) and frontal lobe dysfunction (65%). EEG and brain FDG-PET findings also supported a predominant frontal lobe involvement. The median time at onset and duration were five and eight days, respectively. Baseline EEG abnormalities predicted ICANS development in the multivariable analysis (OR 4.771; CI 1.081-21.048; p = 0.039). Notably, CRS was invariably present before or concomitant with neurotoxicity, and all patients who exhibited severe CRS (grade ≥ 3) developed neurotoxicity. Serum inflammatory markers were significantly higher in patients who developed neurotoxicity. A complete neurological resolution following corticosteroids and anti-cytokines monoclonal antibodies was reached in all patients treated, except for one patient developing a fatal fulminant cerebral edema. All surviving patients completed the 1-year follow-up, and no long-term neurotoxicity was observed. CONCLUSIONS: In the first prospective Italian real-life study, we presented novel clinical and investigative insights into ICANS diagnosis, predictive factors, and prognosis.

Assessment of neurotransmitter release in human iPSC-derived neuronal/glial cells: a missing in vitro assay for regulatory developmental neurotoxicity testing.

Human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) and their differentiated neuronal/glial derivatives have been recently considered suitable to assess in vitro developmental neurotoxicity (DNT) triggered by exposure to environmental chemicals. The use of human-relevant test systems combined with in vitro assays specific for different neurodevelopmental events, enables a mechanistic understanding of the possible impact of environmental chemicals on the developing brain, avoiding extrapolation uncertainties associated with in vivo studies. Currently proposed in vitro battery for regulatory DNT testing accounts for several assays suitable to study key neurodevelopmental processes, including NSC proliferation and apoptosis, differentiation into neurons and glia, neuronal migration, synaptogenesis, and neuronal network formation. However, assays suitable to measure interference of compounds with neurotransmitter release or clearance are at present not included, which represents a clear gap of the biological applicability domain of such a testing battery. Here we applied a HPLC-based methodology to measure the release of neurotransmitters in a previously characterized hiPSC-derived NSC model undergoing differentiation towards neurons and glia. Glutamate release was assessed in control cultures and upon depolarization, as well as in cultures repeatedly exposed to some known neurotoxicants (BDE47 and lead) and chemical mixtures. Obtained data indicate that these cells have the ability to release glutamate in a vesicular manner, and that both glutamate clearance and vesicular release concur in the maintenance of extracellular glutamate levels. In conclusion, analysis of neurotransmitter release is a sensitive readout that should be included in the envisioned battery of in vitro assays for DNT testing.

Considering developmental neurotoxicity in vitro data for human health risk assessment using physiologically-based kinetic modeling: deltamethrin case study.

Developmental neurotoxicity (DNT) is a potential hazard of chemicals. Recently, an in vitro testing battery (DNT IVB) was established to complement existing rodent in vivo approaches. Deltamethrin (DLT), a pyrethroid with a well-characterized neurotoxic mode of action, has been selected as a reference chemical to evaluate the performance of the DNT IVB. The present study provides context for evaluating the relevance of these DNT IVB results for the human health risk assessment of DLT by estimating potential human fetal brain concentrations after maternal exposure to DLT. We developed a physiologically based kinetic (PBK) model for rats which was then translated to humans considering realistic in vivo exposure conditions (acceptable daily intake [ADI] for DLT). To address existing uncertainties, we designed case studies considering the most relevant drivers of DLT uptake and distribution. Calculated human fetal brain concentrations were then compared with the lowest benchmark concentration achieved in the DNT IVB. The developed rat PBK model was validated on in vivo rat toxicokinetic data of DLT over a broad range of doses. The uncertainty based case study evaluation confirmed that repeated exposure to DLT at an ADI level would likely result in human fetal brain concentrations far below the in vitro benchmark. The presented results indicate that DLT concentrations in the human fetal brain are highly unlikely to reach concentrations associated with in vitro findings under realistic exposure conditions. Therefore, the new in vitro DNT results are considered to have no impact on the current risk assessment approach.

Assessment of Pretreatment and Posttreatment Evolution of Neurofilament Light Chain Levels in Patients Who Develop Immune Effector Cell-Associated Neurotoxicity Syndrome.

Importance: Determining whether neurofilament light chain (NfL) elevations in patients who develop immune effector cell-associated neurotoxicity syndrome (ICANS) occur before or after infusion of cellular product is important to identify high-risk patients and inform whether neuroaxonal injury is latent or a consequence of treatment. Objective: To quantify serial NfL levels in patients undergoing cellular therapy. Design, Setting, and Participants: This retrospective 2-center study examined plasma NfL levels in 30 patients with detailed medical and treatment history, including all major pretreatment and posttreatment risk factors. Exclusion criteria included dementia and severe, symptomatic central nervous system (CNS) involvement. Main Outcomes and Measures: Patients' NfL levels were measured at 7 time points: baseline (prelymphodepletion), during lymphodepletion, postinfusion day (D) 1, D3, D7, D14, and D30. Prediction accuracy for the development of ICANS was next modeled using receiver operating characteristic (ROC) classification. Finally, univariate and multivariate modeling examined the association between NfL levels, ICANS, and potential risk factors including demographic (age, sex), oncologic (tumor burden, history of CNS involvement), neurologic (history of nononcologic CNS disease or neuropathy), and neurotoxic exposure histories (vincristine, cytarabine, methotrexate, or CNS radiotherapy). Results: A total of 30 patients (median [range] age, 64 [22-80] years; 12 women [40%] and 18 men [60%]) were included. Individuals who developed ICANS had elevations in NfL prior to lymphodepletion and chimeric antigen receptor T-cell infusion compared with those who did not develop ICANS (no ICANS: 29.4 pg/mL, vs any ICANS: 87.6 pg/mL; P < .001). Baseline NfL levels further predicted ICANS development with high accuracy (area under the ROC curve, 0.96), sensitivity (0.91), and specificity (0.95). Levels of NfL remained elevated across all time points, up to 30 days postinfusion. Baseline NfL levels correlated with ICANS severity but not demographic factors, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies. Conclusions and Relevance: In a subset of patients in this cross-sectional study, the risk of developing ICANS was associated with preexisting neuroaxonal injury that was quantifiable with plasma NfL level. This latent neuroaxonal injury was present prior to drug administration but was not associated with historic neurotoxic therapies or nononcologic neurologic disease. Preinfusion NfL may further permit early screening and identification of patients most at risk for ICANS. Additional studies are needed to determine NfL's utility as a predictive biomarker for early (preemptive or prophylactic) intervention and to delineate the origin of this underlying neural injury.