Toxicology Database Research Articles

A novel integrated testing strategy (ITS) for evaluating acute fish toxicity with new approach methodologies (NAMs)

Acute fish toxicity (AFT) tests are performed in aquatic risk assessments of chemical compounds globally. However, the specific endpoint of in vivo AFT is based on the lethal concentration 50 (LC50), which is a serious challenge in terms of animal welfare. To support the 3Rs principle of replacing, reducing, and refining use of animals, integrated testing strategies (ITS) have recently been developed for environmental risk assessment. ITS efficiently integrates multiple types of information, especially new approach methodologies (NAMs), and further supports regulatory decision-making. Currently, an effective ITS framework for evaluating aquatic toxicity is lacking. Therefore, we aimed to develop a promising ITS for AFT using in silico, in vitro, and in vivo data. We established the ITS via in silico (OECD QSAR Toolbox 4.6), fish cell line acute toxicity (FCT), and fish embryo acute toxicity (FET) tests and then validated the NAMs with AFT testing. The NAM data were derived from the European Chemicals Agency (ECHA) dossier, toxicology databases, peer-reviewed research articles, and this study. For the first step in the ITS process, we aimed to design a high-throughput screening tool to identify non-toxic and toxic chemicals. We found that results of in silico, FCT, and FET tests alone were strongly correlated with AFT. Among the models, the in silico model was most suitable for identifying toxicants due to its high sensitivity and minimal animal use. Next, considering regulatory purposes and flexibility, we determined the predictive LC50 of toxic chemicals by pursuing a preference-dependent strategy, sequential testing strategy, and sensitivity-dependent strategy. All the strategies demonstrated a predictive power equal to or greater than 73%. In addition, to meet user preferences, our ITS approach has high flexibility and supports animal welfare and environmental protection. We have therefore developed multiple powerful, flexible, and more humane ITS methods for acute fish toxicity assessment by integrating NAMs.

Update of the risk assessment of brominated phenols and their derivatives in food.

The European Commission asked EFSA to update its 2012 risk assessment on brominated phenols and their derivatives in food, focusing on five bromophenols and one derivative: 2,4,6-tribromophenol (2,4,6-TBP), 2,4-dibromophenol (2,4-DBP), 4-bromophenol (4-BP), 2,6-dibromophenol (2,6-DBP), tetrabrominated bisphenol S (TBBPS), tetrabromobisphenol S bismethyl ether (TBBPS-BME). Based on the overall evidence, the CONTAM Panel considered invivo genotoxicity of 2,4,6-TBP to be unlikely. Effects in liver and kidney were considered as the critical effects of 2,4,6-tribromophenol (2,4,6-TBP) in studies in rats. A BMDL10 of 353 mg/kg body weight (bw) per day for kidney papillary necrosis in male rats was identified and was selected as the reference point for the risk characterisation. The derivation of a health-based guidance value was not considered appropriate due to major limitations in the toxicological database. Instead, the margin of exposure (MOE) approach was applied to assess possible health concerns. Around 78,200 analytical results for 2,4,6-TBP in food were used to estimate dietary exposure for the European population. Considering the resulting MOE values, all far above an MOE of 6000 that does not raise a health concern, and accounting for the uncertainties affecting the exposure and hazard assessments, the CONTAM Panel concluded with at least 95% probability that the current dietary exposure to 2,4,6-TBP does not raise a health concern. Due to lack of occurrence data, no risk assessment could be performed for breastfed or formula-fed infants. No risk characterisation could be performed for any of the other brominated phenols and derivatives included in the assessment, due to lack of data both on the toxicity and occurrence.

Predicting the ecological risk thresholds of soil metals in Europe using the quantitative ion character-activity relationships (QICAR) model

Metal pollutants have become increasingly diverse. Therefore, managing the ecological risks associated with these elements in soil is urgently required. However, determining the soil ecological risk thresholds of elements through routine toxicological tests is time-consuming and laborious, establishing prediction models is vital to risk management. Accordingly, this study aimed to predict the element toxicity to soil organisms by collecting the toxicological data of eight elements to soil organisms at 18 European and 17 Chinese sites through literature and toxicology databases, using the quantitative ion character-activity relationship (s-QICAR) model. Firstly, the toxicity values (logEC10) of eight elements to five biological species and three microbial processes were obtained through clustering and soil normalization methods in three typical soil scenarios. Correlation analysis revealed that for different species and microbial processes, there are three to six physicochemical properties of elements related to their toxicity, among which, the covalent radius of the element was the best significantly correlated with logEC10 of all organisms (R2 = 0.77–0.95). Based on this, the s-QICAR model was established and used to predict the logEC10 of Sc, Ti, V, Cr, Co, Ni, Cu, and Zn to eight organisms. Furthermore, along with the species sensitivity distribution curve, the HC5 values (i.e., 95% species protection level) for the above eight elements were calculated. Following correction, the predicted no-effect concentrations of these elements ranging from 9 to 189 mg/kg, and the ecological risk threshold map has been produced. In summary, we present a new method to quantify the ecological risk of metal-induced pollution in European soils without routine toxic measurements, and provide important insights into soil pollution risk assessment and management.

Sex differences among patients with intentional poisoning presenting to the emergency Department at a Tertiary Care Centre in Beirut, Lebanon.

Poisoning poses a worldwide public health challenge and recent data from Lebanon in 2020 revealed that over half patients presenting with acute toxicological exposure intentionally poisoned themselves, primarily with suspected suicidal intent. This study aims to assess sex disparities in intentional toxicological exposures among patients presenting to the Emergency Department, at a tertiary care centre in Lebanon. This was a secondary analysis of an existing toxicological database, including patients aged 6 years and older admitted due to acute overdose from March 2015 to August 2022. A total of 444 cases of intentional poisoning were analysed, with 302 (68.0%) women. The primary cause of intentional poisoning was suspected suicide in both sexes, significantly more common in women (85.1% versus 65.5%, P < 0.001). Specific agents exposed to patients varied by sex; sedatives/hypnotics/antipsychotics, antihistamines, and melitracen/flupentixol were significantly more prevalent in women (P < 0.001) while men showed higher prevalence for ethanol (P = 0.02), stimulants, street drugs and opioids (P < 0.001). Our study underscores substantial sex differences in intentional poisoning cases in Lebanon. Women exhibited a higher likelihood of exposures to sedatives/hypnotics/antipsychotics, antihistamines and melitracen/flupentixol, while stimulant drugs, ethanol, and opioids were prevalent in men. Developing proper and effective sex-specific measures may mitigate potential physical and psychological consequences.

Applications of Escherichia Coli Esterases for Bioremediation and Treatment of Wastewater Organic Chemical Pollutants

This study used computational techniques, including 3D enzyme structural modeling and molecular docking, to gain insight into the bioremediation of organic wastewater contaminants using E. coli esterase enzymes. Furthermore, a total of 24 wastewater organic chemicals belonging to different categories, such as pharmaceuticals, artificial sweeteners, pesticides/herbicides, endocrine disrupting chemicals, and persistent organic pollutants, were identified through the toxicology database. Comparative genetics and reported literature. Furthermore, 3D PDB and AlphaFold structures of 194 esterase enzymes from E. coli were retrieved by first identifying a common domain (Alpha Beta hydrolase domain) using the InterPro database. Molecular docking of esterase enzymes and pollutants was used, resulting in the best binding enzymes to their respective organic wastewater pollutants, including bezafibrate which showed the best binding with all enzymes ranging from -6.33 kcal/mol to -9.87 kcal/mol . Subsequently, the majority of the ligands (organic wastewater pollutants) reacted with enzymes such as the ORFC-like enzymes, which were computationally annotated in this study for the first time, yuaR (strain K12), menH (strain ETI89/UPEC), and menH (strain O157). :H7) has significant binding affinities and consists of a common Alpha Beta hydrolasefold-1 domain. This suggests that esterase enzymes containing the Alpha Beta hydrolasefold-1 domain may be involved in the efficient degradation of organic wastewater pollutants.

Risk assessment of small organoarsenic species in food.

The European Commission asked EFSA for a risk assessment on small organoarsenic species in food. For monomethylarsonic acid MMA(V), decreased body weight resulting from diarrhoea in rats was identified as the critical endpoint and a BMDL10 of 18.2 mg MMA(V)/kg body weight (bw) per day (equivalent to 9.7 mg As/kg bw per day) was calculated as a reference point (RP). For dimethylarsinic acid DMA(V), increased incidence in urinary bladder tumours in rats was identified as the critical endpoint. A BMDL10 of 1.1 mg DMA(V)/kg bw per day (equivalent to 0.6 mg As/kg bw per day) was calculated as an RP. For other small organoarsenic species, the toxicological data are insufficient to identify critical effects and RPs, and they could not be included in the risk assessment. For both MMA(V) and DMA(V), the toxicological database is incomplete and a margin of exposure (MOE) approach was applied for risk characterisation. The highest chronic dietary exposure to DMA(V) was estimated in 'Toddlers', with rice and fish meat as the main contributors across population groups. For MMA(V), the highest chronic dietary exposures were estimated for high consumers of fish meat and processed/preserved fish in 'Infants' and 'Elderly' age class, respectively. For MMA(V), an MOE of ≥ 500 was identified not to raise a health concern. For MMA(V), all MOEs were well above 500 for average and high consumers and thus do not raise a health concern. For DMA(V), an MOE of 10,000 was identified as of low health concern as it is genotoxic and carcinogenic, although the mechanisms of genotoxicity and its role in carcinogenicity of DMA(V) are not fully elucidated. For DMA(V), MOEs were below 10,000 in many cases across dietary surveys and age groups, in particular for some 95th percentile exposures. The Panel considers that this would raise a health concern.

Unveiling the Dark Side of Datura in Pediatric Poisoning With Insights From Jordanian Experience : A Retrospective Clinical Study.

Datura stramonium , jimsonweed, is a toxic plant with hallucinogenic properties. Although there are many studies on Datura poisoning, none reported cases in Jordan. This study offers a comprehensive review on D. stramonium ingestion, covering its epidemiology, clinical presentation, and treatment. We aimed to provide better understanding of the factors for Datura ingestion, identify prevention and management strategies, and address research challenges. This study adopted a retrospective review design to evaluate the cases of Datura poisoning in Al Karak, province of Jordan during the spring of 2022. Data collected from medical records, toxicology databases, and consultation records were analyzed using descriptive statistics. The common symptoms of Datura poisoning included agitation, mydriasis, and tachycardia. The management approaches comprised supportive care, administration of Diazepam for agitation, and, in some cases, neostigmine to counteract anticholinergic effects. Understanding the risks associated with D. stramonium poisoning and implementing effective prevention and management strategies are crucial. This study highlights the importance of recognizing Datura poisoning as a potential diagnosis in children presenting with unexplained anticholinergic symptoms or agitation to the emergency room.

An Investigation of the Toxicity and Mechanisms of Food Additives Based on Network Toxicology and GEO Databases: A Case Study of Aspartame

An Investigation of the Toxicity and Mechanisms of Food Additives Based on Network Toxicology and GEO Databases: A Case Study of Aspartame

Biochemical and physiological alterations caused by Diuron and Triclosan in mussels (Mytilus galloprovincialis)

The rise in the utilization of pesticides within industrial and agricultural practices has been linked to the occurrence of these substances in aquatic environments. The objective of this work was to evaluate the uptake and adverse impacts of Diuron (Di) and Triclosan (TCS) on the mussel species Mytilus galloprovincialis. To accomplish this, the accumulation and toxicity of these pesticides were gauged following a brief period of exposure spanning 14 days, during which the mussels were subjected to two concentrations (50 and 100 μg/L) of each substance that are ecologically relevant. Chemical analysis of Di and TCS within gills and digestive gland showed that these pesticides could be accumulated in mussel's tissues. In addition, Di and TCS are preferably accumulated in digestive gland.Measured biomarkers included physiological parameters (filtration FC and respiration RC capacity), antioxidant enzyme activities (superoxide dismutase and catalase), oxidative damage indicator (Malondialdheyde concentration) and neurotoxicity level (acetylcholinesterase activity) were evaluated in gills and digestive glands. Both pesticides were capable of altering the physiology of this species by reducing the FC and RC in concentration and chemical dependent manner. Both pesticides induced also an oxidative imbalance causing oxidative stress. The high considered concentration exceeded the antioxidant defense capacity of the mussel and lead to membrane lipid peroxidation that resulted in cell damage. Finally, the two pesticides tested were capable of interacting with the neuromuscular barrier leading to neurotoxicity in mussel's tissues by inhibiting acetylcholinesterase. The ecotoxicological effect depended on the concentration and the chemical nature of the contaminant. Obtained results revealed also that the Di may exert toxic effects on M. galloprovincialis even at relatively low concentrations compared to TCS.In conclusion, this study presents innovative insights into the possible risks posed by Diuron (Di) and Triclosan (TCS) to the marine ecosystem. Moreover, it contributes essential data to the toxicological database necessary for developing proactive environmental protection measures.

Single-cell and bulk RNA-sequencing analysis to predict the role and clinical value of CD36 in lung squamous cell carcinoma

The majority of patients with lung squamous cell carcinoma are diagnosed at an advanced stage, which poses a challenge to the efficacy of chemotherapy. Therefore, the search for an early biomarker needs to be addressed. CD36 is a scavenger receptor expressed in various cell types. It has been reported that it is closely related to the occurrence and development of many kinds of tumours. However, its role in lung squamous cell carcinoma has not been reported. Our research aims to reveal the role of CD36 in lung squamous cell carcinoma by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. We used bioinformatics methods to explore the potential carcinogenicity of CD36 by analysing the data from the cancer genome map (TCGA), gene expression comprehensive map (GEO), human protein map (HPA) comparative toxicology genomics database (CTD) and other resources. Our study dissected the relationship between CD36 and prognosis and gene correlation, functional analysis, mutation of different tumours, infiltration of immune cells and exploring the interaction between CD36 and chemicals. The results showed that the expression of CD36 was heterogeneous. Compared with normal patients, the expression was low in lung squamous cell carcinoma. In addition, CD36 showed early diagnostic value in four kinds of tumours (LUSC, BLCA, BRCA and KIRC) and was positively or negatively correlated with the prognosis of different tumours. The relationship between CD36 and the tumour immune microenvironment was revealed by immunoinfiltration analysis, and many drugs that might target CD36 were identified by the comparative toxicological genomics database (CTD). In summary, through pancancer analysis, we found and verified for the first time that CD36 may play a role in the detection of lung squamous cell carcinoma. In addition, it has high specificity and sensitivity in detecting cancer. Therefore, CD36 can be used as an auxiliary index for early tumour diagnosis and a prognostic marker for lung squamous cell carcinoma.

Artificial Intelligence in Toxicology and Pharmacology

Methods that utilize machine learning and artificial intelligence have transformed a wide variety of fields, including the field of toxicology. Physiologically based pharmacokinetic (PBPK) modeling, quantitative structure-activity relationship modeling for toxicity prediction, adverse outcome pathway analysis, high-throughput screening, toxicogenomics, big data, and toxicological databases are just some of the areas that are covered in this review. By leveraging machine learning and artificial intelligence approaches, it is now possible to develop PBPK models for hundreds of chemicals in an efficient manner, to create in silico models to predict toxicity for a large number of chemicals with similar accuracies compared with In vivo animal experiments, and to analyze a large amount of data of various types (toxicogenomics, high-content image data, etc.) to generate new insights into toxicity mechanisms rapidly, which was previously impossible. This is an improvement over the previous situation The field of toxicological sciences faces a number of challenges that must be overcome before it can make further progress. These challenges include the following: (1) not all machine learning models are equally useful for a particular type of toxicology data; therefore, it is important to test different methods to determine the optimal approach; (2) the current toxicity prediction is primarily based on bioactivity classification (yes/no); therefore, additional studies are required to predict the intensity of effect or dose-response relationship.

Apoptosis pathways and osteoporosis: An approach to genomic analysis.

Osteoporosis is a disease of the bone system that causes a decrease in skeletal density and degrades skeletal tissue. Decreased bone quality, so that bones are easily broken, damaged and fractured, is an important public health problem. Previous studies have shown that the maintenance of adult bone mass is not only due to changes in bone marrow and bone cells. By regulating apoptosis, they change the lifespan of each individual. This study influences understanding of the function of apoptosis in the pathogenesis of osteoporosis and the importance of controlling the mechanisms of osteoporosis. On the National Institute of Biotechnology Information website, Gene Expression Omnibus (GEO) microarray data and GSE551495 GEO profiles were collected. The gene set enrichment analysis tool was used to confirm the enrichment of genetic sets in relation to the gene set. The collection of C2 gene sets is compiled from the KEGG (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://www.kegg.jp/kegg/) online database and REACTOME (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://reactome.org/) pathway analysis. The Search Tool for the Retrieval of Interaction Genes (STRING) website was used to construct and select proteins and genes. The comparative toxicological genomic database (CTD) tools can be used to predict the relationship between apoptosis, osteoporosis-related genes and interactions between central genes and osteoporosis. These results generally expand our understanding of the path of apoptosis in osteoporosis. We have discovered genes CASP9, CASP8, CASP3, BAX and TP53 associated with osteoporosis. In activation of KEGG apoptosis and REACTOME, caspase activation through the extrinsic apoptotic signaling pathway is characterized by the identification of a subcollection of C2. Other STRINGs show the formation of protein networks and central gene selection, and CTD can accurately predict the relationship between these apoptosis pathways and central genes. Our research has highlighted the importance of the osteoporosis pathway associated with osteoporosis apoptosis with several analytical approaches. These results have broadened our understanding of the pathways of osteoporosis apoptosis. It is particularly possible to predict the sensitivity and vulnerability to osteoporosis.

Follow-up of the re-evaluation of glycerol esters of wood rosins (E 445) as a food additive.

Glycerol esters of wood rosin (GEWR) (E 445) were re-evaluated in 2018. On the toxicity database and given the absence of reproductive and developmental toxicity data, the acceptable daily intake (ADI) of 12.5 mg/kg body weight (bw) per day for GEWR (E 445) established by the Scientific Committee on Food (SCF) in 1994 was considered temporary. The conclusions of the assessment were restricted to GEWR derived from Pinus palustris and Pinus elliottii and with a chemical composition in compliance with GEWR used in the toxicological testing. Following a European Commission call for data to submit data to fill the data gaps, the present follow-up opinion assesses data provided by interested business operators (IBOs). Considering the technical data submitted by IBOs, the EFSA Panel on Food Additives and Flavourings (FAF Panel) recommended some modifications of the existing EU specifications for E445, mainly a revision of the definition of the food additive and lowering the limits for toxic elements. Considering the available toxicological database evaluated during the re-evaluation of E 445 by the ANS Panel in 2018, and the toxicological studies submitted by the IBOs, the Panel established an ADI of 10 mg/kg bw per day based on the no observed adverse effect level (NOAEL) of 976 mg/kg bw per day from the newly available dietary reproduction/developmental toxicity screening study in rats and applying an uncertainty factor of 100. Since GEWR from P. palustris and P. elliottii were tested in the toxicity studies considered to establish the ADI and in the absence of detailed information on the chemical composition (major constituents) in GEWR generated from other Pinus species, thus not allowing read across, the ADI is restricted to the GEWR (E 445) manufactured from P. palustris and P.elliottii. The Panel concluded that there was no safety concern for the use of GEWR (E 445), at either the maximum permitted levels or at the reported uses and use levels.

Supercritical Fluid Chromatography Coupled to High-Resolution Mass Spectrometry Reveals Persistent Mobile Organic Compounds with Unknown Toxicity in Wastewater Effluents.

Broad screening approaches for monitoring wastewater are normally based on reversed-phase liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS). This method is not sufficient for the very polar micropollutants, neglected in the past due to a lack of suitable analytical methods. In this study, we used supercritical fluid chromatography (SFC) to detect very polar and yet-undetected micropollutants in wastewater effluents. We tentatively identified 85 compounds, whereas 18 have only rarely been detected and 11 have not previously been detected in wastewater effluents such as 17α-hydroxypregnenolone, a likely transformation product (TP) of steroids, and 1H-indole-3-carboxamide, a likely TP from new synthetic cannabinoids. Suspect screening of 25 effluent wastewater samples from 8 wastewater treatment plants revealed several distinct potential pollution sources such as a pharmaceutical company and a golf court. The analysis of the same samples with LC-HRMS showed clearly how SFC increases the ionization efficiency for low-molecular-weight micropollutants (m/z < 300 Da) by a factor 2 to 87 times, which significantly improved the mass spectra for identifying very polar compounds. In order to assess which micropollutants might be of environmental concern, literature and toxicological databases were screened. There was a lack of available hazard and bio-activity data for regulatory-relevant in vitro and in vivo assays for >50% of the micropollutants. Especially, 70% of the data were lacking for the whole organism (in vivo) tests.

A new approach methodology using kinetically-derived maximum dose levels in risk assessment – A case study with afidopyropen

We present a case study for afidopyropen (AF; insecticide) to characterize chronic dietary human health risk using a Risk 21-based approach. Our objective is to use a well-tested pesticidal active ingredient (AF) to show how a new approach methodology (NAM), using the kinetically-derived maximum dose (KMD) and with far less animal testing, can reliably identify a health-protective point of departure (PoD) for chronic dietary human health risk assessments (HHRA). Chronic dietary HHRA involves evaluation of both hazard and exposure information to characterize risk. Although both are important, emphasis has been placed on a checklist of required toxicological studies for hazard characterization, with human exposure information only considered after evaluation of hazard data. Most required studies are not used to define the human endpoint for HHRA. The information presented demonstrates a NAM that uses the KMD determined by saturation of a metabolic pathway, which can be used as an alternative POD. In these cases, the full toxicological database may not need to be generated. Demonstration that the compound is not genotoxic and that the KMD is protective of adverse effects in 90-day oral rat and reproductive/developmental studies is sufficient to support the use of the KMD as an alternative POD.

Assessing Hazard Potential of Select Chemicals using Computational Toxicology Models

Release of potentially persistent, bioaccumulative and inherently toxic chemicals into the environment may cause adverse effects to plants and animals. Hundreds of thousands of chemicals are manufactured each year and experimentally assessing them for these parameters is costly, time consuming and requires animal testing. To address these concerns there has been a paradigm shift in adoption of computational chemistry and toxicology methods for assessing environmental risks posed by such chemicals. These computer-based methods harness the power of fast processors, high speed internet, statistical methods, and curated toxicological databases to fulfil this need. In this work a summary of selected publicly available computational models and databases is presented. Global regulatory agencies apply these predictive models to support their decisions. Indian regulatory bodies too could benefit from this exercise in identifying chemicals of ecotoxicological concern and in taking an appropriate regulatory decision thereby protecting the environment.

A Knowledge, Attitude and Practices Study on Clinical Toxicology among Internees and Registered Medical Practitioners at a Tertiary Care Hospital

The present KAP study aimed to ascertain the knowledge, attitudes, and practices on clinical toxicology amonginternees and medical doctors at ACSR Govt. Medical College &amp; Hospital, Nellore, Andhra Pradesh, India, in thelight of implementing new National Medical Commission curriculum (Graduate Medical Regulations 2019). Thestudy also aimed at understanding the knowledge and training gaps pertaining to clinical toxicology in the targetpopulation and thereby propose interventions for proper delivery of toxicology curriculum.A semi structured questionnaire was used to elicit information wherein 120 health care providers voluntarilyparticipated in the study. The results detected significant deficits towards understanding concepts in clinicaltoxicology and implementation of evidence-based approach in providing care. Our study identified the need tostress on toxidrome based approach, use of evidence-based decontamination methods, the necessity to stabilise the patientmore than being enthusiastic in diagnosing the poisoning, increased use of multidose activated charcoal as a primary antidote,use of poison control centre helpline, material safety data sheet &amp; toxicology databases when in doubt, employing holistic caremodels, providing education on social &amp; preventive toxicology and role of screening in chronic paediatric poisonings.

Machine Learning Toxicity Prediction: Latest Advances by Toxicity End Point.

Machine learning (ML) models to predict the toxicity of small molecules have garnered great attention and have become widely used in recent years. Computational toxicity prediction is particularly advantageous in the early stages of drug discovery in order to filter out molecules with high probability of failing in clinical trials. This has been helped by the increase in the number of large toxicology databases available. However, being an area of recent application, a greater understanding of the scope and applicability of ML methods is still necessary. There are various kinds of toxic end points that have been predicted in silico. Acute oral toxicity, hepatotoxicity, cardiotoxicity, mutagenicity, and the 12 Tox21 data end points are among the most commonly investigated. Machine learning methods exhibit different performances on different data sets due to dissimilar complexity, class distributions, or chemical space covered, which makes it hard to compare the performance of algorithms over different toxic end points. The general pipeline to predict toxicity using ML has already been analyzed in various reviews. In this contribution, we focus on the recent progress in the area and the outstanding challenges, making a detailed description of the state-of-the-art models implemented for each toxic end point. The type of molecular representation, the algorithm, and the evaluation metric used in each research work are explained and analyzed. A detailed description of end points that are usually predicted, their clinical relevance, the available databases, and the challenges they bring to the field are also highlighted.

Toxic Effects Produced by Anatoxin-a under Laboratory Conditions: A Review.

The presence of cyanotoxins and its bioaccumulation in the food chain is an increasingly common problem worldwide. Despite the toxic effects produced by Anatoxin-a (ATX-a), this neurotoxin has been less studied compared to microcystins (MCs) and cylindrospermopsin (CYN). Studies conducted under laboratory conditions are of particular interest because these provide information which are directly related to the effects produced by the toxin. Currently, the World Health Organization (WHO) considers the ATX-a toxicological database inadequate to support the publication of a formal guideline reference value. Therefore, the aim of the present work is to compile all of the in vitro and in vivo toxicological studies performed so far and to identify potential data gaps. Results show that the number of reports is increasing in recent years. However, more in vitro studies are needed, mainly in standardized neuronal cell lines. Regarding in vivo studies, very few of them reflect conditions occurring in nature and further studies with longer periods of oral exposure would be of interest. Moreover, additional toxicological aspects of great interest such as mutagenicity, genotoxicity, immunotoxicity and alteration of hormonal balance need to be studied in depth.

Epidemiology meets toxicogenomics: Mining toxicologic evidence in support of an untargeted analysis of pesticides exposure and Parkinson’s disease

BackgroundPesticides have been widely used in agriculture for more than half a century. However, with thousands currently in use, most have not been adequately assessed for influence Parkinson’s disease (PD). ObjectivesHere we aimed to assess biologic plausibility of 70 pesticides implicated with PD through an agnostic pesticide-wide association study using a data mining approach linking toxicology and toxicogenomics databases. MethodsWe linked the 70 targeted pesticides to quantitative high-throughput screening assay findings from the Toxicology in the 21st Century (Tox21) program and pesticide-related genetic/disease information with the Comparative Toxicogenomics Database (CTD). We used the CTD to determine networks of genes each pesticide has been linked to and assess enrichment of relevant gene ontology (GO) annotations. With Tox21, we evaluated pesticide induced activity on a series of 43 nuclear receptor and stress response assays and two cytotoxicity assays. ResultsOverall, 59 % of the 70 pesticides had chemical-gene networks including at least one PD gene/gene product. In total, 41 % of the pesticides had chemical-gene networks enriched for ≥ 1 high-priority PD GO terms. For instance, 23 pesticides had chemical-gene networks enriched for response to oxidative stress, 21 for regulation of neuron death, and twelve for autophagy, including copper sulfate, endosulfan and chlorpyrifos. Of the pesticides tested against the Tox21 assays, 79 % showed activity on ≥ 1 assay and 11 were toxic to the two human cell lines. The set of PD-associated pesticides showed more activity than expected on assays testing for xenobiotic homeostasis, mitochondrial membrane permeability, and genotoxic stress. ConclusionsOverall, cross-database queries allowed us to connect a targeted set of pesticides implicated in PD via epidemiology to specific biologic targets relevant to PD etiology. This knowledge can be used to help prioritize targets for future experimental studies and improve our understanding of the role of pesticides in PD etiology.