Hasil untuk "Toxicology. Poisons"

Laura N. Vandenberg, Elise J. Pierce, Rachel M. Arsenault

There is increasing evidence that pesticides act as endocrine disruptors, developmental toxicants, and reproductive toxicants. In this review, we describe several global challenges associated with pesticide production and use that put the health of human and wildlife populations at risk. These include: (1) the global production and use of pesticides is high, leading to increasing rates of release into the environment; (2) exposures to non-target species (including humans) are well documented, and pesticides often have adverse effects on these species; (3) pesticides, and especially those that are persistent organic pollutants, do not stay where they are used, contributing to ecosystem pollution far from their intended areas of application; (4) climate change can exacerbate the use of pesticides; and (5) social determinants of health (race/ethnicity, sex, and occupation) influence pesticide exposures and the adverse effects associated with these exposures. In 2009, the concept of planetary boundaries was introduced as a framework to evaluate how human actions impact earth systems. The planetary boundaries were based on a shared understanding that human activities have significant and sometimes irreversible effects on key aspects of environmental health. When considering the global impact of pesticides, these products can disrupt several planetary boundaries including biogeochemical cycles, biosphere integrity (e.g., measures of biodiversity), and the availability of clean freshwater, but the greatest challenge posed by pesticides is the “novel entities” boundary (i.e., the introduction of synthetic chemicals and materials into the environment). The planetary boundaries framework makes clear that failure to act against the most concerning chemicals, including pesticides, ultimately puts the survival of human populations at risk.

Yinuo Chen, Yiyang Nan, Lang Xu et al.

Abstract Background Recent studies emphasize the significance of copper dyshomeostasis in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, thereby highlighting the role of copper in neurotoxicity. Cuproptosis, a novel mechanism of copper-dependent cell death, remains underexplored, particularly concerning environmental pollutants like polystyrene nanoplastics (PS-NPs). While PS-NPs are recognized for inducing neurotoxicity through various forms of cell death, including apoptosis and ferroptosis, their potential to trigger neuronal cuproptosis has not yet been investigated. This study aims to determine whether exposure to PS-NPs induces neurotoxicity via cuproptosis and to explore the preliminary molecular mechanisms involved, thereby addressing this significant knowledge gap. Methods Seven-week-old male C57BL/6 mice were exposed to PS-NPs at dose of 12.5 mg/kg, and were co-treated with the antioxidant N-acetylcysteine (NAC). Complementary in vitro experiments were conducted using SH-SY5Y neuronal cells exposed to PS-NPs at a concentration of 0.75 mg/mL, with interventions that included the copper chelator tetrathiomolybdate (TTM), NAC, and the MAPK inhibitor PD98059. Results Exposure to PS-NPs significantly increased cerebral copper accumulation (P < 0.05) and induced cuproptosis, characterized by lipid-acylated DLAT oligomerization, dysregulation of cuproptosis regulators (FDX1, LIAS, HSP70), and mitochondrial damage. In murine models, PS-NPs elicited neurotoxicity, as evidenced by neuronal loss, decreased Nissl body density, impaired synaptic plasticity, and suppressed oxidative stress markers (GSH, SOD, Nrf2), alongside activation of the ERK-MAPK pathway, ultimately resulting in deficits in learning and memory. Treatment with NAC alleviated these adverse effects. In SH-SY5Y cells, exposure to PS-NPs resulted in reduced cell viability (p < 0.01), an effect that was mitigated by TTM. Furthermore, NAC and PD98059 were found to reverse elevated copper levels, cuproptosis markers, and mitochondrial anomalies (p < 0.05). Conclusion This study presents preliminary evidence indicating that PS-NPs may induce neuronal cuproptosis, potentially through the oxidative stress-mediated activation of the ERK-MAPK pathway, which contributes to cognitive dysfunction in mice. These findings provide insights into the potential mechanisms underlying PS-NPs neurotoxicity and highlight possible therapeutic targets, such as copper chelation or MAPK inhibition, for mitigating the neurological risks associated with nanoplastic exposure, pending further validation in human-relevant models.

Maojun Zhou, Manyi Yang, Huiling Wen et al.

Abstract Background: Conotoxins exhibit great potential as neuropharmacology tools and therapeutic candidates due to their high affinity and specificity for ion channels, neurotransmitter receptors or transporters. The traditional methods to discover new conotoxins are peptide purification from the crude venom or gene amplification from the venom duct. Methods: In this study, a novel O1 superfamily conotoxin Tx6.7 was directly cloned from the genomic DNA of Conus textile using primers corresponding to the conserved intronic sequence and 3’ UTR elements. The mature peptide of Tx6.7 (DCHERWDWCPASLLGVIYCCEGLICFIAFCI) was synthesized by solid-phase chemical synthesis and confirmed by mass spectrometry. Results: Patch clamp experiments on rat DRG neurons showed that Tx6.7 inhibited peak calcium currents by 59.29 ± 2.34% and peak potassium currents by 22.33 ± 7.81%. In addition, patch clamp on the ion channel subtypes showed that 10 μM Tx6.7 inhibited 56.61 ± 3.20% of the hCaV1.2 currents, 24.67 ± 0.91% of the hCaV2.2 currents and 7.30 ± 3.38% of the hNaV1.8 currents. Tx6.7 had no significant toxicity to ND7/23 cells and increased the pain threshold from 0.5 to 4 hours in the mouse hot plate assay. Conclusion: Our results suggested that direct cloning of conotoxin sequences from the genomic DNA of cone snails would be an alternative approach to obtaining novel conotoxins. Tx6.7 could be used as a probe tool for ion channel research or a therapeutic candidate for novel drug development.

Ryan J. McNeilly, Jennifer A. Schwanekamp, Logan S. Hyder et al.

Abstract Background Since the introduction of copper based, lead-free frangible (LFF) ammunition to Air Force small arms firing ranges, instructors have reported symptoms including chest tightness, respiratory irritation, and metallic taste. These symptoms have been reported despite measurements determining that instructor exposure does not exceed established occupational exposure limits (OELs). The disconnect between reported symptoms and exposure limits may be due to a limited understanding of LFF firing byproducts and subsequent health effects. A comprehensive characterization of exposure to instructors was completed, including ventilation system evaluation, personal monitoring, symptom tracking, and biomarker analysis, at both a partially enclosed and fully enclosed range. Results Instructors reported symptoms more frequently after M4 rifle classes compared to classes firing only the M9 pistol. Ventilation measurements demonstrated that airflow velocities at the firing line were highly variable and often outside established standards at both ranges. Personal breathing zone air monitoring showed exposure to carbon monoxide, ultrafine particulate, and metals. In general, exposure to instructors was higher at the partially enclosed range compared to the fully enclosed range. Copper measured in the breathing zone of instructors, on rare occasions, approached OELs for copper fume (0.1 mg/m3). Peak carbon monoxide concentrations were 4–5 times higher at the partially enclosed range compared to the enclosed range and occasionally exceeded the ceiling limit (125 ppm). Biological monitoring showed that lung function was maintained in instructors despite respiratory symptoms. However, urinary oxidative stress biomarkers and urinary copper measurements were increased in instructors compared to control groups. Conclusions Consistent with prior work, this study demonstrates that symptoms still occurred despite exposures below OELs. Routine monitoring of symptoms, urinary metals, and oxidative stress biomarkers can help identify instructors who are particularly affected by exposures. These results can assist in guiding protective measures to reduce exposure and protect instructor health. Further, a longitudinal study is needed to determine the long-term health consequences of LFF firing emissions exposure.

Maha Ghanem, Safaa El shanawany, Mona Ashry et al.

Background: Carbon monoxide (CO) poisoning is a widespread cause of morbidity and mortality, with delayed neurological Sequelae  (DNS) among the most severe consequences of this silent killer.Objectives: To study the relationship between neutrophil-lymphocyte ratio (NLR), ischemia-modified albumin (IMA), and severity of acute CO poisoning as well as their role in predicting delayed neurological manifestations.Patients and Methods: Sixty acutely CO-intoxicated patients were admitted to Alexandria Poison Center, Egypt. NLR and IMA were assessed. Six months after discharge, all patients were subjected to neuropsychometric testing using Mini-Mental Status Examination (MMSE). Brain magnetic resonance imaging (MRI) was conducted on cognitively impaired patients.Results: NLR was abnormally high in most patients and the mean serum level of IMA was significantly elevated in acutely CO-intoxicated patients compared to the control group (P<0.001). NLR and IMA were significantly related to neurological manifestations and other laboratory parameters. Patients were subdivided into DNS group (n = 16) and non-DNS group (n = 44), according to MMSE and brain MRI done after six months, with significant elevation of NLR and IMA in DNS group (p<0.001). The accuracy of DNS prediction parameters was measured using the area under the receiver operating characteristics curve. Excellent accuracy was detected for IMA and NLR.Conclusion: The studied markers of NLR and IMA assessed on admission could be employed as useful biomarkers for correlating with acute CO poisoning severity and predicting the outcome including the possibility of development of DNS.

R. Goulding

Giselle Pacifico Sartori, Andréa da Costa, Fernanda Lúcio dos Santos Macarini et al.

Abstract Background Tetanus toxin blocks the release of the inhibitory neurotransmitters in the central nervous system and causes tetanus and its main form of prevention is through vaccination. The vaccine is produced by inactivation of tetanus toxin with formaldehyde, which may cause side effects. An alternative way is the use of ionizing radiation for inactivation of the toxin and also to improve the potential immunogenic response and to reduce the post-vaccination side effects. Therefore, the aim of this study was to characterize the tetanus toxin structure after different doses of ionizing radiation of 60Co. Methods Irradiated and native tetanus toxin was characterized by SDS PAGE in reducing and non-reducing conditions and MALD-TOF. Enzymatic activity was measured by FRET substrate. Also, antigenic properties were assessed by ELISA and Western Blot data. Results Characterization analysis revealed gradual modification on the tetanus toxin structure according to doses increase. Also, fragmentation and possible aggregations of the protein fragments were observed in higher doses. In the analysis of peptide preservation by enzymatic digestion and mass spectrometry, there was a slight modification in the identification up to the dose of 4 kGy. At subsequent doses, peptide identification was minimal. The analysis of the enzymatic activity by fluorescence showed 35 % attenuation in the activity even at higher doses. In the antigenic evaluation, anti-tetanus toxin antibodies were detected against the irradiated toxins at the different doses, with a gradual decrease as the dose increased, but remaining at satisfactory levels. Conclusion Ionizing radiation promoted structural changes in the tetanus toxin such as fragmentation and/or aggregation and attenuation of enzymatic activity as the dose increased, but antigenic recognition of the toxin remained at good levels indicating its possible use as an immunogen. However, studies of enzymatic activity of tetanus toxin irradiated with doses above 8 kGy should be further analyzed.

Jin-Won Kim, Do-Soon Kim

Abstract Paraquat was the most successful nonselective herbicide in Korea due to its rapid herbicidal activity. However, its high mammalian toxicity, frequent self-poisoning incidents, and a lack of effective antidotes led to a paraquat ban in Korea in 2012. Therefore, this review was conducted to revisit the toxicological profile of paraquat and to investigate the impacts of the paraquat ban on human health and agriculture in Korea. A review of toxicological information reconfirmed that paraquat is highly acutely toxic to humans, and ingestion, inhalation, or dermal administration of the herbicide can cause severe clinical signs and inevitably lead to death by respiratory failure. In Korea, the paraquat ban immediately decreased the suicide rate due to pesticides (mainly paraquat) by 46.1%, resulting in a 10% decrease of the total suicide rate. However, this also led to an increase in suicide attempts with other poisons such as carbon monoxide, suggesting that suicide attempts and rates of suicide by poisoning depend on not only the toxicity of the poison but also the accessibility of the poisoning agents. In agriculture, paraquat was quickly replaced by other nonselective herbicides such as glufosinate and glyphosate. Thus, the paraquat ban did not have a significant impact on agricultural practices but influenced the nonselective herbicide market; the use of glufosinate was higher than use of glyphosate due to glufosinate's rapid herbicidal activity, which is similar to that of paraquat. Though the paraquat ban can be considered as a national strategy to lower suicide rates, the increase in suicide attempts with other poisons suggests that multilateral efforts are required for not only keeping suicidal agents away from people but also minimizing motives for suicide.

C. Ornillo, N. Harbord

Management of the poisoned patient begins with supportive care, assessment of organ function and dysfunction, and consideration of known or suspected poisons. The possibility of multiple ingestions should be considered with intentional exposures or suicide attempts. Enteric decontamination involves treatment to prevent the absorption of toxins from the gastrointestinal system and includes the use of activated charcoal. Poisoned patients may benefit from the use if antidotes are available, or enhanced elimination as with salicylate ion trapping during urinary alkalinization. The use of intravenous lipid therapy is of clinical benefit in poisoning from bupivacaine, amitriptyline, and bupropion. Hemodialysis is the most inexpensive, widely available, and most commonly used method of extracorporeal drug removal in the treatment of poisoning. Chelators with different chemical properties can bind toxic metals, providing an essential mechanism for detoxification, and may be used in combination with extracorporeal therapies such as DFO with HD for aluminum or iron, and DMSA or DMPS with HD to treat arsenic or mercury intoxication. The use of displacers with hemodialysis can be considered to augment clearance of protein-bound toxins.

K. Watson

The easy availability of deadly poisons in 19th-century Britain, Western Europe, and the United States led to widespread public anxiety about the prevalence of murder by poison, resulting in what might be termed a “poison panic.” The fear was fed by well-publicized reports of trials and executions which, though not especially numerous, seemed indicative of the dangerous incidence of a unique type of homicide, one that was particularly difficult to prevent or detect. As a result, poisoning crimes stimulated the development of the earliest medicolegal specialism, forensic toxicology, and consequently the careers of some of the best known expert witnesses of the Victorian era, including Mathieu Orfila, Alfred Swaine Taylor, Thomas Stevenson, and Theodore Wormley. This article traces the history of poisoning crimes and the related medico-scientific discipline of forensic toxicology using textbooks, key trials, and crime statistics to examine and evaluate their contribution to the historical development of forensic expertise and practice.

D. Remane, D. Wissenbach, F. Peters

Christine Coméra, Christel Cartier, Eric Gaultier et al.

Abstract Background Food-grade TiO2 (E171 in the EU) is widely used as a coloring agent in foodstuffs, including sweets. Chronic dietary exposure raises concerns for human health due to proinflammatory properties and the ability to induce and promote preneoplastic lesions in the rodent gut. Characterization of intestinal TiO2 uptake is essential for assessing the health risk in humans. We studied in vivo the gut absorption kinetics of TiO2 in fasted mice orally given a single dose (40 mg/kg) to assess the ability of intestinal apical surfaces to absorb particles when available without entrapment in the bolus. The epithelial translocation pathways were also identified ex vivo using intestinal loops in anesthetized mice. Results The absorption of TiO2 particles was analyzed in gut tissues by laser-reflective confocal microscopy and ICP-MS at 4 and 8 h following oral administration. A bimodal pattern was detected in the small intestine: TiO2 absorption peaked at 4 h in jejunal and ileal villi before returning to basal levels at 8 h, while being undetectable at 4 h but significantly present at 8 h in the jejunal Peyer’s patches (PP). Lower absorption occurred in the colon, while TiO2 particles were clearly detectable by confocal microscopy in the blood at 4 and 8 h after treatment. Ex vivo, jejunal loops were exposed to the food additive in the presence and absence of pharmacological inhibitors of paracellular tight junction (TJ) permeability or of transcellular (endocytic) passage. Thirty minutes after E171 addition, TiO2 absorption by the jejunal villi was decreased by 66% (p < 0.001 vs. control) in the presence of the paracellular permeability blocker triaminopyrimidine; the other inhibitors had no significant effect. Substantial absorption through a goblet cell (GC)-associated pathway, insensitive to TJ blockade, was also detected. Conclusions After a single E171 dose in mice, early intestinal uptake of TiO2 particles mainly occurred through the villi of the small intestine, which, in contrast to the PP, represent the main absorption surface in the small intestine. A GC-associated passage and passive diffusion through paracellular TJ spaces between enterocytes appeared to be major absorption routes for transepithelial uptake of dietary TiO2.

T. Jansen, L. Hoegberg, T. Eriksen et al.

M. Akhgari, N. Amini-Shirazi, Fariba Sardari Iravani

R. Jain, Ritu Singh

Roya Kordrostami, M. Akhgari, M. Ameri et al.

BackgroundSuicide ranks among the top ten causes of death in all age groups all over the world. There are many methods for committing suicide including self-poisoning, firearm and hanging. The aim of the present study was to provide an overview of self-poisoning related suicidal deaths with special focus on forensic toxicology analysis results in Tehran, Iran from 2011 to 2015.MethodsAll suspicious cases with the the history of self-poisoning were investigated to define the cause and manner of death under the supervision of forensic medicine practitioners. Postmortem samples were analysed in forensic toxicology laboratory to confirm the presence of drugs in cadaver of suicidal cases. Drugs and poisons were analysed using thin layer chromatography, high performance liquid chromatography, gas chromatography/mass spectrometry, headspace gas chromatography and gas chromatography equipped with nitrogen phosphorus detector. Demographic data were collected from autopsy reports of all cases with confirmed self-poisoning suicidal cause of death.ResultsResults showed that 674 cases of self-poisoning deaths were investigated during a five-year study period, of which 68.55% were male. The most often used suicide method was self-poisoning in young population. Phosphine gas liberated from aluminum phosphide tablets was the most toxic substance detected in postmortem samples (619 cases) followed by opioids, methamphetamine, organophosphates, cyanide and strychnine.ConclusionIn conclusion self-poisoning suicidal death was predominant in young male population in Tehran, Iran. It seems that free access to suicide means such as drugs and poisons should be restricted by national and health authorities.Trial registrationNot applicable.

C. Lionte, V. Șorodoc, C. Tuchiluş et al.

Hamid Reza Rahimi, Mahmoud Reza Jaafari, Amir Hooshang Mohammadpour et al.

Alcoholic liver disease (ALD) is the main cause of chronic liver disease across the world and can lead to fibrosis and cirrhosis. The etiopathogenesis of ALD is related to ethanol-induced oxidative stress, glutathione reduction, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. Curcumin is an active ingredient of the rhizome of turmeric. The substance is shown to have minor adverse effects. As the substance possess low bioavailability in free formulation, different strategies has been conducted to improve its bioavailability which resulted in production of nanomiscels and nanoparticles. Curcumin can provide protection for the liver against toxic effects of alcohol use. Several studies showed curcumin blocks endotoxin-mediated activation of NF-κB and suppresses the expression of cytokines, chemokines, COX-2, and iNOS in Kupffer cells. According to the molecular studies, curcumin inhibits NF-κB signaling pathway, regulates cytokines production and modulates immune response. It has been shown that curcumin can suppress gene expression, especially cytokines genes resulting in down-regulation of tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), IL-6, IL-8, adhesion molecules (ICAM, VCAM) and C-reactive protein. Hence, curcumin can have therapeutic effects on the majority of chronic inflammatory diseases such as asthma, bronchitis, inflammatory bowel disease, rheumatoid arthritis, ALD, fatty liver, and allergy.

Jaana E. Laine, Merja R. Häkkinen, Seppo Auriola et al.

Qualitative trapping profile of reactive metabolites arising from six structurally different compounds was tested with three different d-peptide isomers (Peptide 1, gly–tyr–pro–cys–pro–his-pro; Peptide 2, gly–tyr–pro–ala–pro–his–pro; Peptide 3, gly–tyr–arg–pro–cys–pro–his–lys–pro) and glutathione (GSH) using mouse and human liver microsomes as the biocatalyst. The test compounds were classified either as clinically “safe” (amlodipine, caffeine, ibuprofen), or clinically as “risky” (clozapine, nimesulide, ticlopidine; i.e., associated with severe clinical toxicity outcomes). Our working hypothesis was as follows: could the use of short different amino acid sequence containing d-peptides in adduct detection confer any add-on value to that obtained with GSH? All “risky” agents’ resulted in the formation of several GSH adducts in the incubation mixture and with at least one peptide adduct with both microsomal preparations. Amlodipine did not form any adducts with any of the trapping agents. No GSH and peptide 2 and 3 adducts were found with caffeine, but with peptide 1 one adduct with human liver microsomes was detected. Ibuprofen produced one Peptide 1-adduct with human and mouse liver microsomes but not with GSH. In conclusion, GSH still remains the gold trapping standard for reactive metabolites. However, targeted d-peptides could provide additional information about protein binding potential of electrophilic agents, but their clinical significance needs to be clarified using a wider spectrum of chemicals together with other safety estimates.

Zhiming Li, Yumei Wang

This study was designed to evaluate whether NADPH oxidase inhibitor (apocynin) preconditioning induces expression of Src homology-2 domain-containing phosphatase-1 (SHP-1) to protect against renal ischemia/reperfusion (I/R) injury (RI/RI) in rats. Rats were pretreated with 50 mg/kg apocynin, then subjected to 45 min ischemia and 24 h reperfusion. The results indicated that apocynin preconditioning improved the recovery of renal function and nitroso-redox balance, reduced oxidative stress injury and inflammation damage, and upregulated expression of SHP-1 as compared to RI/RI group. Therefore our study demonstrated that apocynin preconditioning provided a protection to the kidney against I/R injury in rats partially through inducing expression of SHP-1.