A Technical Guide to Sampling the Beagle Dog Nervous System for General Toxicity and Neurotoxicity Studies.

Beagle dogs are a key nonrodent species in nonclinical safety evaluation of new biomedical products. The Society of Toxicologic Pathology (STP) has published "best practices" recommendations for nervous system sampling in nonrodents during general toxicity studies (Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the Beagle dog has not been defined specifically. Here we provide 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the dog brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen test articles with unknown or no anticipated neurotoxic potential; this plan using at least 7 coronal hemisections matches the STP "best practices" recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses up to 14 coronal levels to investigate test articles where the brain is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves for dogs during nonclinical studies should follow published STP "best practices" recommendations for sampling the central (Toxicol Pathol 41[7]: 1028-1048, 2013) and peripheral (Toxicol Pathol 46[4]: 372-402, 2018) nervous systems. This technical guide also demonstrates the locations and approaches to collecting uncommonly sampled peripheral nervous system sites.

Cadmium exposure exerts neurotoxic effects in peacock blennies Salaria pavo.

Cadmium (Cd) is considered as an important factor involved in several neurological disturbances. The aim of this study was to assess the effects of Cd in the brain of peacock blennies Salaria pavo, a species used as a bioindicator of water pollution. A sublethal contamination of 2mg CdCl2 L-1 was performed over periods of 1, 4, 10 and 15 days. Total Cd accumulation was measured in brains and displayed low concentrations throughout the experiment. Partial-length cDNA of different ATP-binding cassette transporters (abcb1, abcc1, abcc2, abcg2 proteins) and acetylcholinesterase (ache) were characterized. mRNA expressions profiles displayed an up-regulation of abcc2 mRNA after 4 days of Cd exposure only while abcg2 mRNA was down-regulated after 10 days only. For AChE, the mRNA transcription and the activity of the enzyme were followed and highlighted that Cd exerted an inhibitory effect on the nervous information transmission. At the histological level, fish exhibited pathological symptoms in the optic tectum and the cerebellum and results showed that the cerebellum was the most affected organ.

Bioaccumulation and neurotoxicity of dithiopyridine herbicide in the brain of freshwater fish, Cyprinus carpio.

The freshwater carp, Cyprinus carpio, was exposed to 0.5 mg (30% of median lethal concentration (LC50)), 1.0 mg (60% of LC50), and 1.6 mg (LC50) of dithiopyridine herbicide per liter for acute (24 h) and 1/10 of LC50 (0.2 mg/L/day) for sublethal (1, 3, 7, 14, and 21 days) experiments. The herbicide bioaccumulation was significantly affected by the acute exposure levels and the experimental periods and was positively correlated with them. One-way analysis of variance revealed that the acute and sublethal exposure to the herbicide as well as the experimental periods caused significant reduction in the concentrations of catecholamines (dopamine (DA) and norepinephrine (NE)), elevation of acetylcholine (ACh), and was associated with a marked decrease in the activity of acetylcholinesterase (AChE). In comparison with the corresponding controls, most levels of the DA and NE and the activity of AChE were significantly decreased, whereas the concentration of ACh was markedly elevated, during acute and sublethal exposure. In the acute and sublethal experiments, the herbicide accumulated in the brain was inversely proportional to the levels of DA and NE and the activity of AChE but has a direct correlation with the concentration of ACh. In addition, the brain's AChE activity was negatively correlated with ACh content during the acute (r = -0.94) and sublethal (r = -0.78) experiments.

Diagnosing domoic acid toxicosis in the California sea lion (Zalophus californianus) using behavioral criteria: A novel approach.

Domoic acid toxicosis in the California sea lion (Zalophus californianus) is difficult to diagnose using presence of toxin alone because the duration of domoic acid presence in blood and urine is generally less than 48 hr following exposure. Because domoic acid toxicosis is often suggested by presentation of behavioral abnormalities, we asked whether assessment of behavior might be useful for diagnostic purposes. We developed an ethogram to categorize behavioral data collected via continuous focal animal sampling. In total, 169 subjects were observed at a rehabilitation center. Sea lions with domoic acid toxicosis displayed head weaving (P < 0.0001) and muscle fasciculations (P < 0.01) significantly more often than animals in a comparison group. Dragging hind flippers and swift scanning were observed exclusively in animals from the domoic acid toxicosis group. The data show that behavioral diagnostic criteria can be effective in the diagnosis of domoic acid toxicosis in the California sea lion.

Neurotoxicity and behavioral disorders induced in mice by acute exposure to the diamide insecticide chlorantraniliprole.

Diamide insecticides activate ryanodine receptors expressed in lepidopteran skeletal muscle and promote Ca2+ release in the sarcoplasmic reticulum, causing abnormal contractions and paralysis, leading to death of the pest. Although they had been thought not to act on nontarget organisms, including mammals, adverse effects on vertebrates were recently reported, raising concerns about their safety in humans. We investigated the neurotoxicity of the acute no-observed-adverse-effect level of chlorantraniliprole (CAP), a diamide insecticide, in mice using clothianidin (CLO), a neonicotinoid insecticide, as a positive control. The CLO-administered group showed decreased locomotor activities, increased anxiety-like behaviors, and abnormal human-audible vocalizations, while the CAP-administered group showed anxiety-like behaviors but no change in locomotor activities. The CAP-administered group had greater numbers of c-fos-immunoreactive cells in the hippocampal dentate gyrus, and similar to the results in a CLO-administered group in our previous study. Blood corticosterone levels increased in the CLO-administered group but did not change in the CAP-administered group. Additionally, CAP was found to decreased 3-Methoxytyramine and histamine in mice at the time to maximum concentration. These results suggest that CAP-administered mice are less vulnerable to stress than CLO-administered mice, and the first evidence that CAP exposure increases neuronal activity and induces anxiety-like behavior as well as neurotransmitter disturbances in mammals.

Transient chemotherapy-induced alopecia after successful reversal of 5-fluorouracil myelosuppression and neurotoxicosis in a 9-month-old dog.

BACKGROUND: 5-Fluorouracil (5-FU) cream is a common human topical chemotherapy agent with potentially fatal neurotoxic effects on dogs if accidentally ingested. There are seldom reports in veterinary literature describing the successful outcome of intervention after accidental ingestion of 5-FU cream. CASE SUMMARY: A 9-month-old spayed female labradoodle presented 14 h after ingesting an unknown amount of 40 g tube of Efudex cream (5% 5-FU). The dog presented in status epilepticus, which was managed with benzodiazepines and levetiracetam in conjunction with induced coma and mechanical ventilation. No further seizure activity occurred throughout the ensuing 5 days of hospitalisation; however, myelosuppression was featured. The dog was discharged home after 5 days of hospitalisation. Three days post discharge, the dog was noted to develop focal alopecia around the eyes and temporal region. 14 days after discharge, the alopecia progressed to a majority of the head and body. CONCLUSION: To the authors' knowledge, this is the first report that documents the enduring adverse effects of 5-FU cream after survival of the initial episode, including an earlier onset of myelosuppression and diffuse alopecia. Successful treatment of accidental 5-FU ingestion is possible several hours after the initial event with minimal long-term consequences.

Cadmium chloride-induced transgenerational neurotoxicity in zebrafish development.

As an important environmental pollutant, the heavy metal cadmium has a significant negative impact on the stability of the ecological environment and on organismal health. Previous studies have shown that cadmium chloride can damage the nervous, skeletal, endocrine, and reproductive systems, but to our knowledge, the effects of cadmium on the behavior, neurotransmitter levels, and neuronal development in the offspring of exposed animals have not been reported. In the present study, sexually-mature zebrafish were exposed to cadmium chloride at different concentrations for 60 days, and in this background, behavior, neurotransmitters level, neuro-development and neurotransmitter metabolism was investigated in the F1 offspring. The results showed that exposure of the parental zebrafish to cadmium chloride resulted swimming speed and distance of F1 offspring significantly reduced; the levels of neurotransmitters, such as dopamine, serotonin, and acetylcholine is disrupted. neuro-development and neurotransmitter metabolism related genes expression pattern was altered, which cause zebrafish F1 offspring developmental neurotoxicity. These findings provide further insights into the harm posed by cadmium chloride to the aquatic ecosystems.

Interactive effects of freshwater acidification and selenium pollution on biochemical changes and neurotoxicity in Oreochromis mossambicus.

Effect of selenium and acidification in freshwater environment was assessed solitary but no reports are available on the impacts of both factors act together. In the present study, effects of combined simultaneous exposure to selenium (Se) and low pH were assessed in Mozambique tilapia, Oreochromis mossambicus. Responses were measured based on antioxidant defenses (enzymatic SOD, CAT, GPx and non-enzymatic GSH), biotransformation enzyme (GST), metallothionein levels (MT), oxidative damage (LPO, CP), Na+/K+-ATPase (NKA) activity in gills and liver tissues and neurotoxicity (acetylcholinesterase, AChE) response in brain tissue. Fish were exposed to combined treatment at different pH levels (7.5, control (optimum pH for tilapia growth); 5.5, low pH) and Se concentrations (0, 10, and 100 µg L-1). Toxicity levels of Se were not significantly different under control and low pH indicating that pH did not affect Se toxicity. Levels of GSH and MT were enhanced in Se-exposed fish at both pH. Combined effects of high Se concentration and low pH decreased SOD and CAT activities and increased those of GPx and GST. However, organisms were not able to prevent cellular damage (LPO and CP), indicating a condition of oxidative stress. Furthermore, inhibition of Na+/K+-ATPase activity was showed. Additionally, neurotoxicity effect was observed by inhibition of cholinesterase activity in organisms exposed to Se at both pH conditions. As a result, the combined stress of selenium and freshwater acidification has a slight impact on antioxidant defense mechanisms while significantly inhibiting cholinesterase and Na+/K + -ATPase activity in fish. The mechanisms of freshwater acidification mediating the toxic effects of trace non-metal element on freshwater fish need to investigate further.

Toxic effects of domoic acid in the seabream Sparus aurata.

Neurotoxicity induced in fish by domoic acid (DA) was assessed with respect to occurrence of neurotoxic signs, lethality, and histopathology by light microscopy. Sparus aurata were exposed to a single dose of DA by intraperitoneal (i.p.) injection of 0, 0.45, 0.9, and 9.0 mg DA kg(-1) bw. Mortality (66.67 ± 16.67%) was only observed in dose of 9.0 mg kg(-1) bw. Signs of neurological toxicity were detected for the doses of 0.9 and 9.0 mg DA kg(-1) bw. Furthermore, the mean concentrations (±SD) of DA detected by HPLC-UV in extracts of brain after exposure to 9.0 mg DA kg(-1) bw were 0.61 ± 0.01, 0.96 ± 0.00, and 0.36 ± 0.01 mg DA kg(-1) tissue at 1, 2, and 4 hours. The lack of major permanent brain damage in S. aurata, and reversibility of neurotoxic signs, suggest that lower susceptibility to DA or neuronal recovery occurs in affected individuals.

Suspected acute meperidine toxicity in a dog.

OBSERVATIONS: A 22-month-old male neutered Coton De Tulear dog was presented for upper gastrointestinal endoscopy under general anesthesia. The anesthetic plan included premedication with intramuscular meperidine (4 mg kg(-1)) but meperidine was inadvertently administered at ten-fold this dose. Within 5 minutes, the dog was unresponsive to external stimulation, and by 10 minutes post-injection developed generalized signs of central nervous system (CNS) excitement. Initial therapy included inspired oxygen supplementation, and single intravenous (IV) doses of diazepam (0.68 mg kg(-1)) and naloxone (0.03 mg kg(-1)) to no effect. A second dose of diazepam (0.46 mg kg(-1), IV) abolished most of the signs of CNS excitement. General anesthesia was induced and the endoscopy performed. Time to extubation was initially prolonged, but administering naloxone (final dose 0.1 mg kg(-1), IV) to effect enabled extubation. After naloxone, the dog became agitated, noise sensitive, and had leg and trunk muscle twitches. Diazepam (0.30 mg kg(-1), IV) abolished these signs and the dog became heavily sedated and laterally recumbent. Naloxone administration was continued as a constant rate infusion (0.02 mg kg(-1) hour(-1), IV) until approximately 280 minutes post-meperidine injection, at which time the dog suddenly sat up. Occasional twitches of the leg and trunk muscles were observed during the night. The dog was discharged the next day appearing clinically normal. CONCLUSIONS: Given that the CNS excitatory effects of normeperidine are not a mu opioid receptor effect, the use of naloxone should be considered carefully when normeperidine excitotoxicity is suspected. Benzodiazepines may be beneficial in ameliorating clinical signs of normeperidine excitotoxicity.

Neurotoxic Plants that Poison Livestock.

In the western United States, poisonous plants most often affect grazing livestock, and the related livestock losses are estimated to cost the grazing livestock industry more than $200 million annually. Many of these toxic plants contain neurotoxins that damage or alter the function of neurologic cells in the central and peripheral nervous systems. The objectives of this article are to present common North American neurotoxic plants, including conditions of poisoning, clinical disease, pathologic changes, and available diagnostics, to identify poisoned animals and the potential prognosis for poisoned animals.

Neurolathyrism in goat (Capra hircus) kid: Model development.

The present study was undertaken to develop an animal model to study neurolathyrism. For this purpose 24 goat (Capra hircus) kids (new born, 15 days old) were divided into four groups. Group I Control, Group II Low toxin (0.17 g% ß-ODAP containing grass pea), Group III high toxin (0.96 g% ß-ODAP containing grass pea) and Group IV high toxin (0.96 g% ß-ODAP containing grass pea flour (powder) fortified with 5 mg% pure ß-ODAP). The experiment was continued for 3 months. Clinical examination was carried out weekly. Muscle conduction velocity (MCV), nerve conduction velocity (NCV), blood and urinary ß-ODAP, nitrite in blood and cerebrospinal fluid (CSF) examination were performed by standard methods. Clinical examination showed neurolathyrism symptoms in three kids. The abnormal MCV and NCV were observed in all the experimental animals. Blood nitrite, blood and urine ß-ODAP levels were significantly increased in experimental groups. Three kids were affected with neurolathyrism due to consumption of grass pea irrespective of its ß-ODAP content and kid may serve as a neurolathyrism model.

Developmental Neurotoxicity of the Harmful Algal Bloom Toxin Domoic Acid: Cellular and Molecular Mechanisms Underlying Altered Behavior in the Zebrafish Model.

BACKGROUND: Harmful algal blooms (HABs) produce potent neurotoxins that threaten human health, but current regulations may not be protective of sensitive populations. Early life exposure to low levels of the HAB toxin domoic acid (DomA) produces long-lasting behavioral deficits in rodent and primate models; however, the mechanisms involved are unknown. The zebrafish is a powerful in vivo vertebrate model system for exploring cellular processes during development and thus may help to elucidate mechanisms of DomA developmental neurotoxicity. OBJECTIVES: We used the zebrafish model to investigate how low doses of DomA affect the developing nervous system, including windows of susceptibility to DomA exposure, structural and molecular changes in the nervous system, and the link to behavioral alterations. METHODS: To identify potential windows of susceptibility, DomA (0.09-0.18 ng) was delivered to zebrafish through caudal vein microinjection during distinct periods in early neurodevelopment. Following exposure, structural and molecular targets were identified using live imaging of transgenic fish and RNA sequencing. To assess the functional consequences of exposures, we quantified startle behavior in response to acoustic/vibrational stimuli. RESULTS: Larvae exposed to DomA at 2 d postfertilization (dpf), but not at 1 or 4 dpf, showed consistent deficits in startle behavior at 7 dpf, including lower responsiveness and altered kinematics. Similarly, myelination in the spinal cord was disorganized after exposure at 2 dpf but not 1 or 4 dpf. Time-lapse imaging revealed disruption of the initial stages of myelination. DomA exposure at 2 dpf down-regulated genes required for maintaining myelin structure and the axonal cytoskeleton. DISCUSSION: These results in zebrafish reveal a developmental window of susceptibility to DomA-induced behavioral deficits and identify altered gene expression and disrupted myelin structure as possible mechanisms. The results establish a zebrafish model for investigating the mechanisms of developmental DomA toxicity, including effects with potential relevance to exposed sensitive human populations. https://doi.org/10.1289/EHP6652.

Mass Occurrence of Anatoxin-a- and Dihydroanatoxin-a-Producing Tychonema sp. in Mesotrophic Reservoir Mandichosee (River Lech, Germany) as a Cause of Neurotoxicosis in Dogs.

In August 2019, three dogs died after bathing in or drinking from Mandichosee, a mesotrophic reservoir of the River Lech (Germany). The dogs showed symptoms of neurotoxic poisoning and intoxication with cyanotoxins was considered. Surface blooms were not visible at the time of the incidents. Benthic Tychonema sp., a potential anatoxin-a (ATX)-producing cyanobacterium, was detected in mats growing on the banks, as biofilm on macrophytes and later as aggregations floating on the lake surface. The dogs' pathological examinations showed lung and liver lesions. ATX and dihydroanatoxin-a (dhATX) were detected by LC-MS/MS in the stomachs of two dogs and reached concentrations of 563 and 1207 µg/L, respectively. Anatoxins (sum of ATX and dhATX, ATXs) concentrations in field samples from Mandichosee ranged from 0.1 µg/L in the open water to 68,000 µg/L in samples containing a large amount of mat material. Other (neuro)toxic substances were not found. A molecular approach was used to detect toxin genes by PCR and to reveal the cyanobacterial community composition by sequencing. Upstream of Mandichosee, random samples were taken from other Lech reservoirs, uncovering Tychonema and ATXs at several sampling sites. Similar recent findings emphasize the importance of focusing on the investigation of benthic toxic cyanobacteria and applying appropriate monitoring strategies in the future.

Impacts of nanoplastics on bivalve: Fluorescence tracing of organ accumulation, oxidative stress and damage.

The outcomes of this research offer novel insights into the toxic effects of nanoparticles (i.e., nanoplastics or other nanomaterials) on the benthos. Herein, this study aimed to evaluate the accumulation pathway, distribution characteristics and potential biotoxicity of polystyrene nanoplastics in C. fluminea. The results revealed that nanoplastics could accumulate in the mantle through adherence, in the visceral mass through ingestion and in the gill through respiration. The gill, intestine and stomach were the main accumulation organs for nanoplastics. The aggregation of nanoplastics was observed in C. fluminea, which may exacerbate their biotoxicity. Moreover, oxidative stress was observed in the visceral mass, gill and mantle. Liver damage, neurotoxicity and intestinal inflammation were caused by imbalance in the antioxidation system. Analysis of IBR values showed that the visceral mass had a more effective response to oxidative stress than the gill and mantle after exposure to nanoplastics.

An extract of Hydrilla verticillata and associated epiphytes induces avian vacuolar myelinopathy in laboratory mallards.

Avian vacuolar myelinopathy (AVM) is a neurological disease affecting bald eagles (Haliaeetus leucocephalus), American coots (Fulica americana), waterfowl, and other birds in the southeastern United States. The cause of the disease is unknown, but is thought to be a naturally produced toxin. AVM is associated with aquatic macrophytes, most frequently hydrilla (Hydrilla verticillata), and researchers have linked the disease to an epiphytic cyanobacterial species associated with the macrophytes. The goal of this study was to develop an extraction protocol for separating the putative toxin from a hydrilla-cyanobacterial matrix. Hydrilla samples were collected from an AVM-affected reservoir (J. Strom Thurmond Lake, SC) and confirmed to contain the etiologic agent by mallard (Anas platyrhynchos) bioassay. These samples were then extracted using a solvent series of increasing polarity: hexanes, acetone, and methanol. Control hydrilla samples from a reference reservoir with no history of AVM (Lake Marion, SC) were extracted in parallel. Resulting extracts were administered to mallards by oral gavage. Our findings indicate that the methanol extracts of hydrilla collected from the AVM-affected site induced the disease in laboratory mallards. This study provides the first data documenting for an "extractable" AVM-inducing agent.

The ABCB1-1Delta mutation is not responsible for subchronic neurotoxicity seen in dogs of non-collie breeds following macrocyclic lactone treatment for generalized demodicosis.

P-glycoprotein (P-gp), encoded by the multiple drug resistance gene ABCB1 (also known as MDR1), is an integral component of the blood brain barrier crucial in limiting drug uptake into the central nervous system. Altered expression or function of P-gp, as seen in dogs of the collie lineage homozygous for the nt228(del4) mutation of the ABCB1 gene (ABCB1-1Delta), can result in potentially fatal neurotoxicosis, especially following administration of systemic macrocyclic lactones (SML). Occasionally, dogs from unrelated breeds develop subchronic signs of neurotoxicity when receiving SML to treat generalized demodicosis. It is possible that these dogs are heterozygous carriers of the ABCB1-1Delta mutation, resulting in decreased P-gp activity and central neurotoxicosis. Cheek swabs were collected from 28 dogs with generalized demodicosis that had shown subchronic signs of neurotoxicity following daily oral administration of ivermectin or other SML. Ten of these animals received concurrent systemic treatment with other confirmed or putative P-gp substrates. After DNA extraction, the relevant portion of the ABCB1 gene was amplified by polymerase chain reaction, and sequenced. Twenty-seven dogs were homozygous normal while one dog was heterozygous for the ABCB1-1Delta mutation. Therefore, with the exception of one dog, the observed neurotoxicity could not be attributed to the ABCB1-1Delta mutation. Possible explanations for the adverse reactions observed include pharmacological interactions (administration of SML with other P-gp substrates or inhibitors), excessively high doses, polymorphisms in P-gp expression, uncharacterized mutations in the ABCB1 gene or in another gene, or phenomena unrelated to the SML-P-gp interaction.

Successful treatment of a southern Pacific rattlesnake (Crotalus viridis helleri) bite in a caracal (Caracal caracal).

A caracal (Caracal caracal) was bitten on the lower lip by a southern Pacific rattlesnake (Crotalus viridis helleri) and quickly developed progressive, severe soft tissue swelling and bruising of this site. Initial laboratory results revealed prolonged clotting times within the first hour of envenomation, followed by signs of vasculitis and anemia. The caracal was successfully treated with intravenous crystalloids, four vials of polyvalent crotalidae antivenom, and transfusions of bovine hemoglobin glutamer-200 (Oxyglobin) and fresh whole blood. The progressive soft tissue swelling and bruising halted and the coagulation parameters improved after administration of antivenom; however, the caracal continued to show neurologic dysfunction, including depression, weakness, muscle fasciculations, anisocoria, and ataxia. Administration of an additional vial of antivenom 72 hr after envenomation quickly corrected the weakness and muscle fasciculations, whereas the anisocoria and mild ataxia persisted for another 24 hr. The caracal remains clinically normal 3 yr after the envenomation.

Mechanisms of engineered nanoparticle induced neurotoxicity in Caenorhabditis elegans.

The wide-spread implementation of nanoparticles poses a major health concern. Unique biokinetics allow them to transfer to neurons throughout the body and inflict neurotoxicity, which is challenging to evaluate solely in mammalian experimental models due to logistics, financial and ethical limitations. In recent years, the nematode Caenorhabditis elegans has emerged as a promising nanotoxicology experimental surrogate due to characteristics such as ease of culture, short life cycle and high number of progeny. Most importantly, this model organism has a well conserved and fully described nervous system rendering it ideal for use in neurotoxicity assessment of nanoparticles. In that context, this mini review aims to summarize the main mechanistic findings on nanoparticle related neurotoxicity in the setting of Caenorhabditis elegans screening. The injury pathway primarily involves changes in intestinal permeability and defecation frequency both of which facilitate translocation at the site of neurons, where toxicity formation is linked partly to oxidative stress and perturbed neurotransmission.

Toxic effects of lead exposure on bioaccumulation, oxidative stress, neurotoxicity, and immune responses in fish: A review.

Lead (Pb) is a highly toxic metal in aquatic environments. Fish are at the top of the food chain in most aquatic environments, and are the most susceptible to the toxic effects of Pb exposure. In addition, fish are one of the most abundant vertebrates, and they can directly affect humans through food intake; therefore, fish can be used to assess the extent of environmental pollution in an aquatic environment. Pb-induced toxicity in fish exposed to toxicants is primarily induced by bioaccumulation in specific tissues, and the accumulation mechanisms vary depending on water habitat (freshwater or seawater) and pathway (waterborne or dietary exposure). Pb accumulation in fish tissues causes oxidative stress due to excessive ROS production. Oxidative stress by Pb exposure induces synaptic damage and neurotransmitter malfunction in fish as neurotoxicity. Moreover, Pb exposure influences immune responses in fish as an immune-toxicant. Therefore, the purpose of this review was to examine the various toxic effects of Pb exposure, including bioaccumulation, oxidative stress, neurotoxicity, and immune responses, and to identify indicators to evaluate the extent of Pb toxicity by based on the level of Pb exposure.