Occupational exposure to lithium-nickel-cobalt-manganese oxide materials in lithium battery: Health risks and mechanisms of toxicity

Particle characteristics and biological reactivity

Particle size, morphology, and surface properties are key determinants of NCM toxicity. Occupational exposure typically involves respirable micro- and nanoscale particles generated during material synthesis, mechanical processing, and recycling operations. Ultrafine NCM particles possess a high surface area-to-volume ratio, which enhances surface reactivity, catalytic activity, and interactions with cellular membranes.

Following inhalation, these particles can deposit deeply within the alveolar region and may persist because of limited clearance. Experimental evidence indicates that NCM particles induce pulmonary inflammation through macrophage activation, lysosomal destabilization, and oxidative stress generation. Moreover, the presence of redox-active transition metals capable of cycling between multiple oxidation states confers substantial intrinsic oxidative potential. These physicochemical features can amplify inflammatory signaling pathways, thereby contributing to chronic tissue injury.

Metal ion dissolution and secondary toxicity

In addition to particle-mediated effects, metal ion dissolution represents a critical pathway of NCM toxicity. Under physiological and environmental conditions, NCM particles can release Li²⁺, Ni²⁺, Co²⁺, and Mn²⁺ ions through proton-mediated lattice degradation and ligand-assisted dissolution processes. Dissolution rates are strongly influenced by environmental factors, particularly pH, organic ligands, and lattice stability, with acidic conditions markedly accelerating metal release (Liu, 2026).

These dual toxicity pathways operate at different biological levels: particulate properties primarily drive local respiratory inflammation and tissue injury, whereas released metal ions contribute to systemic toxicity, bioaccumulation, and long-term health risks.

Although lithium compounds can present occupational hazards, lithium differs fundamentally from Ni, Co, and Mn in its toxicological mechanisms (Bertollo et al., 2026; Bortolozzi et al., 2024; Sakrajda and Rybakowski, 2025). In addition, lithium generally exhibits lower bioaccumulation potential and reduced systemic persistence compared with Ni, Co, and Mn (Bertollo et al., 2026).

Importantly, evidence from mixture toxicology studies and epidemiological investigations consistently indicates that Ni, Co, and Mn are the principal contributors to the toxicity of NCM particulate mixtures, whereas lithium plays a comparatively minor role in driving adverse health outcomes (Brown et al., 2024; Zhang et al., 2026). Accordingly, the scope of this review intentionally prioritized Ni, Co, and Mn because these transition metals represent the dominant determinants of particle-mediated toxicity and long-term occupational health risks.

Although the toxicity mechanisms of NCM materials remain relatively underexplored (Sironval et al., 2019), their biological effects are, to a large extent, driven by the well-established toxicological properties of their constituent metals—Ni, Co, and Mn. This review therefore synthesized current knowledge on the toxicity mechanisms of these individual metals, with the aim of providing a mechanistic framework and comparative insights to inform future studies on NCM-related health risks.

Health effects of Ni, Co, and Mn exposure

During the entire life cycle of NCM materials, workers may be exposed to NCM particles as well as Ni-, Co-, and Mn-containing compounds. These particles can not only directly elicit inflammatory responses in the respiratory system but may also dissolve in the pulmonary fluid environment, releasing bioactive metal ions and secondary compounds. Once absorbed into the bloodstream, these dissolved species can be transported systemically, thereby affecting multiple organ systems beyond the lungs, as shown in Figure 2.

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Figure 2.

Exposure and systemic toxicity of Ni, Co, Mn, and NCM particulate matter. This schematic shows the potential health impacts associated with occupational inhalation of fine particles containing nickel, cobalt, manganese, and NCM materials. Following respiratory deposition, these particles can induce local airway and lung injury. Subsequent systemic absorption and distribution may lead to toxic effects in multiple organ systems, including the cardiovascular, neurological, hepatic, and renal systems.

Health effects of Ni

Ni is a widespread occupational and environmental pollutant, extensively used in industries such as battery manufacturing, electroplating, and alloy production. Exposure to Ni is associated with diverse adverse outcomes, including allergic contact dermatitis, cardiovascular and renal diseases, pulmonary fibrosis, and cancers of the lung and nasal cavity (Genchi et al., 2020). The respiratory system is a primary target. Epidemiological studies consistently link Ni exposure to respiratory toxicity. Chronic inhalation of Ni-containing aerosols is associated with diminished lung function, airway inflammation, and elevated lung cancer risk (Wu et al., 2022; Lu H et al., 2024; Galarneau et al., 2025). Emerging evidence points to neurotoxic potential. An inverted U-shaped association was observed between urinary Ni and neural biomarkers (e.g., neurofilament light chain, dopamine) in welders, suggesting complex, non-linear neurotoxic effects (Wu et al., 2023). Ni exposure is also implicated in hepatic and renal toxicity, as well as gut microbiome dysbiosis. Urinary Ni has been non-monotonically associated with non-alcoholic fatty liver disease and liver fibrosis risk in men (Zhang K et al., 2025). Higher Ni exposure levels are linked to impaired kidney function (Nan et al., 2022), and occupational exposure correlates with elevated serum uric acid and altered gut microbiota (Yang J et al., 2023).

Toxicological studies corroborate these findings and elucidate underlying mechanisms. In the lungs, Ni can induce fibrosis via oxidative stress-mediated activation of the transforming growth factor-β/Smad pathway (Cao et al., 2024). In the liver, nickel nanoparticles disrupt lipid metabolism and cause inflammatory injury (Zhou et al., 2023). Reproductive toxicity is also significant: nickel nanoparticles impair male reproductive function in a dose-dependent manner in rats (Iftikhar et al., 2023) and induce ovarian inflammation, fibrosis, and reduced oocyte quality in female mice (Zhao et al., 2021).

Health effects of Co

Co is a well-established respiratory irritant linked to occupational asthma, pulmonary inflammation, and fibrosis (Chen and Lee., 2023). Cases of work-related asthma among co-exposed workers, some requiring hospitalization, have been documented (Al-Abcha et al., 2021). An exposure-response relationship exists between inhalable cobalt dust and Clara cell protein16, a biomarker of respiratory epithelial damage (Andersson et al., 2020). Severe outcomes include hard metal lung disease, an interstitial lung disease featuring fibrosis and giant cell interstitial pneumonia, reported among Chinese workers (Du et al., 2021). Beyond the lungs, Co is associated with neurotoxicity, indicated by a positive correlation between urinary Co and serum prolactin, a neural damage biomarker (Wu et al., 2023). Its nephrotoxic potential is evidenced by an increased risk of kidney stones with rising urinary Co levels (Lu et al., 2024).

Experimental studies revealed that cobalt chloride induce oxidative stress, inflammation, and histopathological damage across organs. In rats, it impairs cognition and induces anxiety-like behaviors, correlating with hippocampal and amygdala oxidative stress, neuroinflammation, and structural damage (Oria et al., 2022). Cobalt chloride also elevates liver enzymes and renal biomarkers, with histopathology confirming hepatocellular necrosis and tubular degeneration (Iji et al., 2023). Mechanistically, Co genotoxicity is attributed to its catalysis of reactive oxygen species (ROS), leading to oxidative DNA damage and potential carcinogenicity (Angelé-Martínez et al., 2023).

Health effects of Mn

Mn is an essential element but poses health risks at excessive exposure levels, primarily targeting the nervous, respiratory, hepatic, and reproductive systems.

Neurotoxicity is the most recognized effect. Welders exposed to Mn-containing fumes show an increased risk of neurocognitive impairments. MRI studies confirm Mn accumulation in the basal ganglia, cerebellum, and frontal cortex of exposed workers (Alici et al., 2022; Monsivais et al., 2024). Significant correlations exist between airborne Mn, blood Mn levels, and neurobehavioral symptoms (Abdel-Rasoul et al., 2024; Mehrifar et al., 2020). Mn exposure also impairs pulmonary function. Urinary Mn levels, even within reference ranges, are negatively associated with lung function parameters (Shu et al., 2021). Welders exposed to Mn levels above permissible limits exhibit a higher prevalence of respiratory symptoms and reduced spirometric measures (Abdel-Rasoul et al., 2022).

Toxicological evidence confirms multi-organ toxicity. Chronic neurotoxicity manifests as dopaminergic neurodegeneration, microglial activation, and motor deficits (Fan et al., 2020). In the liver, Mn exposure alters serum injury biomarkers, increases liver weight, induces cholestasis (Zhu et al., 2020), and causes hepatocellular degeneration with associated inflammation and oxidative stress (Fan et al., 2020). The male reproductive system is also vulnerable, with Mn exposure reducing the weight of androgen-dependent organs, impairing sperm quality, and causing testicular oxidative damage (Cen et al., 2022; Souza et al., 2020).

Oxidative stress and mitochondrial dysfunction

One of the key mechanisms by which Ni, Co, and Mn exert toxicity is through the generation of ROS. ROS are highly reactive molecules capable of inducing oxidative damage to lipids, proteins, and DNA, ultimately leading to cellular dysfunction and apoptosis.

Exposure to Ni, Co, and Mn inhibits mitochondrial electron transport chain complex, resulting in excessive ROS production and redox imbalance (Dorman, 2023; Tripathi et al., 2024; Martins et al., 2025). The elevated ROS levels directly damage mitochondrial DNA, proteins, and lipids, which disrupt mitochondrial dynamics and exacerbate mitochondrial dysfunction. This creates a self-sustaining cycle of oxidative stress and mitochondrial damage, which serves as a central mechanism driving cellular injury, inflammation, and apoptosis (Morcillo et al., 2021; Smith et al., 2017; Yin et al., 2024a).

Inflammatory response

The production of ROS by Ni, Co, and Mn particles not only induces direct cellular damage but also triggers a robust inflammatory response. Inflammation is a critical defense mechanism designed to eliminate harmful agents and facilitate tissue repair. However, chronic or excessive inflammation can lead to persistent tissue injury, fibrosis, and the progression of inflammatory diseases.

Ni exposure has been extensively linked to immunotoxic and pro-inflammatory effects. Ni activates inflammatory pathways through toll-like receptor 4 (TLR4), initiating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling cascades. These pathways upregulate the expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), thereby amplifying inflammatory responses (Guo et al., 2020). Mn exposure stimulates innate immune activation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, leading to the production of type I interferons and pro-inflammatory cytokines. This immune activation contributes to persistent neuroinflammation. Additionally, Mn exposure enhances the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, promoting the secretion of IL-1β and IL-18, both of which further exacerbate neuroinflammatory processes. Notably, excessive activation of the cGAS-STING/NLRP3 axis has been implicated in Tau hyperphosphorylation, a key pathological feature of Mn-induced neurodegeneration (Liu J et al., 2022).

Oxidative stress and inflammation are intricately linked, with ROS acting as potent activators of inflammatory signaling. ROS can stimulate NF-κB and activator protein-1 (AP-1), transcription factors that drive the expression of pro-inflammatory cytokines such as TNF-α and IL-6. Moreover, the persistent activation of inflammatory pathways exacerbates oxidative stress by enhancing ROS production in immune cells, including macrophages and neutrophils. This self-perpetuating cycle of oxidative stress and inflammation contributes to tissue damage and is a key driver in the pathogenesis of chronic diseases, including fibrosis and cancer.

DNA damage and genotoxicity

DNA damage is a critical toxicological outcome of occupational exposure to Ni, Co, and Mn compounds, with implications for mutagenesis, carcinogenesis, and long-term health risks.

Ni induces DNA strand breaks and oxidative lesions, primarily through ROS generation and direct interaction with DNA. Importantly, Ni compounds inhibit multiple DNA repair pathways, including direct reversal, nucleotide excision repair, base excision repair, mismatch repair, homologous recombination, and nonhomologous end-joining. This suppression occurs both via direct enzyme inhibition and through transcriptional repression of DNA repair genes, exacerbating the genotoxic potential (Guo et al., 2019b). In addition to DNA lesions, Ni significantly affects chromatin architecture and epigenetic regulation. Ni exposure disrupts higher-order chromatin organization, impairing transcriptional homeostasis and facilitating gene silencing or aberrant activation. These epigenetic alterations—such as histone modifications and DNA methylation—are increasingly recognized as key contributors to Ni-induced carcinogenesis, even in the context of its relatively weak mutagenic properties. Thus, the interplay between genomic instability and epigenomic dysregulation is central to Ni toxicity (Gaspar and Cuddapah, 2022).

Cobalt-induced genotoxicity is similarly mediated by oxidative stress, DNA strand breaks, and disruption of redox-sensitive transcription factors. Co (II) ions can directly generate ROS and interact with DNA or DNA-binding proteins, disrupting replication fidelity and cellular stress responses. While the exact molecular pathways remain under investigation, current evidence supports the classification of cobalt compounds as genotoxic carcinogens with threshold-dependent effects (Lison et al., 2018).

Mn exposure, particularly in the form of MnCl₂, has also been linked to DNA damage. In differentiated Lund human mesencephalic cells—an in vitro model of dopaminergic neurons—Mn exposure results in dose- and time-dependent increases in oxidative DNA lesions, including the formation of 8-oxo-7, 8-dihydro-2′-deoxyguanosine and single-strand breaks. This genotoxic insult triggers an enhanced DNA damage response, evidenced by elevated poly (ADP-ribosyl)ation activity, although without significant transcriptional activation of canonical DNA repair pathways (Nicolai et al., 2022). These findings suggest that Mn-induced genotoxicity may compromise neuronal genomic integrity, potentially contributing to neurodegenerative processes.

Autophagy

Autophagy and mitochondrial autophagy (mitophagy) are highly regulated catabolic processes that play essential roles in maintaining cellular homeostasis, particularly under conditions of toxic stress. Dysregulation of these pathways has emerged as a key mechanism underlying the cytotoxicity of Ni, Co, and Mn exposures.

Autophagy generally serves as a compensatory mechanism in response to environmental and pathological stress. However, when dysregulated, it may contribute to cellular dysfunction and disease progression, including neurodegeneration. Ni exposure induces autophagy primarily via oxidative stress-mediated activation of the AMP-activated protein kinase/Protein Kinase B/mammalian target of rapamycin (AMPK/AKT/mTOR) signaling pathway. In renal models, this autophagic response mitigates mitochondrial dysfunction and reduces apoptosis, suggesting a cytoprotective role in Ni-induced kidney injury (Yin et al., 2021, 2024b). In hepatic tissue, Ni disrupts mitochondrial homeostasis by impairing mitochondrial biogenesis and dynamics while simultaneously enhancing mitophagy through both the PTEN-induced kinase 1 (PINK1)/Parkin axis and receptor-mediated pathways. These effects are interpreted as compensatory responses aimed at limiting mitochondrial damage and preserving cellular viability (Guo et al., 2023b).

Cobalt toxicity is closely linked to impaired autophagic flux, particularly within the nervous system. Co exposure activates hypoxia-inducible factor-1α (HIF-1α), leading to excessive ROS production. This oxidative stress disrupts autophagic processing by perturbing the Protein Kinase B/mammalian target of rapamycin/Unc-51-like kinase 1 (AKT/mTOR/ULK1) signaling cascade, ultimately aggravating neuronal degeneration (Tang et al., 2023).

Mn exposure similarly impairs autophagy and mitophagy, with pronounced effects in neural tissues. Mn promotes α-synuclein oligomerization and abnormal protein S-nitrosylation, contributing to protein aggregation and neurotoxicity (Yan et al., 2020). Mechanistically, Mn triggers S-nitrosylation of PINK1), which inhibits the activation and mitochondrial translocation of Parkin. This disruption of the PINK1/Parkin pathway results in defective mitophagy, accumulation of damaged mitochondria, and subsequent induction of apoptosis (Liu K et al., 2022).

Collectively, these findings highlight autophagy and mitophagy as critical, yet vulnerable, defense mechanisms during occupational exposure to Ni, Co, and Mn. Their dysregulation not only compromises cellular resilience but may also serve as a mechanistic link to systemic toxicity and disease progression.

Apoptosis, pyroptosis, and ferroptosis

Ni, Co, and Mn exert toxicological effects through the activation of multiple regulated cell death pathways, including apoptosis, pyroptosis, and ferroptosis. These processes contribute significantly to the pathogenesis of tissue injury and organ dysfunction associated with occupational exposure to transition metal compounds.

Apoptosis, a form of programmed cell death characterized by caspase activation and DNA fragmentation, is a well-established outcome of Ni toxicity. In human astrocytic cells, Ni accumulation induces robust ROS generation, leading to activation of caspase-3/7 and suppression of the anti-apoptotic protein Bcl-2, thereby promoting apoptosis (Yubolphan et al., 2021).

Pyroptosis, an inflammatory form of cell death mediated by caspase-1 and the NLRP3 inflammasome, is increasingly recognized in metal-induced toxicity. Li et al. reported that Ni exposure activates the NLRP3 inflammasome and promotes the release of IL-1β and IL-18, contributing to renal inflammation and dysfunction. This pyroptotic response is exacerbated by inhibition of the nuclear factor erythroid 2–related factor 2 (Nrf2)-mediated antioxidant pathway (Li et al., 2024).

Ferroptosis, a regulated cell death modality driven by iron-dependent lipid peroxidation, has emerged as a critical mechanism in Ni-induced neurotoxicity and nephrotoxicity. In zebrafish models, environmentally relevant Ni exposure disrupted early neurodevelopment and immune homeostasis via ferroptosis (Wang et al., 2023). Moreover, ferroptosis mediates Ni-induced renal injury, linking oxidative stress with lipid peroxidation and cell death.

These cell death pathways do not operate in isolation but interact dynamically with other stress responses. For example, autophagy—typically cytoprotective—is activated in response to Ni-induced mitochondrial ROS via the c-Jun N-terminal kinase (JNK) pathway. However, excessive autophagy may shift toward apoptotic cell death, as observed with nickel oxide nanoparticles (Cho et al., 2020). Furthermore, autophagy-mediated ferroptosis plays a central role in NiCl₂-induced renal toxicity, highlighting the convergence of autophagic and ferroptotic mechanisms (Yang Q et al., 2023).

Similarly, Mn-induced toxicity involves a delicate balance between protective and detrimental outcomes. Initially, autophagy and mitophagy function to counteract Mn-induced oxidative stress and endoplasmic reticulum (ER) dysfunction. However, persistent Mn exposure leads to sustained ER stress, disrupted protein folding, and eventual transition from protective autophagy to apoptosis (Liu and Ju, 2023). Mn-induced oxidative stress also activates mitophagy, which, while initially beneficial, culminates in mitochondrial dysfunction and apoptotic death upon prolonged activation (Huang et al., 2021).

Taken together, Ni, Co, and Mn disrupt cellular homeostasis through complex, interrelated death pathways involving apoptosis, pyroptosis, and ferroptosis. These mechanisms exhibit substantial crosstalk with oxidative stress, mitochondrial dysfunction, ER stress, and autophagy, as summarized in Figure 3 and Table 1.

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Figure 3.

Possible mechanistic pathways underlying cellular toxicity induced by Ni, Co, and Mn in NCM materials. Occupational exposure to NCM particles results in cellular uptake and lysosomal destabilization, leading to excessive generation of ROS and oxidative stress, leading to mitochondrial dysfunction, inflammation and DNA damage. These upstream events activate downstream biological responses— including autophagy, apoptosis, pyroptosis, and ferroptosis—which collectively contribute to multi-organ and cellular injury.

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Table 1.

Mechanisms of Ni, Co, and Mn toxicity.

Experimental animal/Cell line	Exposure metal or compound (dosage/concentration)	Indicator change	Mechanism of action	Reference
Sprague-Dawley rats	NiCl2 (10 mg/kg i.p. for 7 d)	↑MDA, ↓SOD, CAT, GPx activity ↑Inflammatory cytokines, ↑Apoptosis markers	NF-κB/COX-2/TNF-α/IL-1β/IL-6 pathway, apoptosis	Yildiz Deniz (2024)
H9c2 cells	NiSO4 (varying doses for 24 h)	↑Pyroptosis, ↑Apoptosis, ↑ROS, ↑IL-18, IL-1β, caspase-1, NLRP3	ROS/NLRP3/Caspase-1	Zhao (2024)
BEAS-2B cells, Wistar rats	Nickel-refining fumes	↑ ROS, ↑NLRP3 ↑IL-1β, ↓ cell viability	SIRT1-NF-κB-NLRP3	Pan (2024)
MIN6 cells	NiSO4 (0–300 µg/mL, 0–48 h)	↓ GSIS, ↑ ROS, ↑TRABS, 8-OHdG ↓GSH, T-SOD↑ apoptosis ↑FOXO ↓PDX-1,GLUT2	JNK pathway	Sun (2024)
Mice	Ni	↓SOD, CAT, GSH↑ NF-κB, TNF-α, IFN-γ, IL-1a, IL-6	NF-κB pathway	Wang (2024)
BEAS-2B cells	NINPs	↑HIF-1α, downregulation of mTOR	Autophagy, apoptosis	Yuan (2023)
Mice	NiCl2 (dose not specified)	↑ROS, Bax, cleaved caspase-3, cleaved caspase-8, caspase-9, caspase-12 ↓Bcl-2 ↑γ-H2AX ↓ spermatogenesis	ROS-mediated apoptosis and DNA damage	Guo (2023a)
C57BL/6J mice	NiCl2 (10 mg/kg)	↓MDA, T-AOC↑ATF4, IRE1, JNK, CHOP ↑caspase-3, caspase-9, caspase-12, Bax ↓Bcl-2	Oxidative stress, apoptosis, endoplasmic reticulum	Zhang (2023)
C57BL/6J mice (Txnrd3+/+ and Txnrd3−/−)	NiCl2 (10 mg/kg)	↑GSSG, MDA ↓CAT, T-SOD ↑caspase-3, caspase-9, cytochrome c, p53, BAX, ↑LC3, ATG 1, ATG 7, and Beclin-1 ↑TNF-α, COX-2, IL-1β, IL-2, IL-6, IL-7 ↓ BCL-2, p62, mTOR	Oxidative stress, mitochondrial apoptosis, autophagy, inflammation	Liu et al. (2023)
Sprague-Dawley rats/HepG2 cells	NiSO4 (rats: 5.0 mg/kg; HepG2 cells: 1500 μM)	↑SOD, CAT, GSH- px, MDA↓GSH ↑caspase-3, caspase-9, cytochrome c	Apoptosis via PI3K/AKT pathway	Wang (2022)
C57BL/6 mice/Beas-2B cells	Ni (mice: 2 mg/kg),	↑ pyroptosis markers (NLRP3, caspase-1, IL-18, IL-1β), ↓AMPK/CREB/Nrf2 expression	Pyroptosis via Nrf2/GOLPH3 pathway	Zhang (2022)
GC-1 cells (mouse spermatogonia)	Nickel	↓ cell survival, G1 phase arrest	Downregulation of PI3K/AKT/mTOR pathway, apoptosis	Wu (2020)
BMDMs	NiCl2 (dose not specified)	↑mtROS ↑ IL-1β, IL-6, IL-8, IL-18, TNF-α, IFN-β, NLRP3	Inflammation	Guo (2019a)
Human lung cancer A549 cells	NiCl2 (dose not specified)	↑ ER stress markers (BIP, PERK, IRE-1α, XBP-1 s, ATF6) ↓E-cadherin, ↑vimentin ↑Smad2/3, p38 MAPK	ER stress via Smad2/3, p38 MAPK pathways	Yu (2023)
Sprague-Dawley rats	Ni NPs (15, 30, 45 mg/kg for 28 days)	Hepatotoxicity, ↑ ALT, AST, ALP, LDH, TB, ↑NF-kβ, iNOS, NO, caspase-3, caspase-9	Oxidative stress, inflammation	Iqbal (2021)
BEAS-2B cells	NiCl2 (20–100 μmol/L)	↑TNF-α, IL-1β, IL-6, IL-8, C-reaction protein	Apoptosis, oxidative stress, inflammation	Cao (2020)
Human umbilical vein endothelial cells (HUVECs)	NiSO4 (62.5–1000 μM for 24 h)	↑ ROS, cleaved caspase-3, Bax, IL-6,TNF-α ↓Bcl-2, Bcl-XL ↑p-P38、p-JNK, p-ERK1/2	p38, JNK, ERK1/2 MAPK pathways	Liu Y (2022)
HK-2 cells, C57BL/6J mice	CoCl2 (not specified)	↑ pyroptosis, elevated autophagy levels	Autophagy, GSDME-mediated pyroptosis via caspase pathways	Liu et al. (2022)
B6C3F1/N mice	CMD inhalation	↑ oxidative stress, 8-oxo-dG ↑PI3K/AKT, MAPK signaling	NOX4, PI3K/AKT, MAPK pathways, KRAS mutations	Ton (2021)
HT22 cells	CoCl2	↑ROS, Ca2+, mitochondrial fragment ↓ MMP ↓ cell viability, ↑LDH	PI3K-AKT-MAPK signaling pathway	Hou (2023)
Albino Wistar rats	Co (40 mg/kg)	↑TNF-α, IL-1β, microgliosis ↑ERK	ERK/MAPK signaling pathway	Oria (2024)
Male rats	CoCl2 (300 mg/L)	↑ oxidative stress, ↑inflammation markers NF-κB, IL-6	NF-κB signaling pathway	Abdel-Daim (2020)
Rats	CoCl2	↑H2O2, MDA, NO, ↓ GPx, GST, GSH ↑NF-κB, Kim-1	NF-κB/Kim-1 signaling pathway	Oyagbemi (2020)
Buffalo rat liver cells (BRL3A)	CoCl2 (200 µM)	↑ apoptosis, mitochondrial dysfunction, ROS production,	BNIP3-dependent mitophagy; autophagy	Luo (2022)
BRL3A cells	CoCl2 (50–200 µM)	Mitochondrial dysfunction, increased apoptosis, ↑ glycolysis	Downregulation of autophagy and BNIP3-dependent mitophagy pathways	Tang (2022)
Rats	CoCl2 (not specified)	↑ROS ↓TAC ↑oxidative stress, DNA damage markers ↑P53, AIF, Apaf-1, ↑HSP-70	Apoptosis via DNA damage signaling pathways	Khalil (2020)
WT and LRRK2 G2019S mice, BV2 microglia	30 mg/kg (mice), 250 µM (BV2 cells)	↑ NLRP3 inflammasome, ↑ IL-1β, ↑ TNF-α	Upregulation of NLRP3 inflammasome, RAB10	Pajarillo (2023)
Rats	Mn (30 mg/kg)	↑ oxidative stress markers ↑IL-1β, IL-6, caspase-3	Oxidative stress, inflammation	Nkpaa (2022)
Chicken liver	MnCl2 (180 mg/kg 90 days)	↑ AST, ALT levels, oxidative stress markers ↓mTOR	Oxidative stress, autophagy-related gene upregulation, downregulation	Jiang (2020)
BV2 microglial cells	MnCl2 (100 μM)	Lysosomal alterations, ↑LC3-II↑ ROS, cell death	Autophagy activation, lysosomal rupture	Porte Alcon (2020)
Astrocytes (mouse striatum)	MnCl2 (100 μM)	Autophagic dysfunction, mitochondrial respiratory dysfunction	TFEB downregulation, impaired autophagic flux	Zhang (2020)
SH-SY5Y cells, C57BL/6 mice	Mn (various, including subtoxic doses)	↑ ER stress, autophagy	Upregulation of IRE1-JNK-Beclin1 pathway	Liu C (2020)
Hyline cocks	MnCl2 (100–1800 mg/kg)	↑pro-apoptotic genes	PTEN/PI3K/AKT signaling pathway, apoptosis	Liu et al. (2022d)
PC12 cells	MnSO4 (24 h exposure)	↓ SOD, GSH-Px, CAT; ↑ MDA; ↑ apoptosis markers (Bax, Caspase-3); ↓ Bcl-2	Apoptosis via PI3K/Akt signaling pathway	Tan (2022)
CTX cells (rat astrocytes)	Mn (150–300 μmol/L)	↑ ROS; ↑ Bax, Cleaved-Caspase-3; ↓ Bcl-2	ROS-activated JNK/FOXO3a pathway	Li (2023)
Rat thalamus	Mn (sub-acute and sub-chronic Mn exposure)	↑TNF-α, IL-1β, COX-2 ↑JNK/p38 MAPK ↑caspase-3↓Bcl-2	Apoptosis via MAPK pathway	Deng (2023)
Chicken livers	Mn (600, 900, 1800 mg/kg)	↑NO, iNOS activity, NF-κB, TNF-α, COX-2, HSP gene expression	Oxidative stress-mediated inflammation via NF-κB pathway	Liu et al. (2021)
BV2, N2a cells, C57BL/6 mice	MnCl2·4H2O (0–100 mg/kg)	↑ROS, Caspase-3, GSDME expression, neuronal pyroptosis	ROS-stimulated Caspase-3/GSDME signaling pathway	He (2024)
Rat models	Mn (high environmental levels)	↑ ROS, ferroptosis	Ferroptosis via cGAS-STING pathway	Zhang Z (2025)
Rats	MnCl2 (25 mg/kg)	↑GSH, IL-6, TNF-α,↓ Bcl-2 ↑GABA, PERK, ATF-6, Bax, caspase-3	Oxidative stress, inflammation, and apoptosis	Sarawi (2024)
ICR mice and PC12	Mn (not specified)	↓HIF-1α、SLC7A11, GPX4↑p53 ferroptosis	Ferroptosis through the HIF-1α/p53/SLC7A11 pathway	Chen (2024)

Most existing studies on the toxicity mechanisms of Ni, Co, and Mn are based on high-dose, acute exposure models. Although experiments using soluble metal salts may overestimate real-world exposure intensity, they remain valuable for elucidating fundamental toxicological pathways. However, substantial gaps persist in our understanding of chronic, low-dose exposures that more accurately reflect occupational conditions, highlighting the need for further research to evaluate long-term health risks.

Biomonitoring and exposure assessments

Systematic biomonitoring in occupational cohorts is essential to accurately quantify internal and external exposures to Ni, Co, and Mn. Future efforts should integrate multi-matrix biological monitoring (e.g., blood, urine, hair, and exhaled breath condensate) with high-resolution analytical techniques such as ICP-MS–based speciation and omics-enabled exposure profiling. Coupling biomonitoring with real-time personal exposure monitoring and task-based sampling would enable more precise reconstruction of exposure scenarios and better capture the temporal variability and mixed-metal nature of workplace exposures.

Identification of early toxicity biomarkers

The development of sensitive and specific biomarkers for early detection of toxicity is critical. Promising directions include biomarkers reflecting oxidative stress, mitochondrial dysfunction, epigenetic alterations, and regulated cell death pathways. Integrating traditional biomarkers with emerging multi-omics approaches—such as metabolomics, transcriptomics, and epigenomics—may facilitate the identification of early biological perturbations and susceptible subpopulations, thereby enabling preventive interventions before irreversible organ damage occurs.

Toxicokinetic and dose–response studies

Comprehensive investigation of the absorption, distribution, metabolism, and excretion (ADME) of NCM materials in occupationally exposed individuals is required to define toxicokinetic profiles and establish reliable dose–response relationships. Particular attention should be given to particle–ion transformation dynamics, pulmonary retention, systemic redistribution, and long-term tissue accumulation. These data are foundational for setting health-protective regulatory thresholds.

Development of integrated occupational exposure limits (OELs)

Existing OELs—such as those published by the Japan Society for Occupational Health (JSOH) (2024), National Health Commission of the People’s Republic of China (2019), Safe Work Australia (2019), UK Health and Safety Executive (2020), US National Institute for Occupational Safety and Health (2013); —are based primarily on individual metals assessed in isolation. However, workers are typically exposed to complex NCM mixtures rather than isolated metals. This discrepancy highlights the urgent need to develop next-generation, mixture-oriented OELs that incorporate cumulative exposure metrics, interaction-based risk models, and mechanistic evidence of additive or synergistic toxicity.

Protective strategies and regulatory development

Strengthening occupational protection requires a comprehensive, hierarchy-based control strategy. Priority should be given to engineering controls, including closed-system processing, local exhaust ventilation, dust suppression technologies, and prevention of thermal runaway. These measures should be complemented by optimized personal protective equipment, continuous health surveillance programs, and standardized training protocols. At the regulatory level, harmonized international guidelines and life-cycle–oriented risk management frameworks are needed to address emerging hazards associated with large-scale NCM production, use, and recycling.