Mechanisms of Heavy Metal–Induced Hypoxia

Overview

Heavy metals are environmental and occupational toxicants that can disrupt oxygen homeostasis in the human body through both cellular-level mechanisms and systemic effects. Metals such as lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg), nickel (Ni), tin (Sn), aluminum (Al), chromium (Cr), zinc (Zn), and iron (Fe) each have distinct pathways by which they can induce hypoxia or a “pseudohypoxic” state. These include stabilization of hypoxia-inducible factors, impairment of mitochondrial respiration, oxidative stress, enzyme dysfunction, and effects on the blood and vasculature. Below is a structured review of these mechanisms, the hypoxia-related outcomes in various organ systems, heavy metal–specific pathways, and relevant toxicological thresholds.

Cellular and Molecular Mechanisms of Hypoxia Induction

Heavy metals interfere with fundamental cellular processes responsible for oxygen sensing, utilization, and signaling. Key mechanisms include:

HIF-1α Stabilization via Prolyl Hydroxylase Inhibition

Under normoxic conditions, the transcription factor HIF-1α (Hypoxia-Inducible Factor 1α) is marked for degradation by prolyl hydroxylase domain enzymes (PHDs) that require iron and oxygen as cofactors. Certain heavy metals can inhibit PHD enzymes, causing inappropriate stabilization of HIF-1α and activation of hypoxia-responsive genes even in the presence of normal oxygen levels.^[1][2]For example, soluble nickel Ni competes with the ferrous iron cofactor in PHDs, thereby mimicking hypoxia by preventing HIF-1α hydroxylation and degradation.^[3] Nickel exposure has been shown to activate hypoxia signaling in cells via this mechanism. Lead, another divalent cation, similarly induces HIF-1α and its
downstream target VEGF (vascular endothelial growth factor) under normoxia, likely through a combination of PHD inhibition and redox changes.^[4]Arsenic (As), particularly in the trivalent form (arsenite), can also upregulate HIF-1α and VEGF expression; this occurs through signaling pathways (e.g., PI3K/Akt) that are triggered by arsenic-induced ROS, leading to HIF-1 activation.^[5] In summary, by stabilizing HIF-1α, heavy metals create a “pseudohypoxic” transcriptional response: cells increase glycolysis, angiogenesis, and erythropoietin signaling as if oxygen were scarce.^[6][7]

Mitochondrial Inhibition and Impaired Oxidative Phosphorylation

Heavy metals can impair mitochondrial function and thus reduce cellular oxygen utilization. Many metal
ions disrupt the electron transport chain and enzymatic pathways of oxidative phosphorylation, leading to decreased ATP production and a shift to anaerobic metabolism (which simulates hypoxia at the cellular level). Arsenic directly interferes with mitochondrial respiration: arsenite can bind to lipoic acid (a cofactor of pyruvate dehydrogenase) and inhibit Krebs cycle enzymes, while arsenate can substitute for phosphate in ATP synthesis, uncoupling oxidative phosphorylation. In vivo studies show that arsenic exposure inhibits multiple respiratory complexes (I, II, and IV) in mitochondria, diminishing oxygen consumption and ATP metalloenzyme activities, and blood cell formation.^[8]Mercury (Hg), especially organic methylmercury and inorganic Hg, accumulates in mitochondria due to high affinity for thiol groups, and acts as an inhibitor of mitochondrial respiratory enzymes.^[9] Mercury-induced mitochondrial dysfunction is characterized by depressed activity of electron transport complexes, loss of mitochondrial membrane potential, and decreased ATP, along with excessive ROS production.^[10]Cadmium (Cd) and lead (Pb) have also been observed to damage mitochondrial structure and function: low doses of combined Cd, Pb, and Hg in animal models caused dose-dependent mitochondrial swelling and cristae disruption in neurons.^[11] By impairing oxidative phosphorylation, heavy metals effectively make cells less able to use O₂, forcing reliance on glycolysis (the “Warburg-like” effect) and creating a state of intracellular energy deficiency akin to hypoxia. This mitochondrial inhibition can activate HIF-1 as well, since PHD enzymes in mitochondria sense reduced oxidative metabolism. In short, heavy metal–induced mitochondrial dysfunction (e.g., arsenic or mercury poisoning) leads to tissue hypoxia due to both diminished oxygen utilization and secondary signaling effects.^[12]

Disruption of Redox Balance and ROS Generation

Oxidative stress is a unifying mechanism in heavy metal toxicity that connects to hypoxia pathways. Many heavy metals generate reactive oxygen species (ROS) or deplete antioxidants, thereby upsetting the cellular redox balance. Excess ROS can oxidize critical thiols and iron-sulfur clusters, further inhibiting mitochondrial respiration and stabilizing HIF-1α (since PHD activity is sensitive to redox state). For example, cadmium, lead, and nickel all trigger significant ROS formation and glutathione depletion, which in turn activate redox-sensitive hypoxia signaling.^[13] Studies show that divalent heavy metals like Ni and Pb cause an oxidant/antioxidant imbalance that is linked to HIF-1α upregulation.^[14] These metals increase the production of superoxide and H₂O₂ while reducing cellular glutathione and inhibiting antioxidant enzymes.^[15] The result is oxidative damage to lipids, proteins, and DNA, and the activation of hypoxic gene programs (since ROS can act as signaling molecules that stabilize HIF-1 or activate NF-κB). Mercury and arsenic are classic inducers of ROS as well: mercury’s interaction with thiols inactivates antioxidant enzymes and promotes peroxidation, and arsenic’s metabolism generates ROS that are required for arsenic-induced HIF-1 and VEGF induction.^[16] Furthermore, ROS can cause endothelial dysfunction by inactivating nitric oxide (a vasodilator), leading to vasoconstriction and reduced oxygen delivery. In summary, heavy metals impose a state of oxidative stress, which both damages cellular machinery for oxygen utilization and falsely signals a hypoxic condition via ROS-sensitive pathways.^[17][18]

Enzyme Mismetallation and Metabolic Interference

Many enzymes involved in oxygen transport and utilization require specific metal cofactors (e.g., iron in
hemoglobin and cytochromes, copper in oxidative enzymes, zinc in antioxidant enzymes). Heavy metals can cause “mismetallation,” the inappropriate binding or displacement of essential metal ions in enzymes, leading to loss of enzyme function. This has direct consequences for oxygen metabolism. A prime example is lead’s inhibition of heme synthesis: lead avidly binds to sulfhydryl sites in enzymes like delta-aminolevulinate dehydratase (ALAD) and ferrochelatase, displacing the normal zinc or iron cofactors.^[19] Lead’s substitution for zinc in ALAD inactivates this enzyme, causing a buildup of heme precursors (ALA, coproporphyrin) and preventing proper heme formation.^[20] The result is fewer hemoglobin molecules and oxygen-carrying capacity (a cause of anemia discussed below). Arsenic and cadmium have been noted to replace essential metals in proteins as well – for instance, they can compete with zinc or calcium binding sites in various metabolic enzymes and regulatory proteins.^[21] Such replacement can distort enzyme structure or signaling pathways.

Tin (Sn), while less studied, is known to interfere with zinc and copper metabolism: excess tin in the diet increases fecal zinc excretion and lowers plasma copper, thereby impairing metalloenzyme activities and blood cell formation.^[22] This kind of disruption in zinc- and copper-dependent processes can contribute to hypoxia; for example, copper is required for ferroxidase (ceruloplasmin) activity and iron mobilization, so copper deficiency (whether caused by high Zn or Sn) leads to iron misdistribution and anemia. Even essential metals can cause mismetallation problems when imbalanced: iron overload can catalyze Fenton chemistry and damage iron-containing enzymes, while excess zinc intake blocks copper absorption and results in functional copper deficiency anemia (with low hemoglobin).^[23] In summary, heavy metals often hijack enzyme metal-binding sites or alter the pool of bioavailable nutritional metals, leading to dysfunctional metabolic pathways related to oxygen utilization (e.g., impaired heme synthesis, inhibited respiratory enzymes, or compromised antioxidants).^[24][25]These molecular derangements underlie much of the hypoxia seen in heavy metal toxicity

Systemic and Local Effects of Heavy Metal–Induced Hypoxia

Beyond the cellular mechanisms, heavy metal exposure manifests in physiological changes consistent with hypoxia. These include hematological effects (reducing oxygen transport in blood), vascular effects (impairing oxygen delivery to tissues), and tissue-specific injuries often exacerbated by poor oxygenation and oxidative damage.

Hematological Effects: Impaired Hemoglobin Synthesis, Anemia, and Red Blood Cell Turnover

Anemia is a common consequence of chronic exposure to several heavy metals, and it represents a systemic hypoxia risk by lowering the blood’s oxygen-carrying capacity. The etiologies of heavy metal–induced anemia are multifactorial: Inhibition of Hemoglobin Synthesis: Lead is the classic example, as it inhibits key enzymes in heme biosynthesis (ALAD and ferrochelatase), leading to accumulation of intermediates (e.g., zinc protoporphyrin) instead of functional heme.^[26] This results in fewer hemoglobin molecules being produced. Lead toxicity thus causes a microcytic, hypochromic anemia by blocking iron incorporation into heme.^[27] Aluminum, especially in patients with renal failure on dialysis, similarly causes a microcytic anemia by binding to transferrin and preventing iron delivery to developing erythrocytes.^[28] In vitro studies showed that aluminum-bound transferrin significantly inhibits erythroid colony formation, an effect not seen if transferrin is fully saturated with iron.^[29] Thus, aluminum excess functionally starves the bone marrow of iron, leading to impaired hemoglobin synthesis (a reversible anemia when aluminum is removed).

Increased Red Blood Cell Destruction (Hemolysis): Cadmium and arsenic are known to cause direct or indirect hemolytic effects. Cadmium can induce fragility and hemolysis of red blood cells, as evidenced in animal models of cadmium intoxication.^[30] Notably, arsine gas (AsH₃, a form of arsenic exposure) causes a massive acute hemolysis: victims of arsine inhalation develop intravascular hemolysis with resulting hemoglobinuria, anemia, and often acute renal failure due to hemoglobin deposition.^[31] Even subacute arsenic exposure has been associated with hemolytic anemia and a bronze discoloration of skin (from hemoglobin deposits) due to ongoing low-grade RBC destruction.^[32] Mercury can also cause anemia through hemolysis; mercury exposure (e.g., methylmercury) has been linked to oxidative damage to RBC membranes and shortened RBC lifespan.^[33] In fact, mercury has been reported to cause both hemolytic anemia and aplastic anemia, partly because mercury ions may compete with iron for binding to hemoglobin and disturb the red cell’s oxidative balance.^[34]

Suppression of Erythropoiesis: Cadmium is particularly noted for causing insufficient erythropoietin (EPO) production by the kidneys, a form of “renal anemia.” Cadmium accumulates in the kidney and damages EPO-producing cells, thereby reducing the hormonal stimulus for red blood cell production.^[35] Chronic cadmium exposure in rats produces a triad of hemolysis, iron redistribution, and renal anemia (low EPO), with studies showing that insufficient EPO and iron misdistribution are central drivers of the anemia.^[36] Lead can also suppress bone marrow function at high levels, and lead-induced renal damage may indirectly reduce EPO, compounding its anemia effects. Furthermore, heavy metals like zinc (in excess) can indirectly suppress erythropoiesis by inducing copper deficiency; copper is needed for iron mobilization, and if deficient, can lead to refractory anemia with low blood counts (a phenomenon seen in people taking too much zinc supplement). Tin intoxication has similarly been associated with anemia in animals and humans, likely by a combination of gastrointestinal irritation (causing poor iron absorption) and interference with Zn/Cu metabolism required for hematopoiesis.^[37]

Overall, the net effect of these mechanisms is a reduction in red blood cell count or hemoglobin level, manifesting as anemia with lowered oxygen delivery to tissues. In human studies, chronic lead and cadmium exposures correlate with decreased hemoglobin and hematocrit.^[38] Epidemiological data also find that higher blood chromium levels correlate with lower RBC counts and hemoglobin, suggesting chromium (especially hexavalent Cr(VI)) exposure may contribute to anemia as well.^[39] The resulting anemia from heavy metal exposure often presents as microcytic (small, pale RBCs) when iron utilization is blocked (as with Pb, Al) or normocytic with hemolysis. Clinically, this anemia contributes to fatigue, weakness, and organ hypoxia in exposed individuals, and it can exacerbate any tissue-specific toxicities by reducing the oxygen supply.

Endothelial Dysfunction and Impaired Oxygen Delivery

Beyond the blood’s oxygen-carrying capacity, heavy metals can compromise the vascular system that delivers oxygen to tissues. Many heavy metals induce endothelial dysfunction, promote vascular constriction, and contribute to atherosclerosis, all of which can limit tissue perfusion and oxygenation:

Oxidative Damage to Endothelium: Metals such as lead, cadmium, arsenic, and mercury generate ROS that injure endothelial cells and reduce bioavailable nitric oxide (NO). Mercury, for instance, has been documented to cause endothelial dysfunction and vascular disorders.^[40] Mercury and lead both can inactivate endothelial NO synthase and/or quench NO via superoxide, leading to diminished vasodilation. The outcome is a tendency towards vasoconstriction and hypertension. Chronic lead exposure is epidemiologically linked to higher blood pressure, partly explained by lead-induced oxidative stress in blood vessels and interference with calcium signaling in vascular smooth muscle. Cadmium exposure is associated with accelerated atherosclerosis and endothelial inflammation.^[41] Cadmium can replace calcium in cellular processes and disrupt endothelial cell junctions, contributing to vascular leakage or stiffness. Arsenic in drinking water is a known risk factor for peripheral vascular disease; long-term arsenic exposure causes endarteritis and fibrosis in small vessels, exemplified by Blackfoot disease, a severe peripheral artery disease endemic in arsenic-exposed populations.^[42] In Blackfoot disease, arsenic-induced endothelial damage and smooth muscle proliferation lead to vessel narrowing (especially in the lower limbs), resulting in ischemia, ulcers, and gangrene, literally, chronic localized tissue hypoxia from lack of blood flow.

Vasoconstriction and Altered Vascular Tone: Heavy metals can provoke systemic vasoconstriction through multiple mechanisms. As noted, loss of nitric oxide and increased oxidative stress favor a vasoconstricted state. Additionally, some metals influence vasoactive mediators: lead and mercury have been shown to increase endothelin-1 (a potent vasoconstrictor) and decrease prostacyclin (a vasodilator) in experimental models. In acute settings, metal-induced hypoxia can itself trigger reflex vasoconstriction; for example, arsine gas poisoning leads to cardiovascular collapse with generalized vasoconstriction due to peripheral hypoxia and hemoglobin loss.^[43] This is the body’s shock response to sudden anemia and hypoxemia – heart rate increases (tachycardia) and cutaneous vessels constrict to shunt blood to core organs.^[44] Even chronically, tissues sensing low oxygen (from anemia or local oxidative damage) may upregulate HIF-1 and endothelin, contributing to vascular remodeling and higher pulmonary or systemic vascular resistance.

Impaired Microcirculation: Several heavy metals damage the microvasculature or cause rheological changes that impede blood flow through capillaries. Lead can increase red cell rigidity (via membrane oxidation), and cadmium can promote capillary basement membrane thickening in organs like the kidney. Arsenic causes a unique form of angiopathy in the skin and extremities, and it also has pro-thrombotic effects that may reduce tissue perfusion. Iron overload (though an essential metal issue) can be analogously considered in hemochromatosis, iron-mediated ROS injure endothelial cells and promote fibrosis in liver and heart vasculature, leading to portal hypertension and cardiomyopathy that have hypoxic consequences for tissues.

In summary, heavy metals compromise the vascular delivery of oxygen by promoting atherosclerosis, vasospasm, and endothelial injury. Epidemiological studies have linked metal exposures with higher rates of hypertension, coronary artery disease, and stroke.^[45] The net effect is that tissues may not receive adequate oxygenated blood, compounding the direct cellular hypoxic effects of the metals. For example, mercury-exposed individuals may have both anemia and endothelial dysfunction, a double-hit that severely limits oxygen supply to tissues.

Tissue-Specific Hypoxia and Organ Damage

Heavy metal–induced hypoxia manifests in various organ systems, often exacerbating organ-specific toxic effects:

Central Nervous System (Brain): The brain is highly sensitive to oxygen deprivation. Anemia or reduced blood flow due to heavy metals can cause chronic cerebral hypoxia, contributing to cognitive deficits and neurodegeneration. Lead exposure in children is known to cause neurodevelopmental delays; part of this may stem from lead-induced anemia and consequent brain hypoxia during critical developmental periods. Moreover, heavy metals directly accumulate in neural tissue and impair mitochondrial energy production (as discussed for arsenic and mercury), effectively causing cellular hypoxia in neurons. Mercury’s damage to brain mitochondria and arsenic’s inhibition of neuronal respiration lead to neuron cell death and symptoms like memory loss, tremors, and peripheral neuropathy. Hypoxia in the brain triggers gliosis and can activate HIF-1α, which has been observed in cases like methylmercury poisoning, where HIF-1α signaling is upregulated even under normoxia in brain tissue.^[46] Thus, heavy metal neurotoxicity often involves components of hypoxic injury (energy failure, oxidative stress, lactic acidosis in brain tissue). Clinically, this may present as headaches, confusion, or encephalopathy in severe poisoning (e.g., lead encephalopathy has features resembling ischemic encephalopathy).

Liver: The liver receives a dual blood supply and is highly metabolic. Heavy metals accumulate in the liver and can disturb its oxygen balance. For instance, both chronic hypoxia and metals like Ni²⁺ or Pb²⁺ induce similar patterns of hepatic metabolic dysfunction.^[47] Research indicates that toxic metal exposure in the liver can cause steatosis (fatty liver) and hepatocellular injury partly by inducing a state of oxygen deficiency in hepatocytes. Nickel and lead have been shown to generate ROS in the liver and disrupt oxidant/antioxidant balance, triggering HIF-1α and VEGF expression as the liver cells sense a “fake” hypoxia.[x] Over time, this can lead to fibrosis. Many metals also cause sinusoidal endothelial damage (e.g., arsenic and vinyl arsenicals can lead to sinusoidal obstruction syndrome), which reduces oxygen diffusion to hepatocytes. Additionally, iron overload in the liver (as in hemochromatosis) creates focal hypoxic regions: excess iron induces oxidative stress and cell death, leading to nodular fibrosis. Surviving cells around fibrous septa often experience relative hypoxia due to disrupted microcirculation. Thus, heavy metal toxicity is recognized to impair liver oxygen homeostasis and contribute to conditions like non-alcoholic fatty liver disease and cirrhosis.^[48]

Kidney: The kidneys are critical for EPO production and are a target for many heavy metals (cadmium, lead, uranium, etc.). Cadmium in particular accumulates in the renal cortex and causes chronic interstitial damage. A hallmark of cadmium nephrotoxicity is loss of EPO output (hence anemia)^[49], but also a localized hypoxia in the kidney tissue. Cadmium and lead cause tubulointerstitial hypoxia by damaging peritubular microvessels and inducing fibrosis. The resultant chronic kidney disease creates a vicious cycle: renal anemia reduces oxygen delivery, and fibrotic changes impair oxygen diffusion, so the kidney becomes hypoxic. Indeed, studies of metal-induced kidney injury find evidence of HIF-1 activation in renal tissue, suggesting the kidney is experiencing hypoxia. In cadmium-exposed animals, even before overt renal failure, there is upregulation of hypoxia-related genes in the kidney.^[50] Arsenic exposure is associated with an increased risk of chronic kidney disease as well, potentially through vascular effects (Blackfoot disease patients often have renal artery involvement). Mercury can cause acute tubular necrosis (for example, mercury bichloride poisoning), which is essentially ischemic injury to nephrons, partly due to hemolysis (in mercuric chloride poisoning, hemoglobin casts cause renal ischemia). Thus, heavy metals can precipitate local hypoxia in the kidneys through anemia, vascular damage, and direct mitochondrial poisons, leading to compromised renal function.

Reproductive Organs: Heavy metals have been implicated in placental and fetal hypoxia, as well as gonadal injuries. Lead, cadmium, and arsenic readily cross the placenta and have been associated with low birth weight, miscarriage, and preeclampsia. Cadmium accumulates in the placenta, where it can cause inflammation and fibrosis in placental tissue, effectively reducing placental blood flow and oxygen exchange to the fetus. The result can be chronic fetal hypoxia and growth restriction. Studies have found higher cadmium levels in placentas of women with preeclampsia, supporting the idea that cadmium-induced oxidative stress and hypoxic signaling in the placenta contribute to this pregnancy complication. Lead exposure in pregnancy is linked to hypertension and placental abruption, again suggesting vascular effects. Arsenic exposure in utero (e.g., via contaminated water) has been associated with infant cognitive deficits and higher perinatal mortality; one mechanism is likely arsenic’s effect on placental circulation (arsenic induces angiogenesis but of poor quality, and causes oxidative stress in placental villi, leading to insufficiency). In male reproductive organs, a striking example is cadmium: an acute cadmium exposure in animal models can cause testicular ischemia. Cadmium specifically injures testicular blood vessels, leading to hemorrhage and infarction of the testis. This is essentially a high-dose effect, but it underlines how metals can cause localized hypoxic cell death in reproductive glands. Chronic low-level lead exposure has been linked to lower sperm counts; while multifactorial, one aspect is that lead can reduce testicular blood flow and disrupt Sertoli cell function (which depends on oxygen and energy). In summary, heavy metals threaten reproductive organ function often through vascular insults and oxygen deprivation in those tissues, leading to outcomes like infertility, fetal development issues, and pregnancy disorders.^[51]

Other Tissues: Virtually any high-oxygen-demand tissue can suffer from heavy metal toxicity. The heart, for instance, can be affected by cobalt (not in our list, but historically cobalt caused cardiomyopathy with hypoxia) and possibly by arsenic (which increases the risk of ischemic heart disease). Peripheral nerves can be damaged by demyelination when the local blood supply is compromised (as in lead neuropathy or arsenic neuropathy, both show ischemic degeneration of nerves). The immune system and wound healing may also be impaired, as hypoxia in bone marrow or in injured tissue beds delays cell-mediated repair; some metals, like zinc, are essential for wound healing, but in excess, they cause copper deficiency and neutropenia, leading to poor oxygen delivery for repair processes.

In all cases, the interplay of heavy metal direct toxicity with hypoxia means that organs often exhibit exacerbated injury under hypoxic conditions. For example, chronic hypoxia in the liver or brain can amplify heavy metal–induced fibrosis or neurodegeneration. This synergy highlights why hypoxia is a central theme in heavy metal toxicology.

Heavy Metal–Specific Hypoxia-Inducing Pathways

Each heavy metal (or metalloid) has unique toxicodynamic profiles, although overlapping in the general mechanisms described above. Below is a brief metal-by-metal summary highlighting distinctive pathways by which it can induce hypoxia or oxygen-related pathology:

Lead (Pb)

Lead interferes with multiple steps of oxygen transport and utilization. Its most prominent effect is on heme synthesis: Pb²⁺ inhibits δ-ALAD and ferrochelatase in the bone marrow, leading to reduced hemoglobin production.^[52] Consequently, lead exposure often results in anemia (typically microcytic) and elevated circulating protoporphyrin (since iron cannot be inserted into protoporphyrin IX).^[53] This anemia causes systemic hypoxic stress. Lead also shortens RBC lifespan by increasing oxidative membrane damage and can cause hemolysis at high blood lead levels, compounding the anemia. At the cellular level, lead’s ability to substitute for other divalent cations (like Ca²⁺ and Zn²⁺) perturbs signaling and enzyme function; for example, lead binding to ALAD involves displacement of zinc and binding to thiol groups, a classic case of mismetallation.^[54] Lead’s interference with calcium-dependent processes in muscle and endothelium leads to vasoconstriction and hypertension, which impair tissue perfusion. Lead exposure has been shown to activate hypoxia-like pathways: studies found that lead can induce VEGF expression in the spinal cord and brain, suggesting lead triggers HIF-1α or related angiogenic signals in those tissues.^[55]

Experiments from rodent models indicate that chronic lead administration, like hypoxia, increases HIF-1α levels and ROS in metabolically active tissues.^[56] Furthermore, lead accumulates in the kidney and can cause chronic kidney disease with decreased EPO output (a contributor to anemia). Thus, lead induces hypoxia via inhibited oxygen carrying (anemia), pseudo-hypoxic signaling (HIF/VEGF upregulation), and impaired oxygen delivery (vascular effects).^[57][58] Clinically, no level of blood lead is considered completely safe; even low exposures that do not cause overt anemia can impair mitochondrial function and cognitive function in ways analogous to chronic mild hypoxia. Lead is classified as a probable human carcinogen (IARC 2A), and its ability to activate HIF-1 and angiogenesis may partly underlie its co-carcinogenic effects in promoting tumor growth.^[59]

Cadmium (Cd)

Cadmium is a toxic heavy metal well-known for its cumulative nephrotoxicity and propensity to cause anemia through multiple mechanisms.^[60] Cd causes hemolysis (damage to red blood cells), iron sequestration, and EPO suppression, a combined assault on the oxygen transport system.[x] Chronic cadmium exposure leads to iron being misdistributed (deposited in liver, spleen, kidney) and unavailable for erythropoiesis, while at the same time the kidneys produce less erythropoietin (renal anemia) and red cells are destroyed faster.^[61] These effects were demonstrated in rat studies where months of cadmium exposure caused progressive hemolytic anemia, iron-loading of tissues, and low EPO levels; treating the iron-loading alone did not fully correct the anemia, showing that Cd’s impact on the kidney (EPO) is critical.[x] On a molecular level, cadmium disrupts antioxidant defenses by depleting glutathione and replacing zinc in various enzymes. It induces ROS generation, which can stabilize HIF-1α and also injure endothelial cells. Cadmium has been observed to replace Zn and Ca in proteins; for example, cadmium can bind to zinc-finger domains of DNA repair enzymes and to calcium sites in signaling proteins. This broad enzymatic disruption can create a cellular state resembling hypoxic stress (since many of those enzymes are involved in metabolism and antioxidant protection). In the vasculature, cadmium contributes to atherosclerosis: it causes endothelial inflammation and smooth muscle proliferation, reducing lumen diameter.

Cadmium-induced endothelial dysfunction in the lung vasculature may be one reason cadmium exposure is linked to pulmonary hypertension in smokers. In the placenta, cadmium accumulation is particularly problematic because the placenta treats cadmium like calcium and concentrates it, leading to reduced nutrient and oxygen transfer to the fetus. Elevated placental Cd is associated with preeclampsia and lower birth weights, presumably due to placental ischemia and oxidative stress. In the testes, cadmium can acutely destroy the blood-testis barrier; high-dose Cd causes hemorrhage and infarction of testicular tissue (a stark illustration of how cadmium can cause hypoxic necrosis via vascular damage). Regulatory agencies consider cadmium highly toxic even at low doses: to protect against kidney and hematologic effects, EFSA has set a tolerable weekly intake of only 2.5 μg Cd per kg body weight.^[62] In summary, cadmium induces hypoxia by causing anemia (hemolysis + low EPO) and by damaging blood vessels and mitochondria via oxidative mechanisms. The result is impaired oxygen delivery and utilization across multiple organ systems.

Arsenic (As)

Arsenic, a metalloid, exerts its toxicity in both inorganic forms (arsenite As³⁺ and arsenate As⁵⁺) and in toxic gases (arsine AsH₃). Arsenic’s hypoxia-inducing effects are two-fold: (1) Enzymatic inhibition in energy metabolism, and (2) vascular insufficiency. Arsenite (As³⁺) avidly binds to dihydrolipoic acid, inhibiting the pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase, which are key to aerobic respiration. This causes a metabolic shift to glycolysis (less oxygen utilization, more lactate), essentially a pseudo-hypoxic metabolic state. Arsenate (As⁵⁺), being chemically similar to phosphate, can uncouple oxidative phosphorylation by forming unstable ADP-arsenate bonds. Together, these actions mean that cells exposed to arsenic have trouble generating ATP using oxygen, which can stabilize HIF-1α. In fact, arsenic is known to activate HIF-1α and angiogenesis in cells via ROS signaling: studies in cancer cell lines showed arsenite induces HIF-1α protein and increases VEGF expression, primarily through a ROS-dependent PI3K/Akt pathway.^[63] The main ROS involved is H₂O₂, and antioxidants can blunt the HIF/VEGF induction by arsenic.^[64] This “pseudohypoxic” signaling by arsenic may contribute to its pro-angiogenic role in arsenic-induced skin cancers and bladder cancers.

Arsenic’s second major pathway is vascular toxicity. Chronic ingestion of arsenic (e.g., in groundwater) leads to endarteritis obliterans, where small arteries, especially in the limbs, develop intimal fibrosis and thrombi. The classic outcome is Blackfoot disease, a peripheral arterial disease leading to gangrene of the feet.[x] Blackfoot disease is essentially a state of profound, chronic tissue hypoxia in the extremities due to arsenic-driven vascular obliteration.^[65] Additionally, arsenic can cause endothelial dysfunction and hypertension; it reduces endothelial nitric oxide and has been linked to increased risk of ischemic heart disease and strokes in epidemiological studies. In the blood, arsine gas deserves special mention: it causes fulminant hemolysis (by causing oxidative denaturation of hemoglobin and direct membrane damage), leading to acute hemolytic anemia and hemoglobin-induced renal failure.^[66] Victims experience sudden hypoxia (from loss of RBCs) and often die without transfusions. While arsine exposure is occupational and rare, it illustrates arsenic’s potential to cause acute systemic hypoxia. Chronic arsenic exposure can also cause a milder hemolytic anemia and bone marrow suppression. From a regulatory perspective, arsenic is a confirmed human carcinogen (IARC Group 1). No safe threshold has been definitively established; however, risk assessments have estimated a benchmark dose lower limit (BMDL₀.₅) around 3.0 μg As per kg body weight per day for a 0.5% increase in lung cancer risk.^[67] This very low value reflects arsenic’s potency and the need to minimize exposure. In summary, arsenic induces cellular hypoxia by crippling mitochondrial respiration and triggering HIF-1, and it causes tissue hypoxia by damaging blood vessels and blood cells.^[68][69]

Mercury (Hg)

Mercury exists in elemental (Hg⁰), inorganic (Hg⁺/Hg²⁺), and organic (methyl- and ethylmercury) forms, all of which are toxic. Mercury’s hypoxia-related toxicity centers on mitochondrial dysfunction, hemoglobin interactions, and vascular effects. Mercury has a high affinity for thiol (–SH) groups in proteins, which leads it to accumulate in mitochondria (rich in thiols) and inhibit critical enzymes. Numerous studies confirm that mercury causes brain mitochondrial dysfunction, contributing to neurotoxicity.^[70] Mercury (particularly methylmercury and Hg²⁺) increases production of ROS in mitochondria and depletes glutathione.[x] A key disruptive effect is mercury’s inhibition of enzymes in the electron transport chain – for example, mercury can directly inhibit Complex II and III activities, impairing electron flow and ATP synthesis.[x] This results in diminished oxygen consumption (similar to an oxygen deficit state) and triggers cell death pathways. Additionally, mercury-induced ROS can open the mitochondrial permeability transition pore, causing loss of membrane potential and release of apoptogenic factors; neurons essentially undergo apoptosis or necrosis as if they were in a hypoxic/ischemic episode. In parallel, mercury affects the blood’s oxygen transport: it can bind to hemoglobin and compete with iron, hindering hemoglobin’s oxygen-binding capacity.^[71] Mercury has been associated with hemolytic anemia; inorganic mercury poisoning can lead to hemoglobinuria due to RBC lysis, and chronic methylmercury exposure has been linked to anemia and leukopenia in epidemiological studies.^[72]

Mechanistically, mercury’s binding to sulfhydryls in the RBC membrane and oxidative damage reduce RBC deformability and survival. Another facet is endothelial dysfunction: mercury exposure correlates with increased oxidative stress in blood vessels, reduced nitric oxide, and elevated endothelin, promoting vasoconstriction.^[73] Mercury can also induce cardiac mitochondrial dysfunction, which may contribute to cardiomyopathy (the heart muscle in Minamata disease victims shows lesions partly attributable to energy failure and hypoxia). High mercury exposure (e.g., acute inhalation of mercury vapor) can precipitate respiratory failure; one cause is a direct lung injury, but another is that mercury can oxidize hemoglobin to methemoglobin and interfere with oxygen uptake in the lungs. On the regulatory side, mercury guidelines focus on its neurodevelopmental effects. The U.S. EPA reference dose for methylmercury is about 0.1 μg/kg/day, and JECFA’s provisional tolerable weekly intakes (PTWIs) are 1.6 μg/kg/week for methylmercury and 4 μg/kg/week for inorganic mercury, reflecting the low levels at which mercury can harm.^[74] In summary, mercury induces hypoxia at the cellular level by crippling mitochondrial respiration and generating ROS, and systemically by damaging red cells and vessels, thus hindering oxygen delivery.^[75][76] Mercury’s multi-organ toxicity (brain, kidneys, cardiovascular system) is often underpinned by these hypoxic and oxidative mechanisms.

Nickel (Ni)

Nickel is an essential trace element for some organisms but not for humans; in humans, Ni has primarily toxic and allergenic effects. The most significant hypoxia-mimicking action of nickel is its ability to stabilize HIF-1α. Ni²⁺ ions can substitute for Fe²⁺ in the active site of prolyl hydroxylases (PHDs) that regulate HIF, thereby inhibiting HIF degradation.^[77] Nickel (like cobalt) has been used experimentally as a hypoxia mimetic – exposure to nickel chloride causes an accumulation of HIF-1α in cultured cells and subsequent upregulation of hypoxia-responsive genes. For instance, in human lung cells, soluble nickel exposure led to persistent activation of HIF-1 signaling and increased transcription of VEGF and glucose transporters.^[78] This property likely contributes to nickel’s carcinogenicity: nickel compounds (IARC Group 1 carcinogens) can promote tumor angiogenesis and survival via HIF-1 activation in normoxic tumor cells. Beyond HIF, nickel induces oxidative stress and DNA damage. It tends to deplete glutathione and can generate superoxide via Fenton-like reactions (nickel has variable valence states and can participate in redox cycles). The ROS generated by nickel further supports HIF-1α stabilization and also causes lipid peroxidation in cell membranes, potentially impairing mitochondrial membranes. Nickel’s impact on the blood and vasculature is less pronounced than lead or cadmium, but high doses (e.g., nickel carbonyl inhalation) cause acute lung injury with hemorrhage, a condition akin to ARDS where gas exchange is severely compromised (acute hypoxemia results).

Chronic nickel exposure (such as occupational inhalation of dust) has been linked to fibrosis in the lungs and nasal passages, which can reduce oxygen uptake. Nickel does not typically cause anemia; however, some studies suggest that extremely high nickel levels could interfere with iron metabolism. Recent data also indicate nickel might reduce the activity of certain iron-dependent enzymes in cells, contributing to metabolic inefficiency. In the context of the liver, research has shown that nickel can mirror hypoxia’s effects on metabolic gene expression.[x] Nickel’s toxicological thresholds are usually set based on its respiratory and dermatologic effects; for example, the EU has set oral tolerable daily intakes around 13 μg/kg/day for nickel (to protect against reproductive and developmental toxicity) and occupational exposure limits for inhalation. In summary, nickel’s hallmark hypoxia-related mechanism is PHD inhibition leading to HIF-1α stabilization.^[79] By creating a state of “false hypoxia” inside cells, nickel can drive angiogenesis and glycolysis. Combined with oxidative stress, this contributes to nickel’s harmful effects, including cancer promotion and tissue injury.

Tin (Sn)

Tin is a metal that humans encounter mainly in inorganic form (e.g., tin cans, some medications) and organotin compounds (used as biocides and in industry). Tin is generally less inherently toxic than cadmium or lead, but it can cause issues at high doses. Tin toxicity has been associated with anemia and organ damage, suggestive of hypoxic mechanisms. Inorganic tin (such as stannous chloride) can irritate the gut and reduce nutrient absorption – notably, tin can interfere with iron, zinc, and copper uptake.^[80] Chronic ingestion of high tin levels leads to microcytic anemia in animal studies, with decreased hemoglobin, hematocrit, and RBC count observed at high tin doses.^[81] The anemia of tin exposure appears to be related to iron deficiency and impaired heme synthesis, possibly because tin binds to transferrin or intestinal transporters and blocks iron absorption (similar to aluminum’s effect). Additionally, tin has been shown to increase fecal excretion of zinc and reduce plasma copper, as noted earlier, which can induce a secondary copper deficiency.^[82] Copper deficiency, in turn, causes anemia and neutropenia (due to reduced activity of copper-dependent enzymes like ceruloplasmin and cytochrome c oxidase). This cascade from tin excess to micronutrient imbalance exemplifies mismetallation, causing hypoxia (since, without adequate copper/iron, cells become hypoxic).

Organotin compounds (like tributyltin) have a different toxicity profile; they are potent mitochondrial poisons and uncouplers of oxidative phosphorylation. Tributyltin in experimental settings collapses the mitochondrial membrane potential, much like dinitrophenol, forcing cells into glycolysis. Thus, organotins can directly induce a cellular hypoxic-like state by preventing efficient oxygen utilization. Organotins also target the nervous system; trimethyltin causes neuronal death associated with mitochondrial swelling and calcium overload, indicating that mitochondrial dysfunction underlies its neurotoxicity.^[83] In severe cases (e.g., industrial exposure to tin hydride gas, stannane), tin can cause acute hemolysis and liver/kidney injury, symptoms include anemia and jaundice, again linking to oxygen transport disruption. From a regulatory standpoint, inorganic tin in foods is mainly a concern for acute gastrointestinal effects (the EU limit in canned foods is usually 200 mg/kg to avoid acute nausea). Chronic tin exposure limits aren’t as strictly defined as for cadmium/lead because tin is less cumulative. However, the evidence that tin excess leads to anemia and growth retardation in animals prompted guidance values (JECFA proposed a provisional tolerable weekly intake for tin of 14 mg/kg). In summary, tin induces hypoxia primarily by deranging mineral homeostasis (causing functional iron/copper deficiency) and by direct mitochondrial uncoupling at higher doses.^[84] The resulting anemia and energy failure can produce systemic hypoxic effects.

Aluminum (Al)

Aluminum is a ubiquitous metal that has no known biological role in humans. It notoriously accumulates in patients with impaired renal function (due to contamination of dialysis fluids or excessive antacid use) and causes microcytic, iron-resistant anemia and bone disease. Aluminum’s impact on oxygen dynamics is mostly through impairment of heme synthesis and iron transport. Al³⁺ competes with Fe³⁺ for binding sites on transferrin (the iron transport protein), creating an aluminum-transferrin complex that cannot be used by erythroid cells.^[85] In vitro studies clearly demonstrate that adding aluminum to cultures in the presence of transferrin causes a dose-dependent inhibition of erythroid colony formation, which is not observed if transferrin is fully saturated with iron.^[86] This indicates that aluminum inhibits erythropoiesis by occupying transferrin iron-binding sites, thereby blocking iron delivery to red cell precursors. The result is anemia that does not respond well to iron supplementation as long as aluminum overload continues. Clinically, this was seen in chronic dialysis patients: high serum aluminum was associated with low hemoglobin and a failure of hematinic therapies until aluminum chelation (with deferoxamine) was done.^[87] The anemia is typically microcytic with low MCV, resembling iron deficiency anemia.

At the cellular level, aluminum can also inhibit ferrochelatase (the enzyme that inserts iron into protoporphyrin IX) to some extent, further hindering heme formation. Beyond the bone marrow, aluminum may cause neurotoxicity linked to neuronal energy failure. There is evidence that aluminum can substitute for magnesium in ATP or calcium in signaling, disrupting neuronal metabolism and potentiating oxidative stress. In Alzheimer’s disease research, aluminum has been studied for its capacity to promote protein aggregation and neuroinflammation, but importantly, aluminum may exacerbate brain hypometabolism by interfering with mitochondrial enzymes. Animal studies of aluminum neurotoxicity reveal that reduced cytochrome c oxidase activity and antioxidant enzyme activity in the brain, suggestive of a partial hypoxic injury pattern. Endothelial cells exposed to aluminum have shown increased permeability and oxidative stress, which could impair blood-brain barrier function and contribute to reduced tissue oxygenation in the CNS. In the lungs, inhaled aluminum dust (such as in bauxite processing) can cause pulmonary fibrosis (“Shaver’s disease”), which impairs gas exchange (a direct hypoxic outcome). The regulatory threshold for aluminum in the diet was revised by EFSA to a tolerable weekly intake of ~1 mg/kg/week, lowered from earlier guidelines, to protect against accumulative neurotoxic and hematologic effects. In summary, aluminum induces a hypoxic stress mostly via anemia (through iron sequestration) and possibly through direct interference with cellular respiration. Its effects are especially evident in the hematopoietic system and brain, where aluminum’s presence leads to poor oxygen utilization outcomes (fatigue, cognitive slowing, etc.) until the metal burden is reduced.^[88]

Chromium (Cr)

Chromium exists primarily as trivalent Cr(III) (an essential nutrient in trace amounts) and hexavalent Cr(VI) (a toxic form found in industrial compounds like chromates). Cr(VI) is highly oxidative and carcinogenic (IARC Group 1), known for causing lung cancer and ulcerations. In terms of hypoxia-related mechanisms, Cr(VI) is a strong oxidizer that enters cells and generates ROS as it is reduced to Cr(III). This ROS generation can cause oxidative hemolysis exposure to chromate can oxidize hemoglobin to methemoglobin (Fe³⁺ form that can’t carry O₂) and injure red cell membranes. High inhalational exposure to Cr(VI) has caused acute lung damage and methemoglobinemia, a state of functional hypoxia where even if oxygen is present, hemoglobin cannot bind it effectively. Chronic exposure to lower levels of Cr(VI) can lead to anemia, as seen in some chromate plant workers who develop reduced hemoglobin and hematocrit. One study on dietary minerals and blood indices found that higher blood chromium was associated with lower RBC counts and hemoglobin in a general population.^[89] This suggests that excessive chromium (likely reflecting occupational or environmental Cr(VI) exposure) has an adverse effect on erythropoiesis or RBC survival. Mechanistically, Cr(VI) inside the bone marrow can induce DNA damage and apoptosis in progenitor cells, contributing to anemia. Additionally, chromium, especially Cr(VI), causes endothelial dysfunction similar to other metals. It induces inflammation in blood vessels and can lead to fibrosis of small arteries; in the long term, this could compromise tissue perfusion. In animal studies, chromium has a dual nature: at nutritional levels, Cr(III) might improve glucose utilization and redox balance, but at high levels, both Cr(III) and Cr(VI) can cause mitochondrial dysfunction (Cr can bind to phosphate and enzyme sites, interfering with oxidative phosphorylation). For instance, high concentrations of Cr(III) in cell culture decreased ATP levels and increased lactate, indicating a shift to anaerobic metabolism. In the context of hypoxia signaling, some evidence suggests that Cr(VI) may also stabilize HIF-1α. Chromium is known to cause chronic ulcers that are hypoxic (e.g., nasal septum ulcers in chromate workers heal poorly, possibly due to local ischemia and chromate’s oxidative damage). Regulatory limits for Cr(VI) are strict: OSHA’s PEL is 5 μg/m³ in air, and EPA’s drinking water limit for total Cr is 100 μg/L (to minimize Cr(VI) given its toxicity). Ironically, certain Cr(III) supplements marketed for health could, in extreme overdose, cause Cr toxicity with features like anemia and liver damage. In summary, toxic chromium (especially Cr(VI)) induces hypoxia by oxidizing hemoglobin (causing methemoglobinemia), causing hemolysis, and damaging the microvasculature. Its strong oxidative effects also engage HIF pathways in cells (due to ROS signaling), which might contribute to chromium’s carcinogenicity and tissue injury.

Zinc (Zn)

Zinc is an essential metal necessary for numerous enzymes and antioxidant proteins (like superoxide dismutase). Normally, zinc has protective antioxidant roles, but excess zinc or severe zinc deficiency can each create hypoxia-related problems. High zinc intake (often from supplementation) can cause copper deficiency because zinc upregulates metallothionein in enterocytes, which binds copper and prevents its absorption. The resulting copper deficiency leads to anemia and neutropenia medically. This is a known syndrome where patients present with fatigue and cytopenias due to too much zinc intake. Copper deficiency anemia is typically macrocytic or normocytic with low plasma iron despite adequate stores (copper is needed to release iron from stores via ferroxidase). This anemia translates to systemic hypoxia (similar to iron deficiency anemia in symptoms). Case reports document patients with excessive zinc (for example, to treat colds) developing sideroblastic anemia unresponsive to iron until copper supplements were given.^[90][91]Thus, zinc excess induces a functional hypoxia via anemia. On the other hand, zinc deficiency (which can occur due to malnutrition or malabsorption) impairs many zinc-dependent enzymes, including those involved in DNA synthesis and antioxidant defense, leading to poor cell proliferation (affecting blood cell production) and increased oxidative stress. Zinc-deficient animals can have anemia and tissues with elevated oxidative damage, making them more susceptible to hypoxic injury. In terms of direct effects, zinc is relatively benign to mitochondria compared to other metals, but extremely high intracellular Zn²⁺ can precipitate in mitochondria and induce permeability transition (this is seen in ischemic brain injury, where zinc is released from metalloproteins and contributes to neuronal death). So, in acute neuronal injury, Zn might act as a mediator of hypoxic cell death. However, in environmental exposure terms, zinc does not typically cause hypoxia except through the copper deficiency route or in industrial fumes (zinc oxide fumes can cause “metal fume fever” with pulmonary inflammation, potentially reducing oxygenation temporarily). There is also an interesting interplay: adequate zinc is needed for HIF-1 regulation. Some studies suggest that zinc levels can modulate HIF-1α stability – zinc may actually facilitate HIF binding to DNA in hypoxia (as a structural cofactor), whereas severe zinc deprivation could blunt HIF responses. In diabetic kidney disease, for instance, zinc supplementation was observed to reduce HIF-1α overexpression and improve outcomes.^[92] Too little or too much zinc might therefore disturb normal hypoxia signaling. Regulatory-wise, zinc is treated as a nutrient: the RDA is ~8-11 mg/day, and the tolerable upper intake level (UL) is set at 40 mg/day for adults to prevent copper deficiency. In summary, zinc’s connection to hypoxia is mostly indirect – excess zinc causes anemia via copper deficiency (and thus systemic hypoxia)^[93], while zinc deficiency or dysregulation may impair cellular oxidative metabolism and antioxidant defenses, potentially aggravating hypoxic tissue injury.

Iron (Fe)

Iron is essential for oxygen transport (hemoglobin, myoglobin) and for many enzymes in oxidative metabolism (cytochromes, catalase). Iron imbalance, either deficiency or overload, can lead to hypoxia-related pathology:

Iron Deficiency: Iron deficiency is the most common cause of anemia worldwide. Without enough iron, the body cannot synthesize hemoglobin, resulting in iron-deficiency anemia, which directly diminishes oxygen delivery to tissues. Patients experience fatigue, tachycardia, and dyspnea on exertion due to systemic hypoxia. Iron deficiency can also impair muscle function (reducing myoglobin) and reduce the activity of iron-dependent mitochondrial enzymes, leading to diminished physical endurance (a form of functional tissue hypoxia). Developmentally, infants or fetuses that experience iron deficiency (often due to maternal deficiency) can suffer neurocognitive impairment partly from early-life brain hypoxia. In the context of heavy metals, many toxic metals (like lead, cadmium, and aluminum) actually cause a secondary iron deficiency by interfering with iron absorption or utilization. Thus, part of heavy metal-induced hypoxia often presents as or is exacerbated by iron-deficiency anemia. Treating the iron deficiency can improve symptoms, but if the heavy metal is still present, anemia often persists (as seen in aluminum or lead poisoning cases where iron alone doesn’t correct anemia until the metal is removed).

Iron Overload: Conversely, too much iron in the body (as in genetic hemochromatosis or repeated transfusions) leads to excessive ROS generation via Fenton chemistry and deposition of iron in organs, causing tissue injury that often has an ischemic component. For instance, in advanced hemochromatosis, the liver develops cirrhosis – the normal sinusoidal architecture is replaced by fibrous bands, impairing microcirculation and oxygen delivery to hepatocytes. The heart in iron overload can develop restrictive cardiomyopathy; iron-mediated oxidative damage to the myocardium results in heart failure with low cardiac output, meaning inadequate perfusion (and hypoxia) in peripheral tissues. Even though blood oxygen content might be normal in iron overload (there is no anemia unless very severe overload leads to bone marrow suppression), tissues experience “hypoxia” due to poor perfusion or mitochondrial dysfunction. Iron-catalyzed ROS can directly damage mitochondrial DNA and enzymes, reducing cellular respiratory capacity. Paradoxically, high intracellular iron can destabilize HIF-1α (since PHDs are iron-dependent and might work faster with more iron), which could reduce hypoxic responses in cells despite actual oxidative stress. However, iron-overloaded tissues often still show signs of HIF activation, likely because of the ROS inactivation of PHDs or regional hypoperfusion. There is evidence that HIF-1α is inappropriately activated in iron-overloaded cardiomyocytes, contributing to pathological remodeling. Clinically, patients with iron overload often have fatigue and weakness akin to anemia patients – but in this case due to organ dysfunction (heart failure leading to tissue hypoxia, or muscle weakness from iron-induced mitochondrial damage). Treatment of iron overload with chelation can improve organ function, underscoring that the hypoxic tissue stress is reversible if iron is removed.

In conclusion, iron deficiency causes classic systemic hypoxia via anemia, while iron excess causes local hypoxia via oxidative tissue injury and vascular/fibrotic changes. Iron homeostasis is thus crucial for preventing hypoxia – not enough iron, and hemoglobin can’t carry oxygen; too much iron, and tissues are damaged and cannot utilize oxygen effectively. This Jekyll-and-Hyde nature of iron is why both anemia and iron-overload syndromes are closely monitored. From a regulatory standpoint, iron is not regulated as a toxic contaminant in the same way as lead or cadmium (since it’s essential), but there are guidelines for fortification and medical supervision of iron therapy to avoid overload. Iron’s inclusion in this list of metals is a reminder that even essential elements can induce “hypoxic” pathology when present in imbalance.^[94][95]

Regulatory and Toxicological Context

Heavy metals are subject to strict regulatory limits given their potential to induce the toxic effects described above. Agencies have defined various health-based guidance values (No-Observed-Adverse-Effect Levels, Benchmark Dose Lower limits, Tolerable Intakes, etc.) to minimize risk of anemia, organ damage, and other outcomes of hypoxia-inducing toxicity:

Lead (Pb): No safe blood lead level has been identified for children or adults. Regulatory focus is on keeping blood lead levels as low as possible. In 2010, EFSA’s scientific opinion on lead in food used a Benchmark Dose Lower Confidence Limit (BMDL₀.₁) of 12 μg/L in blood associated with a 1% decrease in children’s IQ.^[96] This corresponds to an estimated dietary lead intake of about 0.5 μg/kg body weight per day that would produce that blood lead level.^[97] Another BMDL₀.₁ of 36 μg/L in blood was identified for a 1% rise in adult systolic blood pressure.^[98] These extremely low concentrations illustrate lead’s toxicity at ostensibly “low” exposures. As a result, previous safety limits such as the JECFA Provisional Tolerable Weekly Intake (PTWI) of 25 μg/kg were withdrawn. It is now recommended that lead exposures be reduced wherever possible, rather than using a tolerable intake. Many countries use reference levels (e.g., the U.S. CDC currently uses 3.5 μg/dL for children’s blood lead as a level of concern) to trigger interventions well before clinical toxicity manifests.

Cadmium (Cd): Cadmium’s critical effect is kidney damage (and secondarily bone effects and anemia). Because cadmium accumulates over a lifetime, risk assessors use lifetime intake limits. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) had a PTWI for cadmium of 7 μg/kg, but in 2009 EFSA reassessed cadmium and set a more stringent Tolerable Weekly Intake (TWI) of 2.5 μg/kg body weight.^[99][100] This was based on epidemiological data linking urinary cadmium levels to early kidney tubular effects (β₂-microglobulin elevation).^[101] At the TWI of 2.5 μg/kg/week, even sensitive populations (children, vegetarians in high Cd areas) should remain below the threshold for adverse kidney and hematological changes. It’s worth noting that many people have dietary cadmium exposure close to this TWI,^[102] which is a public health concern. Occupational exposure limits for cadmium in air (for inhalation) are also very low (e.g., 5 μg/m³ in some jurisdictions) due to cadmium’s toxicity and carcinogenicity.

Arsenic (As): Because arsenic is a known carcinogen with seemingly no safe threshold, regulators focus on water standards. The WHO guideline for arsenic in drinking water is 10 μg/L. For risk assessment, JECFA in 2011 withdrew the previous PTWI of 15 μg/kg and instead identified benchmark dose estimates: for lung cancer, a BMDL₀.₅ (0.5% increased incidence) of 3.0 μg/kg body weight per day was estimated.^[103] Similarly, low-dose estimates were made for skin lesions. These values indicate that even an intake of ~0.002–0.003 mg/kg/day (for a 70 kg adult, ~0.14–0.21 mg per week) could produce a very small but measurable increase in risk. In effect, the tolerable intake for arsenic is as low as can be practically achieved – thus the emphasis on keeping arsenic in food and water as low as reasonably achievable (ALARA). Some regions have specific regulations for arsenic in rice, juices, etc., to protect against chronic exposure.

Mercury (Hg): Guidelines differentiate between methylmercury (organic, mainly from fish) and inorganic mercury. JECFA’s PTWI for methylmercury is 1.6 μg/kg body weight (which equals about 0.23 μg/kg per day).^[104] This was based on developmental neurotoxicity data (from the Faroe Islands study on maternal fish consumption and child IQ). For inorganic mercury (which can come from mercury in Ayurvedic medicines, some skin creams, or occupational exposure), JECFA set a PTWI of 4 μg/kg body weight.^[105] Regulatory agencies advise pregnant women to limit high-mercury fish consumption to avoid fetal brain hypoxia and damage (since methylmercury readily crosses the placenta and concentrates in the fetus, interfering with its developing nervous system’s oxygen use). Occupational exposure limits for mercury vapor are around 25 μg/m³ (8-hr TWA in many countries), aiming to prevent tremors and early CNS effects. The fact that mercury ranks in the top 3 of ATSDR’s hazardous substances list underscores how seriously regulators take minimizing exposure.^[106]

Nickel (Ni): Nickel is regulated primarily for its allergenic and carcinogenic potential. In the EU, a Tolerable Daily Intake (TDI) of about 2.8 μg/kg/day was proposed for nickel in food, focusing on reproductive toxicity. The new EU food contaminant limits (2023) set maximum levels for nickel in certain foods like chocolate powders (to protect high consumers, e.g., children). For drinking water, the EU and WHO guideline is 70 μg/L for nickel. Occupational exposure limits to soluble nickel compounds are low (e.g., 0.1 mg/m³), given the lung cancer risk. While these limits aren’t explicitly about hypoxia, they indirectly protect against any nickel-induced anemia or vascular effect by keeping exposure minimal.

Tin (Sn): Regulations for tin largely address acute effects. The EU sets a limit of 200 mg/kg of inorganic tin in canned beverages and 250 mg/kg in solid canned foods to avoid acute nausea, vomiting, and possible subchronic anemia from high tin ingestion. Organotin compounds have separate regulations (as pesticides and antifoulants, many are banned or highly restricted). For example, tributyltin is banned in marine paints due to its extreme toxicity to aquatic life; human exposure to organotins is mostly via contaminated seafood or occupational exposure, and limits are set accordingly. The EPA has not established a reference dose for tin, but its low toxicity relative to other metals means it’s less of a priority unless at very high exposure.

Aluminum (Al): In 2008, EFSA established a TWI for aluminum of 1 mg/kg body weight (per week).^[107] This was a significant reduction from JECFA’s older PTWI of 7 mg/kg/week. The change was motivated by evidence of aluminum’s potential neurotoxicity and effects on fetal development. Many countries have phased out aluminum-containing additives in foods for infants and have lowered allowable aluminum in parenteral nutrition. Dialysis patients are carefully monitored to keep serum aluminum below ~20 μg/L to prevent encephalopathy and anemia. These measures aim to prevent the insidious hypoxia-related impacts of aluminum (microcytic anemia, cognitive impairment due to brain oxidative stress).

Chromium (Cr): Regulatory focus is on Cr(VI). The U.S. EPA has a reference dose (RfD) for Cr(VI) of 0.003 mg/kg/day for oral exposure, based on diffuse hyperplasia in the rat intestine (though there is debate since Cr(VI) is a carcinogen). For inhalation, OSHA’s PEL is extremely low (5 μg/m³). Drinking water standards for total chromium (mostly addressing Cr(VI)) are 50 μg/L (EU) to 100 μg/L (US). California’s public health goal for Cr(VI) in water is as low as 0.02 μg/L, reflecting concern over cancer risk. These tight regulations indirectly shield against any anemia or hypoxia from chronic Cr exposure by minimizing the total body burden.

Zinc (Zn) and Iron (Fe): These essential metals are generally regulated through nutritional guidelines rather than toxicological limits in the environment (except in occupational settings like welding fumes for zinc). The main caution is to avoid excess supplementation: for zinc, the adult UL of 40 mg/day is set to prevent copper-deficiency anemia and neurologic issues.^[108] For iron, the adult UL is 45 mg/day to avoid GI toxicity and iron overload in susceptible individuals. Poisonings (accidental or intentional) with iron tablets can cause shock and metabolic acidosis acute hypoxia due to mitochondrial poisoning, so child-resistant packaging is mandated in many places. Environmental iron levels are not capped in the same way, but in areas of high iron in water, staining and taste become issues before toxicity.

In summary, regulators have set extremely low allowable levels for the non-essential toxic metals to prevent the insidious onset of hypoxic injury in tissues. The values illustrate the sensitivity of processes like hemoglobin synthesis and the narrow margin between physiological necessity and toxic excess for the essential metals. Adherence to these standards is aimed at preventing the cascade of events – from enzyme inhibition to oxidative stress to anemia and tissue hypoxia – that heavy metals can unleash in the human body.

Conclusion

Heavy metals induce hypoxia in the human body through diverse but interlinked mechanisms. At the cellular level, they stabilize hypoxia-inducible factors, cripple mitochondrial respiration, generate oxidative stress, and misallocate essential metals – all of which converge on a state of reduced oxygen utilization or availability in tissues. Systemically, heavy metals cause anemia and vascular dysfunction, impairing oxygen transport and delivery. Each metal has specific pathways (e.g., lead’s heme enzyme inhibition, nickel’s HIF mimicry, arsenic’s mitochondrial poison effect, cadmium’s EPO suppression, etc.), but a unifying theme is the creation of a mismatch between oxygen supply and demand in cells. This can be an actual deficiency of oxygen (as in anemia or ischemia) or a functional deficiency (cells cannot use oxygen due to poisoned enzymes, akin to “histotoxic hypoxia”). The consequences range from organ-specific damage (neurodegeneration, nephropathy, etc.) to general symptoms of hypoxia (fatigue, developmental delays).

From a public health perspective, understanding these hypoxia-inducing mechanisms reinforces why stringent exposure limits have been set for these metals.^[109][110]The toxicological thresholds, such as the low BMDLs for lead and arsenic and the minimal TWIs for cadmium and methylmercury, are grounded in preventing even subtle hypoxia-related effects (like slight IQ loss or kidney stress) on a population level.^[111] Clinicians and researchers can use biomarkers of hypoxia (like HIF-1α activation or lactate levels) as early warning signs of heavy metal stress in the body. Conversely, some heavy metal exposures might be mitigated by therapies that improve oxygen delivery, for example, treating lead-induced anemia with iron, or giving hyperbaric oxygen in cases of acute carbon monoxide (not a metal, but analogous in causing hypoxia) poisoning.

In conclusion, heavy metal toxicity can be viewed through the lens of “cells suffocating in a sea of plenty” – oxygen may be abundant in the environment, but metals prevent its effective use, or reduce its supply, leading to a spectrum of hypoxic injuries. Ongoing research into metallotoxicology continues to unravel these pathways, offering hope for targeted interventions (e.g., HIF inhibitors, antioxidants, chelation therapy) to counteract heavy metal–induced hypoxia and protect human health.^[112]

References

1. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
2. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
3. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
4. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
5. Arsenite induces HIF-1α and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells.. Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH.. (Molecular and Cellular Biochemistry. 2004)
6. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
7. Arsenite induces HIF-1α and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells.. Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH.. (Molecular and Cellular Biochemistry. 2004)
8. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
9. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
10. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
11. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
12. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
13. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
14. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
15. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
16. Arsenite induces HIF-1α and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells.. Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH.. (Molecular and Cellular Biochemistry. 2004)
17. Arsenite induces HIF-1α and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells.. Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH.. (Molecular and Cellular Biochemistry. 2004)
18. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
19. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
20. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
21. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
22. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
23. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
24. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
25. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
26. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
27. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
28. Aluminum inhibits erythropoiesis in vitro. Journal of Clinical Investigation. 1988;81(6):1661-1665.. Mladenovic J.. (Journal of Clinical Investigation)
29. Aluminum inhibits erythropoiesis in vitro. Journal of Clinical Investigation. 1988;81(6):1661-1665.. Mladenovic J.. (Journal of Clinical Investigation)
30. Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. . Horiguchi H, Oguma E, Kayama F.. (Toxicol Sci. 2011)
31. Acute Exposure Guideline Levels for Selected Airborne Chemicals. National Research Council.. (Washington, DC: National Academy Press, Volume 1.)
32. Medical Management Guidelines for Arsine.. Agency for Toxic Substances and Disease Registry.. (Centers for Disease Control and Prevention; archived CDC Toxic Substances Portal page.)
33. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
34. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
35. Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. . Horiguchi H, Oguma E, Kayama F.. (Toxicol Sci. 2011)
36. Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. . Horiguchi H, Oguma E, Kayama F.. (Toxicol Sci. 2011)
37. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
38. Human exposure to mercury and its hematological effects: a systematic review.. Vianna AS, de Matos EP, de Jesus IM, Asmus CIRF, Câmara VM.. (Cad Saude Publica. 2019;35(2):e00091618. doi:)
39. Effect of Whole Blood Dietary Mineral Concentrations on Erythrocytes: Selenium, Manganese, and Chromium: NHANES Data.. Costa AM, Sias RJ, Fuchs SC.. (Nutrients. 2024)
40. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
41. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
42. Non-malignant diseases associated with environmental arsenic exposure in Taiwan, Chile, and Bangladesh.. Himeno S, Hossain K.. (Metallomics Research. 2021)
43. Medical Management Guidelines for Arsine.. Agency for Toxic Substances and Disease Registry.. (Centers for Disease Control and Prevention; archived CDC Toxic Substances Portal page.)
44. Medical Management Guidelines for Arsine.. Agency for Toxic Substances and Disease Registry.. (Centers for Disease Control and Prevention; archived CDC Toxic Substances Portal page.)
45. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
46. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
47. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
48. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
49. Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. . Horiguchi H, Oguma E, Kayama F.. (Toxicol Sci. 2011)
50. Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. . Horiguchi H, Oguma E, Kayama F.. (Toxicol Sci. 2011)
51. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
52. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
53. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
54. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
55. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
56. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
57. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)
58. Heme biosynthesis and the porphyrias.. Phillips JD.. (Molecular Genetics and Metabolism. 2019)
59. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
60. Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. . Horiguchi H, Oguma E, Kayama F.. (Toxicol Sci. 2011)
61. Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. . Horiguchi H, Oguma E, Kayama F.. (Toxicol Sci. 2011)
62. Cadmium in food. European Food Safety Authority Panel on Contaminants in the Food Chain. (EFSA. 2009)
63. Arsenite induces HIF-1α and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells.. Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH.. (Molecular and Cellular Biochemistry. 2004)
64. Arsenite induces HIF-1α and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells.. Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH.. (Molecular and Cellular Biochemistry. 2004)
65. Non-malignant diseases associated with environmental arsenic exposure in Taiwan, Chile, and Bangladesh.. Himeno S, Hossain K.. (Metallomics Research. 2021)
66. Acute Exposure Guideline Levels for Selected Airborne Chemicals. National Research Council.. (Washington, DC: National Academy Press, Volume 1.)
67. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
68. Arsenite induces HIF-1α and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells.. Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH.. (Molecular and Cellular Biochemistry. 2004)
69. Non-malignant diseases associated with environmental arsenic exposure in Taiwan, Chile, and Bangladesh.. Himeno S, Hossain K.. (Metallomics Research. 2021)
70. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
71. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
72. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
73. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
74. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
75. Mitochondrial dysfunction in neurodegenerative diseases induced by metal exposure.. Cheng H, Bai Y, Tang K, Song L, Xu Y, Chen P.. (Toxics. 2021)
76. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
77. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
78. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
79. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
80. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
81. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
82. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
83. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
84. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
85. Aluminum inhibits erythropoiesis in vitro. Journal of Clinical Investigation. 1988;81(6):1661-1665.. Mladenovic J.. (Journal of Clinical Investigation)
86. Aluminum inhibits erythropoiesis in vitro. Journal of Clinical Investigation. 1988;81(6):1661-1665.. Mladenovic J.. (Journal of Clinical Investigation)
87. Aluminum-induced anemia.. Kaiser L, Schwartz KA.. (Am J Kidney Dis. 1985;6(5):348-352.)
88. Aluminum inhibits erythropoiesis in vitro. Journal of Clinical Investigation. 1988;81(6):1661-1665.. Mladenovic J.. (Journal of Clinical Investigation)
89. Effect of Whole Blood Dietary Mineral Concentrations on Erythrocytes: Selenium, Manganese, and Chromium: NHANES Data.. Costa AM, Sias RJ, Fuchs SC.. (Nutrients. 2024)
90. Zinc-Containing Over-The-Counter Product Causing Sideroblastic Anemia and Neutropenia.. Stagg MP, Miatech J, Majid B, Polala R.. (Cureus. 2024 May)
91. Anemia Due to Unexpected Zinc-Induced Copper Deficiency.. Chun N, Aman S, Xu D, Wang J, Zuppan C, Kheradpour A.. (Hematology Reports. 2025)
92. Neuroprotective effect of curcumin in arsenic-induced neurotoxicity in rats.. Yadav RS, Shukla RK, Sankhwar ML, Patel DK, Ansari RW, Pant AB, Islam F, Khanna VK.. (NeuroToxicology. 2010)
93. Toxicological Profile for Tin and Tin Compounds. .. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US). (Agency for Toxic Substances and Disease Registry (US))
94. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
95. The preventive and carcinogenic effect of metals on cancer: a systematic review.. Khoshakhlagh AH, Mohammadzadeh M, Gruszecka-Kosowska A.. (BMC Public Health. 2024)
96. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
97. Statement on the effects of lead on maternal health:. Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT).. (Establishment of a health-based guidance value. 2013.)
98. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
99. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
100. Cadmium in food. European Food Safety Authority Panel on Contaminants in the Food Chain. (EFSA. 2009)
101. Cadmium in food. European Food Safety Authority Panel on Contaminants in the Food Chain. (EFSA. 2009)
102. Cadmium in food. European Food Safety Authority Panel on Contaminants in the Food Chain. (EFSA. 2009)
103. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
104. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
105. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
106. Mercury Exposure and Health Effects: What Do We Really Know?. Charkiewicz, A. E., Omeljaniuk, W. J., Garley, M., & Nikliński, J. (2025).. (International Journal of Molecular Sciences, 26(5), 2326.)
107. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
108. Zinc-Containing Over-The-Counter Product Causing Sideroblastic Anemia and Neutropenia.. Stagg MP, Miatech J, Majid B, Polala R.. (Cureus. 2024 May)
109. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
110. Cadmium in food. European Food Safety Authority Panel on Contaminants in the Food Chain. (EFSA. 2009)
111. Noxious Elements in Milk and Milk Products in Poland.. Starska K, Wojciechowska-Mazurek M, Mania M, Brulińska-Ostrowska E, Biernat U, Karłowski K.. (Polish Journal of Environmental Studies. 2011)
112. Heavy metals and low-oxygen microenvironment—its impact on liver metabolism and dietary supplementation.. Das KK, Honnutagi R, Mullur L, Reddy RC, Das S, Majid DSA, Biradar MS.. (In: Dietary Interventions in Liver Disease. Elsevier; 2019)